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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.
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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
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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
|
2025-02-12T13:47:14.002468
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19510s28lbl20249s11lbl.pdf', 'application_number': 20249, 'submission_type': 'SUPPL ', 'submission_number': 11}
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_______________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use DEPO
PROVERA CI safely and effectively. See full prescribing information for
DEPO-PROVERA CI.
DEPO-PROVERA CI (medroxyprogesterone acetate) injectable
suspension, for intramuscular use
Initial U.S. Approval: 1959
WARNING: LOSS OF BONE MINERAL DENSITY
See full prescribing information for complete boxed warning.
•
Women who use Depo-Provera Contraceptive Injection (Depo-
Provera CI) may lose significant bone mineral density. Bone loss is
greater with increasing duration of use and may not be completely
reversible. (5.1)
•
It is unknown if use of Depo-Provera Contraceptive Injection during
adolescence or early adulthood, a critical period of bone accretion,
will reduce peak bone mass and increase the risk for osteoporotic
fracture in later life. (5.1)
•
Depo-Provera Contraceptive Injection should not be used as a long-
term birth control method (i.e., longer than 2 years) unless other
birth control methods are considered inadequate. (5.1)
----------------------------RECENT MAJOR CHANGES-------------------------
Warnings and Precautions, Cancer Risks (5.3)
01/2015
----------------------------INDICATIONS AND USAGE--------------------------
• Depo-Provera CI is a progestin indicated only for the prevention of
pregnancy. (1)
-------------------------DOSAGE AND ADMINISTRATION--------------------
• The recommended dose is 150 mg of Depo-Provera CI every 3 months (13
weeks) administered by deep, intramuscular (IM) injection in the gluteal
or deltoid muscle. (2.1)
----------------------------DOSAGE FORMS AND STRENGTHS--------------
• Vials containing sterile aqueous suspension: 150 mg per mL (3)
• Prefilled syringes: prefilled syringes are available packaged with 22-gauge
x 1 1/2 inch Terumo® SurGuard™ Needles or with 22 gauge x 1 1/2 inch
BD SafetyGlideTM Needles. (3)
------------------------------------CONTRAINDICATIONS------------------------
• Known or suspected pregnancy or as a diagnostic test for pregnancy. (4)
• Active thrombophlebitis, or current or past history of thromboembolic
disorders, or cerebral vascular disease. (4)
• Known or suspected malignancy of breast. (4)
• Known hypersensitivity to Depo-Provera CI (medroxyprogesterone
acetate or any of its other ingredients). (4)
• Significant liver disease. (4)
• Undiagnosed vaginal bleeding. (4)
------------------------------WARNINGS AND PRECAUTIONS----------------
• Thromboembolic Disorders: Discontinue Depo-Provera CI in patients
who develop thrombosis. (5.2)
• Cancer Risks: Monitor women with a strong family history of breast
cancer carefully. (5.3)
• Ectopic Pregnancy: Consider ectopic pregnancy if a woman using
Depo-Provera CI becomes pregnant or complains of severe abdominal
pain. (5.4)
• Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical
treatment. (5.5)
• Liver Function: Discontinue Depo-Provera CI if jaundice or
disturbances of liver function develop. (5.6)
• Carbohydrate Metabolism: Monitor diabetic patients carefully. (5.11)
----------------------------------ADVERSE REACTIONS--------------------------
Most common adverse reactions (incidence >5%) are: menstrual irregularities
(bleeding or spotting) 57% at 12 months, 32% at 24 months, abdominal
pain/discomfort 11%, weight gain > 10 lbs at 24 months 38%, dizziness 6%,
headache 17%, nervousness 11%, decreased libido 6%. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
1-800-438-1985 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 contraceptive drug products. Counsel
patients to use a back-up method or alternative method of contraception when
enzyme inducers are used with Depo-Provera CI. (7.1)
-------------------------------USE IN SPECIFIC POPULATIONS---------------
• Nursing Mothers: Detectable amounts of drug have been identified in
the milk of mothers receiving Depo-Provera CI. (8.3)
• Pediatric Patients: Depo-Provera CI is not indicated before menarche.
(8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 01/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LOSS OF BONE MINERAL DENSITY
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Prevention of Pregnancy
2.2 Switching from other Methods of Contraception
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Loss of Bone Mineral Density
5.2 Thromboembolic Disorders
5.3 Cancer Risks
5.4 Ectopic Pregnancy
5.5 Anaphylaxis and Anaphylactoid Reaction
5.6 Liver Function
5.7 Convulsions
5.8 Depression
5.9 Bleeding Irregularities
5.10 Weight Gain
5.11 Carbohydrate Metabolism
5.12 Lactation
5.13 Fluid Retention
5.14 Return of Fertility
5.15 Sexually Transmitted Diseases
5.16 Pregnancy
5.17 Monitoring
5.18 Interference with Laboratory Tests
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-marketing Experience
7
DRUG INTERACTIONS
7.1 Changes in Contraceptive Effectiveness Associated with Co-
Administration of Other Products
7.2 Laboratory Test Interactions
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
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 BMD Changes in Adult Women
14.3 BMD Changes in Adolescent Females (12-18 years of age)
14.4 Relationship of fracture incidence to use of DMPA 150 mg IM or
non-use by women of reproductive age
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
1
Reference ID: 3694962
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: LOSS OF BONE MINERAL DENSITY
Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density.
Bone loss is greater with increasing duration of use and may not be completely reversible.
It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a
critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic
fracture in later life.
Depo-Provera Contraceptive Injection should not be used as a long-term birth control method (i.e.,
longer than 2 years) unless other birth control methods are considered inadequate [see Warnings and
Precautions (5.1)].
1 INDICATIONS AND USAGE
Depo-Provera CI is indicated only for the prevention of pregnancy. The loss of bone mineral density
(BMD) in women of all ages and the impact on peak bone mass in adolescents should be considered,
along with the decrease in BMD that occurs during pregnancy and/or lactation, in the risk/benefit
assessment for women who use Depo-Provera CI long-term [see Warnings and Precautions (5.1)].
2 DOSAGE AND ADMINISTRATION
2.1
Prevention of Pregnancy
Both the 1 mL vial and the 1 mL prefilled syringe of Depo-Provera CI should be vigorously shaken just
before use to ensure that the dose being administered represents a uniform suspension.
The recommended dose is 150 mg of Depo-Provera CI every 3 months (13 weeks) administered by deep IM
injection in the gluteal or deltoid muscle. Depo-Provera CI should not be used as a long-term birth control
method (i.e. longer than 2 years) unless other birth control methods are considered inadequate. Dosage does
not need to be adjusted for body weight [see Clinical Studies (14.1)].
To ensure the patient is not pregnant at the time of the first injection, the first injection should be given
ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not
breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval
between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant
before administering the drug. The efficacy of Depo-Provera CI depends on adherence to the dosage
schedule of administration.
2.2
Switching from other Methods of Contraception
When switching from other contraceptive methods, Depo-Provera CI should be given in a manner that
ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g.,
patients switching from oral contraceptives should have their first injection of Depo-Provera CI on the day
after the last active tablet or at the latest, on the day following the final inactive tablet).
3 DOSAGE FORMS AND STRENGTHS
Sterile Aqueous suspension: 150mg/ml
Prefilled syringes are available packaged with 22-gauge x 1 1/2 inch Terumo® SurGuard™ Needles or with
22 gauge x 1 1/2 inch BD SafetyGlideTM Needles.
2
Reference ID: 3694962
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 Depo-Provera CI is contraindicated in the following conditions:
• Known or suspected pregnancy or as a diagnostic test for pregnancy.
• Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular
disease [see Warnings and Precautions (5.2)].
• Known or suspected malignancy of breast [see Warnings and Precautions (5.3)].
• Known hypersensitivity to Depo-Provera CI (medroxyprogesterone acetate) or any of its other
ingredients [see Warnings and Precautions (5.5)].
• Significant liver disease [see Warnings and Precautions (5.6)].
• Undiagnosed vaginal bleeding [see Warnings and Precautions (5.9)].
5 WARNINGS AND PRECAUTIONS
5.1
Loss of Bone Mineral Density
Use of Depo-Provera CI reduces serum estrogen levels and is associated with significant loss of bone
mineral density (BMD). This loss of BMD is of particular concern during adolescence and early
adulthood, a critical period of bone accretion. It is unknown if use of Depo-Provera CI by younger
women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life.
After discontinuing Depo-Provera CI in adolescents, mean BMD loss at total hip and femoral neck did not
fully recover by 60 months (240 weeks) post-treatment [see Clinical Studies (14.3)]. Similarly, in adults,
there was only partial recovery of mean BMD at total hip, femoral neck and lumbar spine towards
baseline by 24 months post-treatment. [See Clinical Studies (14.2).]
Depo-Provera CI should not be used as a long-term birth control method (i.e., longer than 2 years) unless
other birth control methods are considered inadequate. BMD should be evaluated when a woman needs to
continue to use Depo-Provera CI long-term. In adolescents, interpretation of BMD results should take
into account patient age and skeletal maturity.
Other birth control methods should be considered in the risk/benefit analysis for the use of Depo-Provera CI
in women with osteoporosis risk factors. Depo-Provera CI can pose an additional risk in patients with risk
factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa,
strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as
anticonvulsants or corticosteroids). Although there are no studies addressing whether calcium and Vitamin-
D may lessen BMD loss in women using Depo-Provera CI, all patients should have adequate calcium and
Vitamin D intake.
5.2
Thromboembolic Disorders
There have been reports of serious thrombotic events in women using Depo-Provera CI (150 mg). However,
Depo-Provera CI has not been causally associated with the induction of thrombotic or thromboembolic
disorders. Any patient who develops thrombosis while undergoing therapy with Depo-Provera CI should
discontinue treatment unless she has no other acceptable options for birth control.
Do not re-administer Depo-Provera CI pending examination if there is a sudden partial or complete loss of
vision or if there is a sudden onset of proptosis, diplopia, or migraine. Do not re-administer if examination
reveals papilledema or retinal vascular lesions.
3
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.3
Cancer Risks
Breast Cancer
Women who have or have had a history of breast cancer should not use hormonal contraceptives,
including Depo-Provera CI, because breast cancer may be hormonally sensitive [see Contraindications
(4)]. Women with a strong family history of breast cancer should be monitored with particular care.
The results of five large case-control studies1, 2, 3, 4, 5 assessing the association between depo
medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 1. Three
of the studies suggest a slightly increased risk of breast cancer in the overall population of users; these
increased risks were statistically significant in one study. One recent US study1 evaluated the recency and
duration of use and found a statistically significantly increased risk of breast cancer in recent users (defined
as last use within the past five years) who used DMPA for 12 months or longer; this is consistent with
results of a previous study4 .
4
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 1 Risk estimates for breast cancer in DMPA users graph
Odds ratio estimates were adjusted for the following covariates:
Lee et al. (1987): age, parity, and socioeconomic status.
Paul et al. (1989): age, parity, ethnic group, and year of interview.
WHO (1991): age, center, and age at first live birth.
Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use.
Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history
of screening mammography.
Based on the published SEER-18 2011 incidence rate (age-adjusted to the 2000 US Standard Population ) of
breast cancer for US women, all races, age 20 to 49 years6, a doubling of risk would increase the incidence
of breast cancer in women who use Depo-Provera CI from about 72 to about 144 cases per 100,000 women.
Cervical Cancer
5
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A statistically nonsignificant increase in RR estimates of invasive squamous-cell cervical cancer has been
associated with the use of Depo-Provera CI in women who were first exposed before the age of 35 years
(RR 1.22 to 1.28 and 95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive
squamous-cell cervical cancer in women who ever used Depo-Provera CI was estimated to be 1.11 (95%
CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were
observed.
Other Cancers
Long-term case-controlled surveillance of users of Depo-Provera CI found no overall increased risk of
ovarian or liver cancer.
5.4
Ectopic Pregnancy
Be alert to the possibility of an ectopic pregnancy among women using Depo-Provera CI who become
pregnant or complain of severe abdominal pain.
5.5
Anaphylaxis and Anaphylactoid Reaction
Anaphylaxis and anaphylactoid reaction have been reported with the use of Depo-Provera CI. Institute
emergency medical treatment if an anaphylactic reaction occurs.
5.6
Liver Function
Discontinue Depo-Provera CI use if jaundice or acute or chronic disturbances of liver function develop. Do
not resume use until markers of liver function return to normal and Depo-Provera CI causation has been
excluded.
5.7
Convulsions
There have been a few reported cases of convulsions in patients who were treated with Depo-Provera CI.
Association with drug use or pre-existing conditions is not clear.
5.8
Depression
Monitor patients who have a history of depression and do not readminister Depo-Provera CI if depression
recurs.
5.9
Bleeding Irregularities
Most women using Depo-Provera CI experience disruption of menstrual bleeding patterns. Altered
menstrual bleeding patterns include amenorrhea, irregular or unpredictable bleeding or spotting,
prolonged spotting or bleeding, and heavy bleeding. Rule out the possibility of organic pathology if
abnormal bleeding persists or is severe, and institute appropriate treatment.
As women continue using Depo-Provera CI, fewer experience irregular bleeding and more experience
amenorrhea. In clinical studies of Depo-Provera CI, by month 12 amenorrhea was reported by 55% of
women, and by month 24, amenorrhea was reported by 68% of women using Depo-Provera CI.
5.10
Weight Gain
Women tend to gain weight while on therapy with Depo-Provera CI. From an initial average body weight of
136 lb, women who completed 1 year of therapy with Depo-Provera CI gained an average of 5.4 lb. Women
who completed 2 years of therapy gained an average of 8.1 lb. Women who completed 4 years gained an
average of 13.8 lb. Women who completed 6 years gained an average of 16.5 lb. Two percent of women
withdrew from a large-scale clinical trial because of excessive weight gain.
6
Reference ID: 3694962
This label may not be the latest approved by FDA.
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5.11
Carbohydrate Metabolism
A decrease in glucose tolerance has been observed in some patients on Depo-Provera CI treatment. Monitor
diabetic patients carefully while receiving Depo-Provera CI.
5.12
Lactation
Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. In
nursing mothers treated with Depo-Provera CI, milk composition, quality, and amount are not adversely
affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for
developmental and behavioral effects through puberty. No adverse effects have been noted.
5.13
Fluid Retention
Because progestational drugs including Depo-Provera CI may cause some degree of fluid retention, monitor
patients with conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and
cardiac or renal dysfunction.
5.14
Return of Fertility
Return to ovulation and fertility is likely to be delayed after stopping Depo-Provera CI. In a large US study
of women who discontinued use of Depo-Provera CI to become pregnant, data are available for 61% of
them. Of the 188 women who discontinued the study to become pregnant, 114 became pregnant. Based on
Life-Table analysis of these data, it is expected that 68% of women who do become pregnant may conceive
within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the
last injection. The median time to conception for those who do conceive is 10 months following the last
injection with a range of 4 to 31 months, and is unrelated to the duration of use. No data are available for
39% of the patients who discontinued Depo-Provera CI to become pregnant and who were lost to follow-up
or changed their mind.
5.15
Sexually Transmitted Diseases
Patients should be counseled that Depo-Provera CI does not protect against HIV infection (AIDS) and other
sexually transmitted diseases.
5.16
Pregnancy
Although Depo-Provera CI should not be used during pregnancy, there appears to be little or no increased
risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate
injections in early pregnancy. Neonates exposed to medroxyprogesterone acetate in-utero and followed to
adolescence showed no evidence of any adverse effects on their health including their physical, intellectual,
sexual or social development.
5.17
Monitoring
A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a
blood pressure check and for other indicated healthcare.
5.18
Interference with Laboratory Tests
The use of Depo-Provera CI may change the results of some laboratory tests, such as coagulation factors,
lipids, glucose tolerance, and binding proteins. [See Drug Interactions (7.2).]
6 ADVERSE REACTIONS
The following important adverse reactions observed with the use of Depo-Provera CI are discussed in greater
detail in the Warnings and Precautions section (5):
•
Loss of Bone Mineral Density [see Warnings and Precautions (5.1)]
•
Thromboembolic disease [see Warnings and Precautions (5.2)]
7
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•
Breast Cancer [see Warnings and Precautions (5.3)]
•
Anaphylaxis and Anaphylactoid Reactions [see Warnings and Precautions (5.5)]
•
Bleeding Irregularities[see Warnings and Precautions (5.9)]
•
Weight Gain [see Warnings and Precautions (5.10)]
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 trials of another drug and may
not reflect the rates observed in practice.
In the two clinical trials with Depo-Provera CI, over 3,900 women, who were treated for up to 7 years,
reported the following adverse reactions, which may or may not be related to the use of Depo-Provera CI.
The population studied ranges in age from 15 to 51 years, of which 46% were White, 50% Non-White, and
4.9% Unknown race. The patients received 150 mg Depo-Provera CI every 3-months (90 days). The
median study duration was 13 months with a range of 1-84 months. Fifty eight percent of patients remained
in the study after 13 months and 34% after 24 months.
Table 1 Adverse Reactions that Were Reported by More than 5% of Subjects
Body System*
Adverse Reactions [Incidence (%)]
Body as a Whole
Headache (16.5%)
Abdominal pain/discomfort (11.2%)
Metabolic/Nutritional
Increased weight> 10lbs at 24 months (37.7%)
Nervous
Nervousness (10.8%)
Dizziness (5.6%)
Libido decreased (5.5%)
Urogenital
Menstrual irregularities:
(bleeding (57.3% at 12 months, 32.1% at 24 months)
amenorrhea (55% at 12 months, 68% at 24 months)
* Body System represented from COSTART medical dictionary.
8
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Table 2 Adverse Reactions that Were Reported by between 1 and 5% of Subjects
Body System*
Adverse Reactions [Incidence (%)]
Body as a Whole
Asthenia/fatigue (4.2%)
Backache (2.2%)
Dysmenorrhea (1.7%)
Hot flashes (1.0%)
Digestive
Nausea (3.3%)
Bloating (2.3%)
Metabolic/Nutritional
Edema (2.2%)
Musculoskeletal
Leg cramps (3.7%)
Arthralgia (1.0%)
Nervous
Depression (1.5%)
Insomnia (1.0%)
Skin and Appendages
Acne (1.2%)
No hair growth/alopecia (1.1%)
Rash (1.1%)
Urogenital
Leukorrhea (2.9%)
Breast pain (2.8%)
Vaginitis (1.2%)
* Body System represented from COSTART medical dictionary.
Adverse reactions leading to study discontinuation in ≥ 2% of subjects: bleeding (8.2%), amenorrhea
(2.1%), weight gain (2.0%)
6.2
Post-marketing Experience
The following adverse reactions have been identified during post approval use of Depo-Provera CI.
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.
There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients
taking Depo-Provera CI.
9
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Table 3 Adverse Reactions Reported during Post-Marketing Experience
Body System*
Adverse Reactions
Body as a Whole
Chest pain, Allergic reactions including angioedema, Fever, Pain at
injection site, Chills, Axillary swelling
Cardiovascular
Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis,
Pulmonary embolus, Varicose veins
Digestive
Changes in appetite, Gastrointestinal disturbances, Jaundice,
Excessive thirst, Rectal bleeding
Hematologic and Lymphatic
Anemia, Blood dyscrasia
Musculoskeletal
Osteoporosis
Neoplasms
Cervical cancer, Breast cancer
Nervous
Paralysis, Facial palsy, Paresthesia, Drowsiness
Respiratory
Dyspnea and asthma, Hoarseness
Skin and Appendages
Hirsutism, Excessive sweating and body odor, Dry skin,
Scleroderma
Urogenital
Lack of return to fertility, Unexpected pregnancy, Prevention of
lactation, Changes in breast size, Breast lumps or nipple bleeding,
Galactorrhea, Melasma, Chloasma, Increased libido, Uterine
hyperplasia, Genitourinary infections, Vaginal cysts, Dyspareunia
* Body System represented from COSTART medical dictionary.
7 DRUG INTERACTIONS
7.1
Changes in Contraceptive Effectiveness Associated with Co-Administration of
Other Products
If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including
CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different
method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma
concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives.
Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include:
• barbiturates
• bosentan
• carbamazepine
• felbamate
• griseofulvin
• oxcarbazepine
• phenytoin
• rifampin
• St. John’s wort
• topiramate
HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or
decrease) in the plasma levels of progestin have been noted in some cases of co-administration of HIV
10
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protease inhibitors. Significant changes (increase or decrease) in the plasma levels of the progestin have
been noted in some cases of co-administration with non-nucleoside reverse transcriptase inhibitors.
Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but
clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations
of synthetic steroids.
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with
hormonal contraceptives or the potential for enzyme alterations.
7.2
Laboratory Test Interactions
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
The following laboratory tests may be affected by progestins including Depo-Provera CI:
(a)
Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol,
testosterone, cortisol).
(b)
Gonadotropin levels are decreased.
(c)
Sex-hormone-binding-globulin concentrations are decreased.
(d)
Protein-bound iodine and butanol extractable protein-bound iodine may increase.
T3-uptake values may decrease.
(e)
Coagulation test values for prothrombin (Factor II), and
Factors VII, VIII, IX, and X may increase.
(f)
Sulfobromophthalein and other liver function test values may be increased.
(g)
The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both
increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL)
cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Depo-Provera CI should not be administered during pregnancy. [See Contraindications and Warnings and
Precautions (5.16).]
8.3
Nursing Mothers
Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. [See
Warnings and Precautions (5.12).]
8.4
Pediatric Use
Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI is associated with significant
loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a critical
period of bone accretion. In adolescents, interpretation of BMD results should take into account patient
age and skeletal maturity. It is unknown if use of Depo-Provera CI by younger women will reduce peak
bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of
BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult
women.
8.5
Geriatric Use
This product has not been studied in post-menopausal women and is not indicated in this population.
11
Reference ID: 3694962
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For current labeling information, please visit https://www.fda.gov/drugsatfda
stru
ct
ural
f
or
mu
la
8.6
Renal Impairment
The effect of renal impairment on Depo-Provera CI pharmacokinetics has not been studied.
8.7
Hepatic Impairment
The effect of hepatic impairment on Depo-Provera CI pharmacokinetics has not been studied. Depo-
Provera CI should not be used by women with significant liver disease and should be discontinued if
jaundice or disturbances of liver function occur. [See Contraindications (4) and Warnings and Precautions
(5.6).]
11 DESCRIPTION
Depo-Provera CI contains medroxyprogesterone acetate, a derivative of progesterone, as its active
ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a
white to off-white; odorless crystalline powder that is stable in air and that melts between 200°C and 210°C.
It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol,
slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-,
(6α-).
The structural formula is as follows:
Depo-Provera CI for intramuscular (IM) injection is available in vials and prefilled syringes, each
containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL.
For Depo-Provera CI vials, each mL of sterile aqueous suspension contains:
Medroxyprogesterone acetate
150 mg
Polyethylene glycol 3350
28.9 mg
Polysorbate 80
2.41 mg
Sodium chloride
8.68 mg
Methylparaben
1.37 mg
Propylparaben
0.150 mg
Water for injection
quantity sufficient
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
For Depo-Provera CI prefilled syringes, each mL of sterile aqueous suspension contains:
Medroxyprogesterone acetate
150 mg
Polyethylene glycol 3350
28.5 mg
Polysorbate 80
2.37 mg
Sodium chloride
8.56 mg
Methylparaben
1.35 mg
12
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Propylparaben
0.147 mg
Water for injection
quantity sufficient
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Depo-Provera CI (medroxyprogesterone acetate [MPA]), when administered at the recommended dose to
women every 3 months, inhibits the secretion of gonadotropins which, in turn, prevents follicular
maturation and ovulation and results in endometrial thinning. These actions produce its contraceptive
effect.
12.2
Pharmacodynamics
No specific pharmacodynamic studies were conducted with Depo-Provera CI.
12.3
Pharmacokinetics
Absorption
Following a single 150 mg IM dose of Depo-Provera CI in eight women between the ages of 28 and 36
years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay
procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL.
Distribution
Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No
binding of MPA occurs with sex-hormone-binding globulin (SHBG).
Metabolism
MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A
and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a
combination of these positions, resulting in more than 10 metabolites.
Excretion
The concentrations of medroxyprogesterone acetate decrease exponentially until they become
undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted
radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life
for medroxyprogesterone acetate following IM administration of Depo-Provera CI is approximately 50
days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates
with only minor amounts excreted as sulfates.
Specific Populations
The effect of hepatic and/or renal impairment on the pharmacokinetics of Depo-Provera CI is unknown.
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
[See Warnings and Precautions, (5.3, 5.14, and 5.16).]
14 CLINICAL STUDIES
13
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14.1
Contraception
In five clinical studies using Depo-Provera CI, the 12-month failure rate for the group of women treated
with Depo-Provera CI was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of
Depo-Provera CI is dependent on the patient returning every 3 months (13 weeks) for reinjection.
14.2
Bone Mineral Density (BMD) Changes in Adult Women
In a controlled, clinical study, adult women using Depo-Provera CI for up to 5 years showed spine and hip
BMD mean decreases of 5–6%, compared to no significant change in BMD in the control group. The
decline in BMD was more pronounced during the first two years of use, with smaller declines in
subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38%
after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and
femoral neck were similar.
After stopping use of Depo-Provera CI (150 mg), there was partial recovery of BMD toward baseline
values during the 2-year post-therapy period. Longer duration of treatment was associated with less
complete recovery during this 2-year period following the last injection. Table 4 shows the change in
BMD in women after 5 years of treatment with Depo-Provera CI and in women in a control group, as well
as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were
available.
Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort
(5 Years of Treatment and 2 Years of Follow-Up)
Time in
Study
Spine
Total Hip
Femoral Neck
Depo-Provera*
Control**
Depo-Provera*
Control**
Depo-Provera*
Control**
5 years
-5.38%
n=33
0.43%
n=105
-5.16%
n=21
0.19%
n=65
-6.12%
n=34
-0.27%
n=106
7 years
-3.13%
n=12
0.53%
n=60
-1.34%
n=7
0.94%
n=39
-5.38%
n=13
-0.11%
n=63
*The treatment group consisted of women who received Depo-Provera CI for 5 years and were then followed for 2
years post-use (total time in study of 7 years).
**The control group consisted of women who did not use hormonal contraception and were followed for 7 years.
14.3
Bone Mineral Density Changes in Adolescent Females (12-18 years of age)
The impact of Depo-Provera CI (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-
label non-randomized clinical study in 389 adolescent females (12-18 years). Use of Depo-Provera CI was
associated with a significant decline from baseline in BMD.
Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections
per Depo-Provera CI user was 9.3. The decline in BMD at total hip and femoral neck was greater with
longer duration of use (see Table 5). The mean decrease in BMD at 240 weeks was more pronounced at
total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).
In general, adolescents increase bone density during the period of growth following menarche, as seen in
14
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For current labeling information, please visit https://www.fda.gov/drugsatfda
the untreated cohort. However, the two cohorts were not matched at baseline for age, gynecologic age,
race, BMD and other factors that influence the rate of acquisition of bone mineral density.
Table 5. Mean Percent Change from Baseline in BMD in Adolescents Receiving ≥4
Injections per 60-week Period, by Skeletal Site and Cohort
Duration of
Treatment
Depo-Provera CI
(150 mg IM)
Unmatched, Untreated
Cohort
N
Mean % Change
N
Mean % Change
Total Hip BMD
Week 60 (1.2 years)
Week 120 (2.3 years)
Week 240 (4.6 years)
113
73
28
-2.75
-5.40
-6.40
166
109
84
1.22
2.19
1.71
Femoral Neck BMD
Week 60
Week 120
Week 240
113
73
28
-2.96
-5.30
-5.40
166
108
84
1.75
2.83
1.94
Lumbar Spine BMD
Week 60
Week 120
Week 240
114
73
27
-2.47
-2.74
-2.11
167
109
84
3.39
5.28
6.40
BMD recovery post-treatment in adolescent women
Longer duration of treatment and smoking were associated with less recovery of BMD following the last
injection of Depo-Provera CI. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment
for adolescent women who received Depo-Provera CI for two years or less compared to more than two
years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine
BMD recovered to baseline levels after treatment was discontinued. Subjects treated with Depo-Provera
for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to
60 months post-treatment. Adolescent women in the untreated cohort gained BMD throughout the trial
period (data not shown).
15
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Table 6: Extent of BMD Recovery (Months Post-Treatment) in Adolescents by Years of
Depo Provera CI Use (2 Years or Less vs. More than 2 Years)
Duration of
Treatment
2 years or less
More than 2 years
N
Mean % Change
from baseline
N
Mean % Change from
baseline
Total Hip BMD
End of Treatment
49
-1.5%
49
-6.2%
12 M post-treatment
33
-1.4%
24
-4.6%
24 M post-treatment
18
0.3%
17
-3.6%
36 M post-treatment
12
2.1%
11
-4.6%
48 M post-treatment
10
1.3%
9
-2.5%
60 M post-treatment
3
0.2%
2
-1.0%
Femoral Neck BMD
End of Treatment
49
-1.6%
49
-5.8%
12 M post-treatment
33
-1.4%
24
-4.3%
24 M post-treatment
18
0.5%
17
-3.8%
36 M post-treatment
12
1.2%
11
-3.8%
48 M post-treatment
10
2.0%
9
-1.7%
60 M post-treatment
3
1.0%
2
-1.9%
Lumbar Spine BMD
End of Treatment
49
-0.9%
49
-3.5%
12 M post-treatment
33
0.4%
23
-1.1%
24 M post-treatment
18
2.6%
17
1.9%
36 M post-treatment
12
2.4%
11
0.6%
48 M post-treatment
10
6.5%
9
3.5%
60 M post-treatment
3
6.2%
2
5.7%
14.4
Relationship of fracture incidence to use of DMPA 150 mg IM or non-use by
women of reproductive age
A retrospective cohort study to assess the association between DMPA injection and the incidence of bone
fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture
were compared between DMPA users and contraceptive users who had no recorded use of DMPA. The
Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95%
CI 1.35, 1.47). It is not known if this is due to DMPA use or to other related lifestyle factors that have a
bearing on fracture rate.
In the study, when cumulative exposure to DMPA was calculated, the fracture rate in users who received
fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is
not clear that cumulative exposure, which may include periods of intermittent use separated by periods of
non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.
There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study
overall, and the incidence of osteoporotic fractures was not found to be higher in DMPA users compared
to non-users. Importantly, this study could not determine whether use of DMPA has an effect on fracture
rate later in life.
16
Reference ID: 3694962
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For current labeling information, please visit https://www.fda.gov/drugsatfda
15 REFERENCES
1. Li CI, Beaber EF, Tang, MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer
Risk among Women 20 to 44 years of Age. Cancer Research 2012;72:2028-2035.
2. Shapiro S, Rosenberg L, Hoffman M et al. Risk of Breast Cancer in Relation to the Use of Injectable
Progestogen Contraceptives and Combined Estrogen/Progestogen Contraceptives. Am J Epidemiol
2000:Vol.151, No. 4, 396-403.
3. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot
medroxyprogesterone acetate: a multinational study. Lancet 1991; 338:833-38
4. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast
cancer. Br Med J 1989; 299:759-62.
5. Lee NC, Rosero-Bixby L, Oberle MW et al. A Case-Control Study of Breast Cancer and Hormonal
Contraception in Costa Rica. JNCI 1987; 79:1247-1254
6. http://seer.cancer.gov/faststats/index.php (Accessed on August 14, 2014)
16 HOW SUPPLIED/STORAGE AND HANDLING
Depo-Provera CI is supplied in the following strengths and package configurations:
Package
Configuration
Strength
NDC
Depo-Provera CI (medroxyprogesterone acetate sterile aqueous
suspension 150 mg/mL)
1 mL vial
150 mg/mL
NDC 0009-0746-30
25 x 1 mL vials
150 mg/mL
NDC 0009-0746-35
Depo-Provera CI prefilled syringes packaged with 22 gauge x 1 1/2
inch Terumo® SurGuard™ Needles
1 mL prefilled
syringe
150 mg/mL
NDC 0009-7376-11
Depo-Provera CI prefilled syringes packaged with 22 gauge x 1 1/2
inch BD SafetyGlideTM Needles
1 mL prefilled
syringe
150 mg/mL
NDC 0009-7376-07
Vials MUST be stored upright at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
17 PATIENT COUNSELING INFORMATION
“See FDA-approved patient labeling (Patient Information).”
• Advise patients at the beginning of treatment that their menstrual cycle may be disrupted and that irregular
and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea
as treatment with Depo-Provera CI continues, without other therapy being required.
• Counsel patients about the possible increased risk of breast cancer in women who use Depo-Provera CI
[see Warnings and Precautions (5.3)].
• Counsel patients that this product does not protect against HIV infection (AIDS) and other sexually
transmitted diseases.
• Counsel patients on Warnings and Precautions associated with use of Depo-Provera CI.
17
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• Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers
are used with Depo-Provera CI.
This product’s label may have been updated. For current full prescribing information, please visit
www.pfizer.com. company logo
LAB-0149-13.1
Revised January 2015
18
Reference ID: 3694962
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Patient Information
Depo-Provera® (DEP-po pro-VAIR-ah) CI
(medroxyprogesterone acetate injectable suspension)
Contraceptive Injection
Read this Patient Information carefully before you decide if Depo-Provera CI is right for
you. This information does not take the place of talking with your gynecologist or other
healthcare provider who specializes in women’s health. If you have any questions about
Depo-Provera CI, ask your healthcare provider. You should also learn about other birth
control methods to choose the one that is best for you.
What is the most important information I should know about Depo-Provera CI?
Depo-Provera CI can cause serious side effects, including:
• Use of Depo-Provera CI may cause you to lose calcium stored in your bone
and decrease your bone mass. The longer you use Depo-Provera CI, the
greater your loss of calcium from your bones. Your bones may not
recover completely when you stop using Depo-Provera CI.
• If you use Depo-Provera CI continuously for a long time (for more than 2
years), it may increase the risk of weak, porous bones (osteoporosis) that
could increase the risk of broken bones, especially after menopause.
• You should not use Depo-Provera CI for more than two years unless you
cannot use other birth control methods.
• It is not known if your risk of developing osteoporosis is greater if you are
a teenager or young adult when you start to use Depo-Provera CI (see
“What are the possible side effects of Depo-Provera CI?”).
Depo-Provera CI is intended to prevent pregnancy. Depo-Provera CI does not
protect against HIV infection (AIDS) and other sexually transmitted diseases
(STDs).
What is Depo-Provera CI?
Depo-Provera CI is a progestin hormone birth control method that is given by injection
(a shot) to prevent pregnancy.
How well does Depo-Provera CI work?
Your chance of getting pregnant depends on how well you follow the directions for taking
your Depo-Provera CI. The more carefully you follow the directions (such as returning
every 3 months for your next injection), the less chance you have of getting pregnant.
In clinical studies, about 1 out of 100 women got pregnant during the first year that
they used Depo-Provera CI.
The following chart shows the chance of getting pregnant for women who use different
19
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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. flow chart
How should I take Depo-Provera CI?
• Depo-Provera CI is given by your healthcare provider as a shot into your muscle
(intramuscular injection). The shot is given in your buttock or upper arm 1 time
every 3 months. At the end of the 3 months, you will need to return to your
healthcare provider for your next injection in order to continue your protection
against pregnancy.
20
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• To make sure that you are not pregnant before you take Depo-Provera CI,
the first injection should be given only:
o during the first 5 days of a normal menstrual period, or
o within the first 5 days after giving birth, if you are not breastfeeding, or
o at the 6th week after giving birth, if you are feeding your baby only
breastmilk.
• Depo-Provera CI may be given at other times than those listed above, but you will
likely need to have a pregnancy test first to show that you are not pregnant.
• During treatment with Depo-Provera CI, you should see your healthcare provider
every year for a blood pressure check and other healthcare needs.
Who Should Not Use Depo-Provera CI?
Do not use Depo-Provera CI if you:
• are pregnant or think you might be pregnant
• have bleeding from your vagina that has not been explained
• have breast cancer now or in the past, or think you have breast cancer
• have had a stroke
• ever had blood clots in your arms, legs or lungs
• have problems with your liver or liver disease
• are allergic to medroxyprogesterone acetate or any of the other ingredients in
Depo-Provera CI. See the end of this leaflet for a complete list of ingredients in
Depo-Provera CI.
What should I tell my healthcare provider before taking Depo-Provera CI?
Before taking Depo-Provera CI, tell your healthcare provider if you have:
• risk factors for weak bones (osteoporosis) such as bone disease, use alcohol or
smoke regularly, anorexia nervosa, or a strong family history of osteoporosis
• irregular or lighter than usual menstrual periods
• breast cancer now or in the past, or think you have breast cancer
• a family history of breast cancer
• an abnormal mammogram (breast X-ray), lumps in your breasts, or bleeding from
your nipples
• kidney problems
• high blood pressure
• had a stroke
• had blood clots in your arms, legs or lungs
• migraine headaches
• asthma
• epilepsy (convulsions or seizures)
• diabetes
• depression or a history of depression
• any other medical conditions
21
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If you are breastfeeding or plan to breastfeed, Depo-Provera CI can pass into your
breast milk. Talk to your healthcare provider about the best way to feed your baby if
you take Depo-Provera CI.
Tell your healthcare provider about all of the medicines you take, including prescription
and nonprescription medicines, vitamins, and herbal supplements.
Depo-Provera CI and certain other medicines may affect each other, causing serious side
effects. Sometimes the doses of other medicines may need to be changed while you are
taking Depo-Provera CI.
Some medicines may make Depo-Provera CI less effective at preventing pregnancy,
including those listed below.
Especially tell your healthcare provider if you take:
• medicine to help you sleep
• bosentan
• medicine for seizures
• griseofulvin
• an antibiotic
• medicine for HIV (AIDS)
• St. John’s wort
Know the medicines you take. Keep a list of your medicines with you to show your
healthcare provider or pharmacist before you first start taking Depo-Provera CI or when
you get a new medicine.
Follow your healthcare provider’s instructions about using a back-up method of
birth control if you are taking medicines that may make Depo-Provera CI less
effective.
What are the possible side effects of Depo-Provera CI?
Depo-Provera CI can cause serious side effects, including:
• Effect on the bones: See ”What is the most important information I should know
about Depo-Provera CI?”.
Teenage years are the most important years to gain bone strength. The decrease
in calcium in your bones is of most concern if you are a teenager or have the
following problems:
• bone disease
• an eating disorder (anorexia nervosa)
• a strong family history of osteoporosis
• you take a drug that can lower the amount of calcium in your bones (drugs for
epilepsy or steroid drugs)
• you drink a lot of alcohol (more than 2 drinks a day)
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Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• you smoke
If you need a birth control method for more than 2 years, your healthcare provider
may switch you to another birth control method instead of using Depo-Provera CI.
If you continue using Depo-Provera CI, your healthcare provider may ask you to
have a bone test, especially if you have other risks for weak bones.
When Depo-Provera CI is stopped, your bones may start to regain calcium.
However, in a study of teenage girls who used Depo-Provera CI for more than 2
years, their hip bones did not completely recover by 5 years after they stopped
using Depo-Provera CI. Taking calcium and Vitamin D and exercising daily may
lessen the loss of calcium from your bones.
• possible increased risk of breast cancer. Women who use Depo-Provera CI may
have a slightly increased risk of breast cancer compared to non-users.
• blood clots in your arms, legs, lungs, and eyes
• stroke
• a pregnancy outside of your uterus (ectopic pregnancy). Ectopic pregnancy is a
medical emergency that often requires surgery. Ectopic pregnancy can cause
internal bleeding, infertility, and even death.
• allergic reactions. Severe allergic reactions have been reported in some women
using Depo-Provera CI.
• loss of vision or other eye problems
• migraine headaches
• depression
• convulsions or seizures
• liver problems
Call your healthcare provider right away if you have:
• sharp chest pain, coughing up blood, or sudden shortness of breath (indicating a
possible clot in the lung)
• sudden severe headache or vomiting, dizziness or fainting, problems with your
eyesight or speech, weakness, or numbness in an arm or leg (indicating a possible
stroke)
• severe pain or swelling in the calf (indicating a possible clot in the leg)
• sudden blindness, partial or complete (indicating a possible clot in the blood
vessels of the eye)
• unusually heavy vaginal bleeding
• severe pain or tenderness in the lower abdominal area
• persistent pain, pus, or bleeding at the injection site
• yellowing of the eyes or skin
• hives
• difficulty breathing
• swelling of the face, mouth, tongue or neck
23
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The most common side effects of Depo-Provera CI include:
• irregular vaginal bleeding, such as lighter or heavier menstrual bleeding, or
continued spotting
• weight gain. You may experience weight gain while you are using Depo-Provera
CI. About two-thirds of the women who used Depo-Provera CI in the clinical trials
reported a weight gain of about 5 pounds during the first year of use. You may
continue to gain weight after the first year. Women who used Depo-Provera CI for
2 years gained an average of 8 pounds over those 2 years.
• abdominal pain
• headache
• weakness
• tiredness
• nervousness
• dizziness
Tell your healthcare provider if you have any side effect that bothers you or does not go
away.
These are not all the possible side effects of Depo-Provera CI. 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.
What other information should I know before choosing Depo-Provera CI?
• Pregnancy. When you take Depo-Provera CI every 3 months, your chance of
getting pregnant is very low. You could miss a period or have a light period and
not be pregnant. If you miss 1 or 2 periods and think you might be pregnant, see
your healthcare provider as soon as possible. You should not use Depo-Provera CI
if you are pregnant. However, Depo-Provera CI taken by accident during
pregnancy does not seem to cause birth defects.
• Nursing Mothers. Although Depo-Provera CI can be passed to the nursing baby
in the breast milk, no harmful effects on babies have been found. Depo-Provera CI
does not stop the breasts from producing milk, so it can be used by nursing
mothers. However, to minimize the amount of Depo-Provera CI that is passed to
the baby in the first weeks after birth, you should wait until your baby is 6 weeks
old before you start using Depo-Provera CI for birth control.
How will Depo-Provera CI change my periods?
• Change in normal menstrual cycle. The side effect reported most frequently by
women who use Depo-Provera CI for birth controls is a change in their normal
menstrual cycle. During the first year of using Depo-Provera CI, you might have
one or more of the following changes:
o irregular or unpredictable bleeding or spotting
o an increase or decrease in menstrual bleeding
o no bleeding at all. In clinical studies of Depo-Provera CI, 55% of women
24
Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
reported no menstrual bleeding (amenorrhea) after one year of use and
68% of women reported no menstrual bleeding after two years of use.
• Missed period. During the time you are using Depo-Provera CI for birth controls,
you may skip a period, or your periods may stop completely. If you have been
receiving your shot of Depo-Provera CI regularly every 3 months, then you are
probably not pregnant. However, if you think that you may be pregnant, see your
healthcare provider.
Unusually heavy or continuous bleeding is not a usual effect of Depo-Provera CI and if
this happens you should see your healthcare provider right away.
With continued use of Depo-Provera CI, bleeding usually decreases and many women
stop having periods completely. When you stop using Depo-Provera CI your menstrual
period will usually, in time, return to its normal cycle.
What if I want to become pregnant?
Because Depo-Provera CI is a long-acting birth control method, it takes some time after
your last shot for its effect to wear off. Most women who try to get pregnant after using
Depo-Provera CI get pregnant within 18 months after their last shot. The length of time
you use Depo-Provera CI has no effect on how long it takes you to become pregnant
after you stop using it.
General Information about Depo-Provera CI
Medicines are sometimes prescribed for conditions that are not mentioned in patient
information leaflets. This leaflet summarizes the most important information about
Depo-Provera CI. If you would like more information, talk with your healthcare provider.
You can ask your healthcare provider for information about Depo-Provera CI that is
written for healthcare providers.
What are the ingredients in Depo-Provera CI?
Active ingredient: medroxyprogesterone acetate
Inactive ingredients: polyethylene glycol 3350, polysorbate 80, sodium chloride,
methylparaben, propylparaben, and water for injection. When necessary, pH is adjusted
with sodium hydroxide or hydrochloric acid, or both.
This product’s label may have been updated. For current full prescribing information,
please visit www.pfizer.com. company logo
LAB-0148-10.1
Reference ID: 3694962
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised January 2015
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Reference ID: 3694962
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020246s053lbl.pdf', 'application_number': 20246, 'submission_type': 'SUPPL ', 'submission_number': 53}
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1
HL:L4
PRESCRIBING INFORMATION
HALFAN
brand of
halofantrine hydrochloride
Tablets
WARNING: HALFAN HAS BEEN SHOWN TO PROLONG QTc INTERVAL AT THE
RECOMMENDED THERAPEUTIC DOSE. THERE HAVE BEEN RARE REPORTS
OF SERIOUS VENTRICULAR DYSRHYTHMIAS SOMETIMES ASSOCIATED WITH
DEATH, WHICH MAY BE SUDDEN. HALFAN IS THEREFORE NOT
RECOMMENDED FOR USE IN COMBINATION WITH DRUGS OR CLINICAL
CONDITIONS KNOWN TO PROLONG QTc INTERVAL, OR IN PATIENTS WHO
HAVE PREVIOUSLY RECEIVED MEFLOQUINE, OR IN PATIENTS WITH KNOWN
OR SUSPECTED VENTRICULAR DYSRHYTHMIAS, A-V CONDUCTION
DISORDERS OR UNEXPLAINED SYNCOPAL ATTACKS. HALFAN SHOULD BE
PRESCRIBED ONLY BY PHYSICIANS WHO HAVE SPECIAL COMPETENCE IN
THE DIAGNOSIS AND TREATMENT OF MALARIA, AND WHO ARE EXPERIENCED
IN THE USE OF ANTIMALARIAL DRUGS. PHYSICIANS SHOULD THOROUGHLY
FAMILIARIZE THEMSELVES WITH THE COMPLETE CONTENTS OF THIS
LEAFLET BEFORE PRESCRIBING HALFAN.
DESCRIPTION
Halfan (halofantrine hydrochloride) is an antimalarial drug available as tablets containing
250 mg of halofantrine hydrochloride (equivalent to 233 mg of the free base) for oral
administration.
The chemical name of halofantrine hydrochloride is 1,3-dichloro-α-[2-(dibutylamino) ethyl]-
6-(trifluoromethyl)-9-phenanthrene-methanol hydrochloride.
The drug, a white to off-white crystalline compound, is practically insoluble in water.
Halofantrine hydrochloride has a calculated molecular weight of 536.89. The empirical
formula is C26H30Cl2F3NOHCl and the structural formula is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Inactive Ingredients
Inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone,
pregelatinized starch, sodium starch glycolate and talc.
CLINICAL PHARMACOLOGY
The interindividual variability in the pharmacokinetic parameters of halofantrine is very wide
and has led to great difficulty in precisely determining the pharmacokinetic characteristics
of this product.
Following administration of halofantrine hydrochloride tablets in single oral doses of 250
mg to 1000 mg to healthy volunteers, peak plasma levels were reached in 5 to 7 hours.
High variability in the peak plasma levels was observed in all studies, suggesting erratic
absorption from the gastrointestinal tract. An approximately seven-fold increase in peak
plasma concentration and a three-fold increase in area under the curve (AUC) of
halofantrine were obtained when a single 250 mg tablet was administered with high-fat
food to healthy subjects.
Healthy volunteers who were given three oral doses of 500 mg of halofantrine hydrochloride
(500 mg every 6 hours), when fed 2 hours before the second and third doses, had similar
three- to five-fold increases in absorption. A mean Cmax of 3200 ng/mL (range 1555 to
4920 ng/mL) with a corresponding Tmax of 9 to 17 hours was attained following this multiple-
dose regimen.
Halofantrine has a relatively long distribution phase with a half-life of 16 hours and a
variable terminal elimination half-life of 6 to 10 days. The half-life of halofantrine varies
considerably among individuals.
The primary metabolite of halofantrine is n-desbutyl halofantrine. Cmax values ranging from
310 to 410 ng/mL were observed to occur between 32 and 56 hours following oral
administration of multiple doses of 500 mg halofantrine q6h for three doses. The apparent
terminal elimination half-life of the metabolite is 3 to 4 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Based on animal studies, hepatobiliary clearance with fecal elimination of halofantrine
parent compound and metabolite predominates. The extent to which halofantrine is bound
to plasma proteins and the extent to which halofantrine is taken up into red blood cells are
unknown.
The pharmacokinetics of halofantrine in patients with compromised renal or hepatic
function has not been investigated.
The course of the anemia developed by a few malaria patients treated with halofantrine
whose red blood cells were deficient in glucose-6-phosphate dehydrogenase (G6PD) was
not different from that in malaria patients with normal G6PD values.
Microbiology
Halofantrine is a blood schizonticidal antimalarial agent with no apparent action on the
sporozoite, gametocyte or hepatic stages of the infection. The exact mechanism of its
action is unknown. The primary metabolite, n-desbutyl halofantrine, and the parent
compound are equally active in vitro.
While in vitro studies indicate that there may be cross-resistance between halofantrine and
mefloquine, the clinical data do not support this view. No significant correlation between
halofantrine and mefloquine resistance was observed in clinical trials.
Clinical Trials
In controlled clinical trials involving 90 non-immune patients with malaria due to
Plasmodium falciparum, treatment with Halfan (500 mg every 6 hours for three doses on
days 0 and 7) had a cure rate of 99%. Patients were followed for 28 days or more after
initiation of treatment.
In trials involving 583 acute malaria patients, the majority of whom were semi-immune,
treatment with Halfan (500 mg every 6 hours for three doses) produced a cure rate of 90%
against Plasmodium falciparum infection (n=512), and a cure rate of 99% against
Plasmodium vivax (n=71).
INDICATIONS AND USAGE
Halfan tablets are indicated for the treatment of adults who can tolerate oral medication
and who have mild to moderate malaria (equal to or less than 100,000 parasites/mm3)
caused by Plasmodium falciparum or Plasmodium vivax.
NOTE: Patients with acute P. vivax malaria treated with Halfan are at risk of relapse
because halofantrine does not eliminate the exoerythrocytic (hepatic phase) parasites. To
avoid relapse after initial treatment of the acute P. vivax infection with Halfan, patients
should subsequently be treated with an 8-aminoquinoline to eradicate the exoerythrocytic
parasites.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
NOTE: THE EFFICACY OF HALFAN (HALOFANTRINE HYDROCHLORIDE) IN THE
PROPHYLAXIS OF MALARIA HAS NOT BEEN ESTABLISHED.
CONTRAINDICATIONS
Halfan is contraindicated in patients with a known family history of congenital QTc
prolongation. (See BOXED WARNING.) Use of this drug is contraindicated in patients
with a known hypersensitivity to halofantrine.
WARNINGS
In life-threatening, severe, or overwhelming malarial infections, patients should be treated
immediately with an appropriate parenteral antimalarial drug. The safety and efficacy of
Halfan in the treatment of patients with cerebral malaria or other forms of complicated
malaria have not been established.
Halfan has been shown to prolong QTc interval at the recommended therapeutic dose.
There have been rare reports of serious ventricular dysrhythmias sometimes associated
with death, which may be sudden. Halfan is therefore not recommended in combination
with drugs, or clinical conditions, known to prolong QTc interval, or in patients with known or
suspected ventricular dysrhythmias, A-V conduction
disorders or unexplained syncopal attacks. Physicians should perform an ECG prior to
dosing to ensure that the patient’s baseline QTc interval is within normal limits. Cardiac
rhythm should be monitored during and for 8-12 hours following completion of therapy.
Caution should be used with concomitant intake of drugs which are known to significantly
inhibit cytochrome P450IIIA4.
Halfan should be taken on an empty stomach as increased absorption and, thus,
increased toxicity may result from dosing in association with food. Do not exceed
recommended doses, as higher than recommended doses of Halfan have been shown to
further prolong QTc interval.
Data on the use of Halfan subsequent to administration of mefloquine suggest a
significant, potentially fatal, prolongation of the QTc interval.
1 Therefore, Halfan should not
be given simultaneously with or subsequent to mefloquine. (See PRECAUTIONS—Drug
Interactions.)
Halofantrine has been shown to be embryotoxic in animal tests. Use in women of
childbearing potential only with due caution regarding the potential effect on the fetus if the
patient is pregnant. (See PRECAUTIONS—Pregnancy subsection.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
PRECAUTIONS
General
A phototoxic potential cannot be ruled out on the basis of the chemical moiety of
halofantrine and the results of animal tests. (See ANIMAL TOXICOLOGY.) However, there
is no evidence for this effect in humans.
Drug Interactions
Although no drug interaction studies have been conducted, Halfan should not be
administered with drugs known to prolong the QTc interval. In clinical use, an interaction
with mefloquine has been reported to lead to further prolongation of the QTc interval.
1 The
prolongation may be significant and potentially fatal; therefore, Halfan should not be given
simultaneously with or subsequent to mefloquine. There have been no drug interactions
reported when halofantrine is coadministered with chloroquine.
In vitro studies have shown that drugs which inhibit cytochrome CYPIIIA 4, e.g.,
ketoconazole, lead to an inhibition of halofantrine metabolism. Further, in dogs orally
administered ketoconazole, the metabolism of halofantrine was decreased (SEE
WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies of halofantrine hydrochloride in animals have not been performed to
evaluate carcinogenic potential.
Genotoxicity of halofantrine hydrochloride was evaluated in five assay test systems
including an Ames test, a gene mutation test in Chinese hamster ovary cells, a
chromosomal aberration analysis in Chinese hamster ovary cells, a micronucleus test in
mice, and a dominant lethal assay. No mutagenic potential was demonstrated in any of
these test systems.
Halofantrine hydrochloride did not adversely affect male or female fertility in the rat at an
oral dose of 30 mg/kg (1/6 of the maximum recommended human dose based on mg/m2).
Pregnancy
Teratogenic Effects: Pregnancy Category C
In pregnant rabbits, maternal-lethal doses (decremental dose schedule of 360 to 120
mg/kg, equivalent to 3.6 times to 1.2 times the maximum recommended human dose,
respectively, based on mg/m2) were associated with abortion and an increased incidence
of skeletal malformations, but oral doses up to 60 mg/kg (6/10 of the maximum
recommended human dose based on mg/m2) did not produce maternal or fetal
developmental toxicity.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Non-teratogenic Effects
In reproduction teratology studies in the rat, oral doses >30 mg/kg (1/6 of the maximum
recommended human dose based on mg/m2) produced postimplantation embryonic death
and reduced fetal weight and viability. Halofantrine hydrochloride at doses of 15
mg/kg/day (1/10 of the maximum recommended human dose based on mg/m2) had no
embryotoxicity or teratogenicity. These effects occurred at and below doses that produced
overt maternal toxicity in the rats.
Halofantrine has been shown to be embryocidal in rats. There are no adequate and well-
controlled studies in pregnant women. Halfan (halofantrine hydrochloride) should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
In lactation studies performed in rats, dose-related decreases in offspring body weight
were observed at a dose of 25 mg/kg/day and above (1/8 of the maximum recommended
human dose based on mg/m2). Control pups breast-fed by high-dosed mothers had
significant decreases in body weight and survival at doses of 50 and 100 mg/kg/day (1/4 to
1/2 of the maximum recommended human dose based on mg/m2).
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in
nursing infants from halofantrine hydrochloride, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Safety and effectiveness of halofantrine hydrochloride tablets in the pediatric population
have not been established.
Geriatric Use
There are no studies on the use of halofantrine hydrochloride in elderly individuals.
ADVERSE REACTIONS
Normal Subjects
The following adverse events were reported in normal subjects given Halfan 1000 mg to
1500 mg in a single dosing course.
Gastrointestinal: Abdominal pain (10%), anorexia (5%), diarrhea (5%), nausea (10%),
vomiting (10%).
Central Nervous System: Dizziness (5%), headache (5%).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Clinical Trials
In clinical trials involving 933 patients treated with three 500 mg doses (500 mg every 6
hours), the following clinical adverse events were reported.
There were no deaths or permanent disabilities thought related to drug toxicity. Five
patients discontinued medication due to adverse events. Three patients vomited medicine
repeatedly.
Though temporally related to drug administration, the relationship of the following serious
adverse events to malaria or underlying illness as opposed to drug toxicity could not be
established. Two patients had decreased consciousness; other serious adverse events
reported during clinical trials included convulsions (3 cases), stomatitis (3 cases),
moderately severe diarrhea (2 cases), pulmonary edema (1 case), tetany (1 case),
hypertensive crisis (1 case), cerebrovascular accident (1 case).
The most frequently reported adverse events thought possibly- or probably-related to
halofantrine were: abdominal pain (8.5%), diarrhea (6.0%), dizziness (4.5%), vomiting
(4.3%), nausea (3.4%), cough (3.0%), headache (3.0%), pruritus (2.6%), rigors (1.7%) and
myalgias (1.3%). These events are also characteristic of malaria.
Pruritus was reported in a higher proportion of highly pigmented patients than in other
patients.
Adverse events thought possibly- or probably-related to halofantrine affecting <1% of
patients studied in the clinical trials included:
Body as a Whole: Fatigue, malaise.
Cardiovascular: Chest pain, palpitations, postural hypotension.
Dermatologic: Rash.
Gastrointestinal: Abdominal distention, anorexia, constipation, dyspepsia.
Mucous Membrane: Stomatitis.
Musculoskeletal: Arthralgia, back pain.
Central Nervous System: Asthenia, confusion, convulsions, depression, paresthesia,
sleep disorder.
Renal: Urinary frequency.
Special Senses: Abnormal vision, tinnitus.
Laboratory
The most frequently noted laboratory abnormalities that occurred following drug
administration in the clinical trials were decreased hematocrit, elevated hepatic
transaminases, decreased and increased white blood cell counts, and decreased platelet
counts. These alterations returned to normal limits within 2 to 3 weeks post-infection. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
causal relationship of these changes to Halfan is unclear, as these laboratory
abnormalities can also occur with acute malaria.
Postmarketing Experience
Halofantrine was marketed in Europe starting in 1988. The following additional adverse
experiences have been reported in postmarketing surveillance outside the United States:
Facial edema and urticaria (allergic/anaphylactic reactions) in rare cases.
Hemolysis/hemolytic anemia (including immune hemolytic anemia) which may compromise
renal function have been reported in patients with malaria who have been treated with
halofantrine. Hemolytic reactions may also be observed in patients with malaria in the
absence of halofantrine.
Prolongation of QT interval has been reported. There have been rare reports of serious
ventricular dysrhythmias sometimes associated with death. These cases have occurred
particularly under certain conditions which include uses of doses higher than
recommended, recent or concomitant treatment with mefloquine, or presence of pre-
existing prolongation of QT interval.
1
OVERDOSAGE
In case of overdosage, vomiting should be induced, in conjunction with appropriate
supportive measures, which should include ECG monitoring. The possibility of neurologic
toxicity, especially decreased consciousness and seizures, should be evaluated.
Dehydration secondary to gastrointestinal toxicity with diarrhea and vomiting may require
treatment with intravenous fluid therapy.
Gastrointestinal distress with abdominal pain, vomiting, cramping, and diarrhea occurs at
doses higher than the recommended therapeutic regimen. Palpitations have also been
reported at these higher doses.
DOSAGE AND ADMINISTRATION
(See INDICATIONS AND USAGE.)
Halfan should be given on an empty stomach at least 1 hour before or 2 hours after food.
(See WARNINGS.) The recommended dosage regimen to treat adults able to tolerate oral
medications, who have mild to moderate malaria caused by P. falciparum or P. vivax is:
Non-immune Patients
Patients with no previous exposure or minimal exposure to malaria should be considered
“non-immune.” These patients should receive 500 mg (2 x 250 mg tablets) of halofantrine
hydrochloride every 6 hours for three doses (total first course dosage 1500 mg). This
course of therapy should be repeated 7 days after the first course.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Semi-immune Patients
Patients with a history of life-long residence in endemic areas and a clear history of recent
previous malaria caused by the same Plasmodium species may be considered semi-
immune. In these patients, omitting the second course of therapy may be considered.
Clinical trials in semi-immune patients have utilized this one-course regimen with
satisfactory efficacy and safety.
Hepatic or Renally Impaired Patients
There is no information on dosing alterations needed because of hepatic or renal
impairment.
HOW SUPPLIED
Halfan (halofantrine hydrochloride) is available as a white to off-white, capsule-shaped
tablet containing 250 mg of halofantrine hydrochloride in bottles of 60 tablets. The tablets
are imprinted HALFAN on one side.
Store at controlled room temperature between 20° to 25°C (68° to 77°F) and protect from
light.
250 mg 60’s: NDC 0007-4195-18
ANIMAL TOXICOLOGY
In a phototoxicity study, halofantrine hydrochloride was phototoxic to mice at 80 mg/kg
(6/10 of the maximum recommended human dose based on mg/m2). At 40 mg/kg, the
lowest dose tested, there was a slight erythematous response.
In a whole-body radioautographic study in the rat, it was demonstrated that high drug levels
of halofantrine are retained in the retina and in the Harderian gland for an entire 4-week
observation period. Moreover, the estimated half-lives for the radiolabeled equivalents in
the retina and Harderian gland were from 91 to 778 hours for the 4-week observation
period. The drug passes the blood-brain barrier and is retained for an undetermined time
in the central nervous system.
Elevated cholesterol values have been reported in the rat when halofantrine hydrochloride
is administered for 4 weeks at oral doses of 30 mg/kg (2/10 of the maximum
recommended human dose based on mg/m2) and higher.
Increases in serum cholesterol have also been reported in dogs administered halofantrine
hydrochloride for 28 days at oral doses of 25 mg/kg (1/2 of the recommended human dose
based on mg/m2) and higher.
REFERENCES
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
1. Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment
with halofantrine. Lancet. 1993;341:1054-56.
DATE OF ISSUANCE OCT. 2001
SmithKline Beecham, 2001
Rx only
Manufactured by King Pharmaceuticals, Inc.
Bristol, TN 37620
for
SmithKline Beecham Pharmaceuticals
Philadelphia, PA 19101
HL:L4
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
---------------------------------------------------------------------------------------------------------------------
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
8/1/02 09:54:21 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:14.178508
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20250s7s8lbl.pdf', 'application_number': 20250, 'submission_type': 'SUPPL ', 'submission_number': 7}
|
12,375
|
PRESCRIBING INFORMATION
ZANTAC® 150
(ranitidine hydrochloride)
Tablets, USP
ZANTAC® 300
(ranitidine hydrochloride)
Tablets, USP
ZANTAC® 25
(ranitidine hydrochloride effervescent)
EFFERdose® Tablets
ZANTAC®
(ranitidine hydrochloride)
Syrup, USP
DESCRIPTION
The active ingredient in ZANTAC 150 Tablets, ZANTAC 300 Tablets, ZANTAC 25
EFFERdose Tablets, and ZANTAC Syrup is ranitidine hydrochloride (HCl), USP, a histamine
H2-receptor antagonist. Chemically it is N[2-[[[5-[(dimethylamino)methyl]-2
furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine, HCl. It has the following
structure: Structural Formula
The empirical formula is C13H22N4O3S•HCl, representing a molecular weight of 350.87.
Ranitidine HCl is a white to pale yellow, granular substance that is soluble in water. It has a
slightly bitter taste and sulfurlike odor.
Each ZANTAC 150 Tablet for oral administration contains 168 mg of ranitidine HCl
equivalent to 150 mg of ranitidine. Each tablet also contains the inactive ingredients FD&C
Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose,
titanium dioxide, triacetin, and yellow iron oxide.
Each ZANTAC 300 Tablet for oral administration contains 336 mg of ranitidine HCl
equivalent to 300 mg of ranitidine. Each tablet also contains the inactive ingredients
croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium
stearate, microcrystalline cellulose, titanium dioxide, and triacetin.
1
ZANTAC 25 EFFERdose Tablets for oral administration is an effervescent formulation of
ranitidine that must be dissolved in water before use. Each individual tablet contains 28 mg of
ranitidine HCl equivalent to 25 mg of ranitidine and the following inactive ingredients:
aspartame, monosodium citrate anhydrous, povidone, and sodium bicarbonate. Each tablet also
contains sodium benzoate. The total sodium content of each tablet is 30.52 mg (1.33 mEq) per
25 mg of ranitidine.
Each 1 mL of ZANTAC Syrup contains 16.8 mg of ranitidine HCl equivalent to 15 mg of
ranitidine. ZANTAC Syrup also contains the inactive ingredients alcohol (7.5%), butylparaben,
dibasic sodium phosphate, hypromellose, peppermint flavor, monobasic potassium phosphate,
propylparaben, purified water, saccharin sodium, sodium chloride, and sorbitol.
CLINICAL PHARMACOLOGY
ZANTAC is a competitive, reversible inhibitor of the action of histamine at the histamine
H2-receptors, including receptors on the gastric cells. ZANTAC does not lower serum Ca++ in
hypercalcemic states. ZANTAC is not an anticholinergic agent.
Pharmacokinetics:
Absorption: ZANTAC is 50% absorbed after oral administration, compared to an
intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours
after a 150-mg dose. The syrup and EFFERdose formulations are bioequivalent to the tablets.
Absorption is not significantly impaired by the administration of food or antacids. Propantheline
slightly delays and increases peak blood levels of ranitidine, probably by delaying gastric
emptying and transit time. In one study, simultaneous administration of high-potency antacid
(150 mmol) in fasting subjects has been reported to decrease the absorption of ZANTAC.
Distribution: The volume of distribution is about 1.4 L/kg. Serum protein binding averages
15%.
Metabolism: In humans, the N-oxide is the principal metabolite in the urine; however, this
amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine
(1%). The remainder of the administered dose is found in the stool. Studies in patients with
hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically
insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability.
Excretion: The principal route of excretion is the urine, with approximately 30% of the
orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is
about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours.
Four patients with clinically significant renal function impairment (creatinine clearance 25 to
35 mL/min) administered 50 mg of ranitidine intravenously had an average plasma half-life of
4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of distribution of 1.76 L/kg. In
general, these parameters appear to be altered in proportion to creatinine clearance (see
DOSAGE AND ADMINISTRATION).
Geriatrics: The plasma half-life is prolonged and total clearance is reduced in the elderly
population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak
2
levels average 526 ng/mL following a 150-mg twice-daily dose and occur in about 3 hours (see
PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment
for Patients With Impaired Renal Function).
Pediatrics: There are no significant differences in the pharmacokinetic parameter values for
ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when
correction is made for body weight. The average bioavailability of ranitidine given orally to
pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult
population. All other pharmacokinetic parameter values (t1/2, Vd, and CL) are similar to those
observed with intravenous ranitidine use in pediatric patients. Estimates of Cmax and Tmax are
displayed in Table 1.
Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing
Population
(age)
n
Dosage Form
(dose)
Cmax
(ng/mL)
Tmax
(hours)
Gastric or duodenal ulcer
(3.5 to 16 years)
12
Tablets
(1 to 2 mg/kg)
54 to 492
2.0
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Single dose)
10
Syrup
(2 mg/kg)
244
1.61
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Multiple dose)
10
Syrup
(2 mg/kg)
320
1.66
Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably
lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed
in this population (see PRECAUTIONS: Pediatric Use and DOSAGE AND
ADMINISTRATION: Pediatric Use).
Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric
acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum
concentrations of ranitidine are in this range up to 12 hours. However, blood levels bear no
consistent relationship to dose or degree of acid inhibition.
In a pharmacodynamic comparison of the EFFERdose with the ZANTAC Tablets, during the
first hour after administration, the EFFERdose tablet formulation gave a significantly higher
intragastric pH, by approximately 1 pH unit, compared to the ZANTAC Tablets.
Antisecretory Activity: 1. Effects on Acid Secretion: ZANTAC inhibits both daytime
and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food,
betazole, and pentagastrin, as shown in Table 2.
3
Table 2. Effect of Oral ZANTAC on Gastric Acid Secretion
Time After
Dose, hours
% Inhibition of Gastric Acid Output by Dose, mg
75-80
100
150
200
Basal
Up to 4
99
95
Nocturnal
Up to 13
95
96
92
Betazole
Up to 3
97
99
Pentagastrin
Up to 5
58
72
72
80
Meal
Up to 3
73
79
95
It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to
inhibition by ZANTAC, responding almost completely to doses of 100 mg or less, while
pentagastrin- and food-stimulated secretions are more difficult to suppress.
2. Effects on Other Gastrointestinal Secretions:
Pepsin: Oral ZANTAC does not affect pepsin secretion. Total pepsin output is reduced
in proportion to the decrease in volume of gastric juice.
Intrinsic Factor: Oral ZANTAC has no significant effect on pentagastrin-stimulated
intrinsic factor secretion.
Serum Gastrin: ZANTAC has little or no effect on fasting or postprandial serum
gastrin.
Other Pharmacologic Actions:
1. Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
2. Prolactin levels—no effect in recommended oral or IV dosage, but small, transient,
dose-related increases in serum prolactin have been reported after IV bolus injections of
100 mg or more.
3. Other pituitary hormones—no effect on serum gonadotropins, TSH, or GH. Possible
impairment of vasopressin release.
4. No change in cortisol, aldosterone, androgen, or estrogen levels.
5. No antiandrogenic action.
6. No effect on count, motility, or morphology of sperm.
Pediatrics: Oral doses of 6 to 10 mg/kg/day in 2 or 3 divided doses maintain gastric pH >4
throughout most of the dosing interval.
Clinical Trials: Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US
study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients
treated with ZANTAC as shown in Table 3.
4
Table 3. Duodenal Ulcer Patient Healing Rates
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
195
69/182
(38%)†
188
31/164
(19%)
Week 4
137/187
(73%)†
76/168
(45%)
*All patients were permitted antacids as needed for relief of pain.
†P<0.0001.
In these studies, patients treated with ZANTAC reported a reduction in both daytime and
nocturnal pain, and they also consumed less antacid than the placebo-treated patients.
Table 4. Mean Daily Doses of Antacid
Ulcer Healed
Ulcer Not Healed
ZANTAC
0.06
0.71
Placebo
0.71
1.43
Foreign studies have shown that patients heal equally well with 150 mg twice daily and
300 mg at bedtime (85% versus 84%, respectively) during a usual 4-week course of therapy. If
patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg twice
daily as compared to 300 mg at bedtime (92% versus 87%, respectively).
Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose
ulcers healed during therapy had recurrences of ulcers at the usual rates.
Maintenance Therapy in Duodenal Ulcer: Ranitidine has been found to be effective as
maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent,
double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was
significantly less in patients treated with ZANTAC (150 mg at bedtime) than in patients treated
with placebo over a 12-month period.
5
Table 5. Duodenal Ulcer Prevalence
Double-Blind, Multicenter, Placebo-Controlled Trials
Multicenter
Trial
Drug
Duodenal Ulcer Prevalence
No. of
Patients
0-4
Months
0-8
Months
0-12
Months
USA
RAN
20%*
24%*
35%*
138
PLC
44%
54%
59%
139
Foreign
RAN
12%*
21%*
28%*
174
PLC
56%
64%
68%
165
% = Life table estimate.
* = P<0.05 (ZANTAC versus comparator).
RAN = ranitidine (ZANTAC).
PLC = placebo.
As with other H2-antagonists, the factors responsible for the significant reduction in the
prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of
ulcers that may occur during maintenance therapy, or both.
Gastric Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically
diagnosed gastric ulcers, earlier healing was seen in the patients treated with ZANTAC as shown
in Table 6.
Table 6. Gastric Ulcer Patient Healing Rates
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
92
16/83
(19%)
94
10/83
(12%)
Week 6
50/73
(68%)†
35/69
(51%)
*All patients were permitted antacids as needed for relief of pain.
†P = 0.009.
In this multicenter trial, significantly more patients treated with ZANTAC became pain free
during therapy.
Maintenance of Healing of Gastric Ulcers: In 2 multicenter, double-blind, randomized,
placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been
6
previously healed, ZANTAC 150 mg at bedtime was significantly more effective than placebo in
maintaining healing of gastric ulcers.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
ZANTAC inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain
in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome,
systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative,
"short-gut" syndrome, idiopathic). Use of ZANTAC was followed by healing of ulcers in 8 of 19
(42%) patients who were intractable to previous therapy.
Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind,
placebo-controlled, 6-week trials performed in the United States and Europe, ZANTAC 150 mg
twice daily was more effective than placebo for the relief of heartburn and other symptoms
associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did
placebo-treated patients.
The US trial indicated that ZANTAC 150 mg twice daily significantly reduced the frequency
of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The
improvement was maintained throughout the 6-week trial period. Moreover, patient response
rates demonstrated that the effect on heartburn extends through both the day and night time
periods.
In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ZANTAC
150 mg twice daily was shown to provide relief of heartburn pain within 24 hours of initiating
therapy and a reduction in the frequency of severity of heartburn. In these trials, ZANTAC
EFFERdose Tablets were shown to provide heartburn relief within 45 minutes of dosing.
Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled,
12-week trials performed in the United States, ZANTAC 150 mg 4 times daily was significantly
more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in
relieving associated heartburn. The erosive esophagitis healing rates were as follows:
Table 7. Erosive Esophagitis Patient Healing Rates
Healed/Evaluable
Placebo*
n = 229
ZANTAC
150 mg 4 times daily*
n = 215
Week 4
43/198 (22%)
96/206 (47%)†
Week 8
63/176 (36%)
142/200 (71%)†
Week 12
92/159 (58%)
162/192 (84%)†
*All patients were permitted antacids as needed for relief of pain.
†P<0.001 versus placebo.
No additional benefit in healing of esophagitis or in relief of heartburn was seen with a
ranitidine dose of 300 mg 4 times daily.
7
Maintenance of Healing of Erosive Esophagitis: In 2 multicenter, double-blind,
randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis
had been previously healed, ZANTAC 150 mg twice daily was significantly more effective than
placebo in maintaining healing of erosive esophagitis.
INDICATIONS AND USAGE
ZANTAC is indicated in:
1. Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks. Studies
available to date have not assessed the safety of ranitidine in uncomplicated duodenal ulcer
for periods of more than 8 weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute
ulcers. No placebo-controlled comparative studies have been carried out for periods of longer
than 1 year.
3. The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome
and systemic mastocytosis).
4. Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and
the usefulness of further treatment has not been demonstrated. Studies available to date have
not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of
more than 6 weeks.
5. Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers.
Placebo-controlled studies have been carried out for 1 year.
6. Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting
therapy with ZANTAC 150 mg twice daily.
7. Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn
commonly occurs within 24 hours of therapy initiation with ZANTAC 150 mg 4 times daily.
8. Maintenance of healing of erosive esophagitis. Placebo-controlled trials have been carried
out for 48 weeks.
Concomitant antacids should be given as needed for pain relief to patients with active
duodenal ulcer; active, benign gastric ulcer; hypersecretory states; GERD; and erosive
esophagitis.
CONTRAINDICATIONS
ZANTAC is contraindicated for patients known to have hypersensitivity to the drug or any of
the ingredients (see PRECAUTIONS).
PRECAUTIONS
General:
1. Symptomatic response to therapy with ZANTAC does not preclude the presence of gastric
malignancy.
8
2. Since ZANTAC is excreted primarily by the kidney, dosage should be adjusted in patients
with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be
observed in patients with hepatic dysfunction since ZANTAC is metabolized in the liver.
3. Rare reports suggest that ZANTAC may precipitate acute porphyric attacks in patients with
acute porphyria. ZANTAC should therefore be avoided in patients with a history of acute
porphyria.
Information for Patients: Phenylketonurics: ZANTAC 25 EFFERdose Tablets contain
phenylalanine 2.81 mg per 25 mg of ranitidine. ZANTAC EFFERdose Tablets should not be
chewed, swallowed whole, or dissolved on the tongue.
Laboratory Tests: False-positive tests for urine protein with MULTISTIX® may occur during
therapy with ZANTAC, and therefore testing with sulfosalicylic acid is recommended.
Drug Interactions: Ranitidine has been reported to affect the bioavailability of other drugs
through several different mechanisms such as competition for renal tubular secretion, alteration
of gastric pH, and inhibition of cytochrome P450 enzymes.
Procainamide: Ranitidine, a substrate of the renal organic cation transport system, may
affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g., such as
those used in the treatment of Zollinger-Ellison syndrome) have been shown to reduce the renal
excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of
these drugs. Although this interaction is unlikely to be clinically relevant at usual ranitidine
doses, it may be prudent to monitor for procainamide toxicity when administered with oral
ranitidine at a dose exceeding 300 mg per day.
Warfarin: There have been reports of altered prothrombin time among patients on
concomitant warfarin and ranitidine therapy. Due to the narrow therapeutic index, close
monitoring of increased or decreased prothrombin time is recommended during concurrent
treatment with ranitidine.
Ranitidine may alter the absorption of drugs in which gastric pH is an important determinant
of bioavailability. This can result in either an increase in absorption (e.g., triazolam, midazolam,
glipizide) or a decrease in absorption (e.g., ketoconazole, atazanavir, delavirdine, gefitinib).
Appropriate clinical monitoring is recommended.
Atazanavir: Atazanavir absorption may be impaired based on known interactions with other
agents that increase gastric pH. Use with caution. See atazanavir label for specific
recommendations.
Delavirdine: Delavirdine absorption may be impaired based on known interactions with
other agents that increase gastric pH. Chronic use of H2-receptor antagonists with delavirdine is
not recommended.
Gefitinib: Gefitinib exposure was reduced by 44% with the coadministration of ranitidine and
sodium bicarbonate (dosed to maintain gastric pH above 5.0). Use with caution.
Glipizide: In diabetic patients, glipizide exposure was increased by 34% following a single
150-mg dose of oral ranitidine. Use appropriate clinical monitoring when initiating or
discontinuing ranitidine.
9
Ketoconazole: Oral ketoconazole exposure was reduced by up to 95% when oral ranitidine
was coadministered in a regimen to maintain a gastric pH of 6 or above. The degree of
interaction with usual dose of ranitidine (150 mg twice daily) is unknown.
Midazolam: Oral midazolam exposure in 5 healthy volunteers was increased by up to 65%
when administered with oral ranitidine at a dose of 150 mg twice daily. However, in another
interaction study in 8 volunteers receiving IV midazolam, a 300 mg oral dose of ranitidine
increased midazolam exposure by about 9%. Monitor patients for excessive or prolonged
sedation when ranitidine is coadministered with oral midazolam.
Triazolam: Triazolam exposure in healthy volunteers was increased by approximately 30%
when administered with oral ranitidine at a dose of 150 mg twice daily. Monitor patients for
excessive or prolonged sedation.
Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no indication of
tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to
2,000 mg/kg/day.
Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for
mutagenicity at concentrations up to the maximum recommended for these assays.
In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect
on the outcome of 2 matings per week for the next 9 weeks.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
performed in rats and rabbits at doses up to 160 times the human dose and have revealed no
evidence of impaired fertility or harm to the fetus due to ZANTAC. There are, however, no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
Nursing Mothers: Ranitidine is secreted in human milk. Caution should be exercised when
ZANTAC is administered to a nursing mother.
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers,
gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal
and gastric ulcer. Use of ZANTAC in this age-group is supported by adequate and
well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients
and an analysis of the published literature (see CLINICAL PHARMACOLOGY: Pediatrics and
DOSAGE AND ADMINISTRATION: Pediatric Use).
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory
conditions or the maintenance of healing of erosive esophagitis have not been established.
Safety and effectiveness in neonates (less than 1 month of age) have not been established (see
CLINICAL PHARMACOLOGY: Pediatrics).
Geriatric Use: Of the total number of subjects enrolled in US and foreign controlled clinical
trials of oral formulations of ZANTAC, for which there were subgroup analyses, 4,197 were 65
and over, while 899 were 75 and over. No overall differences in safety or effectiveness were
10
observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, caution should be exercised in dose selection, and
it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY:
Pharmacokinetics: Geriatrics and DOSAGE AND ADMINISTRATION: Dosage Adjustment for
Patients With Impaired Renal Function).
ADVERSE REACTIONS
The following have been reported as events in clinical trials or in the routine management of
patients treated with ZANTAC. The relationship to therapy with ZANTAC has been unclear in
many cases. Headache, sometimes severe, seems to be related to administration of ZANTAC.
Central Nervous System: Rarely, malaise, dizziness, somnolence, insomnia, and vertigo.
Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been
reported, predominantly in severely ill elderly patients. Rare cases of reversible blurred vision
suggestive of a change in accommodation have been reported. Rare reports of reversible
involuntary motor disturbances have been received.
Cardiovascular: As with other H2-blockers, rare reports of arrhythmias such as tachycardia,
bradycardia, atrioventricular block, and premature ventricular beats.
Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and
rare reports of pancreatitis.
Hepatic: There have been occasional reports of hepatocellular, cholestatic, or mixed hepatitis,
with or without jaundice. In such circumstances, ranitidine should be immediately discontinued.
These events are usually reversible, but in rare circumstances death has occurred. Rare cases of
hepatic failure have also been reported. In normal volunteers, SGPT values were increased to at
least twice the pretreatment levels in 6 of 12 subjects receiving 100 mg intravenously 4 times
daily for 7 days, and in 4 of 24 subjects receiving 50 mg intravenously 4 times daily for 5 days.
Musculoskeletal: Rare reports of arthralgias and myalgias.
Hematologic: Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia)
have occurred in a few patients. These were usually reversible. Rare cases of agranulocytosis,
pancytopenia, sometimes with marrow hypoplasia, and aplastic anemia and exceedingly rare
cases of acquired immune hemolytic anemia have been reported.
Endocrine: Controlled studies in animals and man have shown no stimulation of any pituitary
hormone by ZANTAC and no antiandrogenic activity, and cimetidine-induced gynecomastia and
impotence in hypersecretory patients have resolved when ZANTAC has been substituted.
However, occasional cases of impotence and loss of libido have been reported in male patients
receiving ZANTAC, but the incidence did not differ from that in the general population. Rare
11
cases of breast symptoms and conditions, including galactorrhea and gynecomastia, have been
reported in both males and females.
Integumentary: Rash, including rare cases of erythema multiforme. Rare cases of alopecia and
vasculitis.
Respiratory: A large epidemiological study suggested an increased risk of developing
pneumonia in current users of histamine-2-receptor antagonists (H2RAs) compared to patients
who had stopped H2RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07
2.48). However, a causal relationship between use of H2RAs and pneumonia has not been
established.
Other: Rare cases of hypersensitivity reactions (e.g., bronchospasm, fever, rash, eosinophilia),
anaphylaxis, angioneurotic edema, acute interstitial nephritis, and small increases in serum
creatinine.
OVERDOSAGE
There has been limited experience with overdosage. Reported acute ingestions of up to 18 g
orally have been associated with transient adverse effects similar to those encountered in normal
clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and
hypotension have been reported.
When overdosage occurs, the usual measures to remove unabsorbed material from the
gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.
Studies in dogs receiving dosages of ZANTAC in excess of 225 mg/kg/day have shown
muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and
rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer: The current recommended adult oral dosage of ZANTAC for
duodenal ulcer is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of
ranitidine) twice daily. An alternative dosage of 300 mg or 20 mL of syrup (4 teaspoonfuls of
syrup equivalent to 300 mg of ranitidine) once daily after the evening meal or at bedtime can be
used for patients in whom dosing convenience is important. The advantages of one treatment
regimen compared to the other in a particular patient population have yet to be demonstrated (see
Clinical Trials: Active Duodenal Ulcer). Smaller doses have been shown to be equally effective
in inhibiting gastric acid secretion in US studies, and several foreign trials have shown that
100 mg twice daily is as effective as the 150-mg dose.
Antacid should be given as needed for relief of pain (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Maintenance of Healing of Duodenal Ulcers: The current recommended adult oral dosage
is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
bedtime.
12
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
The current recommended adult oral dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of
syrup equivalent to 150 mg of ranitidine) twice daily. In some patients it may be necessary to
administer ZANTAC 150-mg doses more frequently. Dosages should be adjusted to individual
patient needs, and should continue as long as clinically indicated. Dosages up to 6 g/day have
been employed in patients with severe disease.
Benign Gastric Ulcer: The current recommended adult oral dosage is 150 mg or 10 mL of
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice daily.
Maintenance of Healing of Gastric Ulcers: The current recommended adult oral dosage is
150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
bedtime.
GERD: The current recommended adult oral dosage is 150 mg or 10 mL of syrup
(2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice daily.
Erosive Esophagitis: The current recommended adult oral dosage is 150 mg or 10 mL of
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) 4 times daily.
Maintenance of Healing of Erosive Esophagitis: The current recommended adult oral
dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine)
twice daily.
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics
of ZANTAC in neonatal patients (less than 1 month of age) to make dosing recommendations.
The following 3 subsections provide dosing information for each of the pediatric indications.
Also, see the subsection on Preparation of ZANTAC 25 EFFERdose Tablets, below.
Treatment of Duodenal and Gastric Ulcers: The recommended oral dose for the
treatment of active duodenal and gastric ulcers is 2 to 4 mg/kg twice daily to a maximum of
300 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic
data in pediatric patients.
Maintenance of Healing of Duodenal and Gastric Ulcers: The recommended oral
dose for the maintenance of healing of duodenal and gastric ulcers is 2 to 4 mg/kg once daily to a
maximum of 150 mg/day. This recommendation is derived from adult clinical studies and
pharmacokinetic data in pediatric patients.
Treatment of GERD and Erosive Esophagitis: Although limited data exist for these
conditions in pediatric patients, published literature supports a dosage of 5 to 10 mg/kg/day,
usually given as 2 divided doses.
Dosage Adjustment for Patients With Impaired Renal Function: On the basis of
experience with a group of subjects with severely impaired renal function treated with ZANTAC,
the recommended dosage in patients with a creatinine clearance <50 mL/min is 150 mg or 10 mL
of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) every 24 hours. Should the
patient's condition require, the frequency of dosing may be increased to every 12 hours or even
further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing
13
C
ompany logo
schedule should be adjusted so that the timing of a scheduled dose coincides with the end of
hemodialysis.
Elderly patients are more likely to have decreased renal function, therefore caution should be
exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Geriatrics and PRECAUTIONS: Geriatric Use).
Preparation of ZANTAC 25 EFFERdose Tablets: Tablets should not be chewed,
swallowed whole, or dissolved on the tongue. Dissolve 1 tablet in no less than 5 mL
(1 teaspoonful) of water in an appropriate measuring cup. Wait until the tablet is completely
dissolved before administering the solution to the infant/child. The solution may be administered
to infants by medicine dropper or oral syringe.
HOW SUPPLIED
ZANTAC 150 Tablets (ranitidine HCl equivalent to 150 mg of ranitidine) are peach,
film-coated, 5-sided tablets embossed with "ZANTAC 150" on one side and "Glaxo" on the
other. They are available in bottles of 60 (NDC 0173-0344-42), 180 (NDC 0173-0344-17), and
500 (NDC 0173-0344-14) tablets.
ZANTAC 300 Tablets (ranitidine HCl equivalent to 300 mg of ranitidine) are yellow,
film-coated, capsule-shaped tablets embossed with "ZANTAC 300" on one side and "Glaxo" on
the other. They are available in bottles of 30 (NDC 0173-0393-40) tablets.
Store between 15° and 30°C (59°and 86°F) in a dry place. Protect from light. Replace
cap securely after each opening.
ZANTAC 25 EFFERdose Tablets (ranitidine HCl equivalent to 25 mg of ranitidine) are white
to pale yellow, round, flat-faced, bevel-edged tablets embossed with “GS” on one side and
“25C” on the other side. They are packaged in foil strips and are available in a carton of 60
(NDC 0173-0734-00) tablets.
Store between 2° and 30°C (36° and 86°F).
ZANTAC Syrup, a clear, pale yellow, peppermint-flavored liquid, contains 16.8 mg of
ranitidine HCl equivalent to 15 mg of ranitidine per 1 mL (75 mg/5 mL) in bottles of 16 fluid
ounces (one pint) (NDC 0173-0383-54).
Store between 4° and 25°C (39° and 77°F). Dispense in tight, light-resistant containers as
defined in the USP/NF.
Research Triangle Park, NC 27709
ZANTAC and EFFERdose are registered trademarks of Warner-Lambert Company, used under
license.
14
MULTISTIX is a registered trademark of Bayer Healthcare LLC.
©2009, GlaxoSmithKline. All rights reserved.
April 2009
ZNT:5PI
15
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018703s068,019675s035,020251s019lbl.pdf', 'application_number': 20251, 'submission_type': 'SUPPL ', 'submission_number': 19}
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_______________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use DEPO
PROVERA CI safely and effectively. See full prescribing information for
DEPO-PROVERA CI.
DEPO-PROVERA CI (medroxyprogesterone acetate) injectable
suspension, for intramuscular use
Initial U.S. Approval: 1959
WARNING: LOSS OF BONE MINERAL DENSITY
•
Women who use Depo-Provera Contraceptive Injection (Depo-
Provera CI) may lose significant bone mineral density. Bone loss is
greater with increasing duration of use and may not be completely
reversible. (5.1)
•
It is unknown if use of Depo-Provera Contraceptive Injection during
adolescence or early adulthood, a critical period of bone accretion,
will reduce peak bone mass and increase the risk for osteoporotic
fracture in later life. (5.1)
•
Depo-Provera Contraceptive Injection should not be used as a long-
term birth control method (i.e., longer than 2 years) unless other
birth control methods are considered inadequate. (5.1)
----------------------------RECENT MAJOR CHANGES--------------------------
Boxed Warning: Loss of Bone Mineral Density
10/2010
Warnings and Precautions; Loss of Bone Mineral Density (5.1)
10/2010
------------------------INDICATIONS AND USAGE------------------------
• Depo-Provera CI is a progestin indicated only for the prevention of
pregnancy. (1)
-----------------------DOSAGE AND ADMINISTRATION----------------
• The recommended dose is 150 mg of Depo-Provera CI every 3 months (13
weeks) administered by deep, intramuscular (IM) injection in the gluteal
or deltoid muscle. (2.1)
----------------------------DOSAGE FORMS AND STRENGTHS---------------
•
Vials containing sterile aqueous suspension: 150 mg per mL (3)
•
Prefilled syringes: prefilled syringes are available packaged with 22-gauge
x 1 1/2 inch BD SafetyGlide Needles (3)
------------------------------------CONTRAINDICATIONS-------------------------
• Known or suspected pregnancy or as a diagnostic test for pregnancy. (4)
• Active thrombophlebitis, or current or past history of thromboembolic
disorders, or cerebral vascular disease. (4)
• Known or suspected malignancy of breast. (4)
• Known hypersensitivity to Depo-Provera CI (medroxyprogesterone
acetate or any of its other ingredients). (4)
• Significant liver disease. (4)
• Undiagnosed vaginal bleeding. (4)
------------------------------WARNINGS AND PRECAUTIONS-----------------
•
Thromboembolic Disorders: Discontinue Depo-Provera CI in patients
who develop thrombosis (5.2)
•
Cancer Risks: Monitor women with breast nodules or a strong family
history of breast cancer carefully. (5.3)
•
Ectopic Pregnancy: Consider ectopic pregnancy if a woman using
Depo-Provera CI becomes pregnant or complains of severe abdominal
pain. (5.4)
•
Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical
treatment. (5.5)
•
Liver Function: Discontinue Depo-Provera CI if jaundice or
disturbances of liver function develop (5.6)
•
Carbohydrate Metabolism: Monitor diabetic patients carefully. (5.11)
----------------------------------ADVERSE REACTIONS---------------------------
Most common adverse reactions (incidence >5%) are: menstrual irregularities
(bleeding or spotting) 57% at 12 months, 32% at 24 months, abdominal
pain/discomfort 11%, weight gain > 10 lbs at 24 months 38%, dizziness 6%,
headache 17%, nervousness 11%, decreased libido 6%. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
1-800-438-1985 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 contraceptive drug products. Counsel
patients to use a back-up method or alternative method of contraception when
enzyme inducers are used with Depo-Provera CI. (7.1)
-------------------------------USE IN SPECIFIC POPULATIONS----------------
•
Nursing Mothers: Detectable amounts of drug have been identified in the
milk of mothers receiving Depo-Provera CI. (8.2)
•
Pediatric Patients: Depo-Provera CI is not indicated before menarche.
(8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 7/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LOSS OF BONE MINERAL DENSITY
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Prevention of Pregnancy
2.2 Switching from other Methods of Contraception
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Loss of Bone Mineral Density
5.2 Thromboembolic Disorders
5.3 Cancer Risks
5.4 Ectopic Pregnancy
5.5 Anaphylaxis and Anaphylactoid Reaction
5.6 Liver Function
5.7 Convulsions
5.8 Depression
5.9 Bleeding Irregularities
5.10 Weight Gain
5.11 Carbohydrate Metabolism
5.12 Lactation
5.13 Fluid Retention
5.14 Return of Fertility
5.15 Sexually Transmitted Diseases
5.16 Pregnancy
5.17 Monitoring
5.18 Interference with Laboratory Tests
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-marketing Experience
7
DRUG INTERACTIONS
7.1 Changes in Contraceptive Effectiveness Associated with Co-
Administration of Other Products
7.2 Laboratory Test Interactions
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
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 BMD Changes in Adult Women
14.3 BMD Changes in Adolescent Females (12-18 years of age)
14.4 Relationship of fracture incidence to use of DMPA 150 mg IM or
non-use by women of reproductive age
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
1
Reference ID: 2980748
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: LOSS OF BONE MINERAL DENSITY
Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density.
Bone loss is greater with increasing duration of use and may not be completely reversible.
It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a
critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic
fracture in later life.
Depo-Provera Contraceptive Injection should not be used as a long-term birth control method (i.e.,
longer than 2 years) unless other birth control methods are considered inadequate. [(See Warnings and
Precautions (5.1)].
1 INDICATIONS AND USAGE
Depo-Provera CI is indicated only for the prevention of pregnancy. The loss of bone mineral density
(BMD) in women of all ages and the impact on peak bone mass in adolescents should be considered,
along with the decrease in BMD that occurs during pregnancy and/or lactation, in the risk/benefit
assessment for women who use Depo-Provera CI long-term [see Warnings and Precautions (5.1)].
2 DOSAGE AND ADMINISTRATION
2.1
Prevention of Pregnancy
Both the 1 mL vial and the 1 mL prefilled syringe of Depo-Provera CI should be vigorously shaken just
before use to ensure that the dose being administered represents a uniform suspension.
The recommended dose is 150 mg of Depo-Provera CI every 3 months (13 weeks) administered by deep
IM injection in the gluteal or deltoid muscle. Depo-Provera CI should not be used as a long-term birth
control method (i.e. longer than 2 years) unless other birth control methods are considered inadequate.
Dosage does not need to be adjusted for body weight [See Clinical Studies (14.1)].
To ensure the patient is not pregnant at the time of the first injection, the first injection should be given
ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not
breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval
between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant
before administering the drug. The efficacy of Depo-Provera CI depends on adherence to the dosage
schedule of administration.
2.2
Switching from other Methods of Contraception
When switching from other contraceptive methods, Depo-Provera CI should be given in a manner that
ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g.,
patients switching from oral contraceptives should have their first injection of Depo-Provera CI on the day
after the last active tablet or at the latest, on the day following the final inactive tablet).
3 DOSAGE FORMS AND STRENGTHS
Sterile Aqueous suspension: 150mg/ml
Prefilled syringes are available packaged with 22-gauge x 1 1/2 inch BD SafetyGlideTM Needles.
2
Reference ID: 2980748
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 Depo-Provera CI is contraindicated in the following conditions:
• Known or suspected pregnancy or as a diagnostic test for pregnancy.
• Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular
disease [see Warnings and Precautions (5.2)].
• Known or suspected malignancy of breast [see Warnings and Precautions (5.3)].
• Known hypersensitivity to Depo-Provera CI (medroxyprogesterone acetate) or any of its other
ingredients [see Warnings and Precautions (5.5)].
• Significant liver disease [see Warnings and Precautions (5.6)].
• Undiagnosed vaginal bleeding [see Warnings and Precautions (5.9)].
5 WARNINGS AND PRECAUTIONS
5.1
Loss of Bone Mineral Density
Use of Depo-Provera CI reduces serum estrogen levels and is associated with significant loss of bone
mineral density (BMD). This loss of BMD is of particular concern during adolescence and early
adulthood, a critical period of bone accretion. It is unknown if use of Depo-Provera CI by younger
women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life.
After discontinuing Depo-Provera CI in adolescents, mean BMD loss at total hip and femoral neck did not
fully recover by 60 months (240 weeks) post-treatment [see Clinical Studies (14.3)]. Similarly, in adults,
there was only partial recovery of mean BMD at total hip, femoral neck and lumbar spine towards
baseline by 24 months post-treatment. [See Clinical Studies (14.2).]
Depo-Provera CI should not be used as a long-term birth control method (i.e., longer than 2 years) unless
other birth control methods are considered inadequate. BMD should be evaluated when a woman needs to
continue to use Depo-Provera CI long-term. In adolescents, interpretation of BMD results should take
into account patient age and skeletal maturity.
Other birth control methods should be considered in the risk/benefit analysis for the use of Depo-Provera CI
in women with osteoporosis risk factors. Depo-Provera CI can pose an additional risk in patients with risk
factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa,
strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as
anticonvulsants or corticosteroids). Although there are no studies addressing whether calcium and Vitamin
D may lessen BMD loss in women using Depo-Provera CI, all patients should have adequate calcium and
Vitamin D intake.
5.2 Thromboembolic Disorders
There have been reports of serious thrombotic events in women using Depo-Provera CI (150 mg).
However, Depo-Provera CI has not been causally associated with the induction of thrombotic or
thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with Depo-
Provera CI should discontinue treatment unless she has no other acceptable options for birth control.
Do not re-administer Depo-Provera CI pending examination if there is a sudden partial or complete loss of
vision or if there is a sudden onset of proptosis, diplopia, or migraine. Do not re-administer if examination
reveals papilledema or retinal vascular lesions.
3
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.3 Cancer Risks
Breast Cancer
Women who currently have or have had breast cancer should not use hormone contraceptives, including
Depo-Provera CI, because breast cancer may be hormonally sensitive. Women with a strong family history
of breast cancer or who have breast nodules should be monitored with particular care.
A pooled analysis from two case-control studies, the World Health Organization Study and the New
Zealand Study, reported the relative risk (RR) of breast cancer for women who had ever used Depo-
Provera CI as 1.1 (95% confidence interval [CI] 0.97 to 1.4). Overall, there was no increase in risk with
increasing duration of use of Depo-Provera CI. The RR of breast cancer for women of all ages who had
initiated use of Depo-Provera CI within the previous 5 years was estimated to be 2.0 (95% CI 1.5 to 2.8).
The World Health Organization Study, a component of the pooled analysis described above, showed an
increased RR of 2.19 (95% CI 1.23 to 3.89) of breast cancer associated with use of Depo-Provera CI in
women whose first exposure to drug was within the previous 4 years and who were under 35 years of age.
However, the overall RR for ever-users of Depo-Provera CI was 1.2 (95% CI 0.96 to 1.52).
The National Cancer Institute reports an average annual incidence rate for breast cancer for US women,
all races, age 15 to 34 years, of 8.7 per 100,000. A RR of 2.19, thus, increases the possible risk from 8.7
to 19.0 cases per 100,000 women.
Cervical Cancer
A statistically nonsignificant increase in RR estimates of invasive squamous-cell cervical cancer has been
associated with the use of Depo-Provera CI in women who were first exposed before the age of 35 years
(RR 1.22 to 1.28 and 95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive
squamous-cell cervical cancer in women who ever used Depo-Provera CI was estimated to be 1.11 (95%
CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were
observed.
Other Cancers
Long-term case-controlled surveillance of users of Depo-Provera CI found no overall increased risk of
ovarian or liver cancer.
5.4
Ectopic Pregnancy
Be alert to the possibility of an ectopic pregnancy among women using Depo-Provera CI who become
pregnant or complain of severe abdominal pain.
5.5 Anaphylaxis and Anaphylactoid Reaction
Anaphylaxis and anaphylactoid reaction have been reported with the use of Depo-Provera CI. Institute
emergency medical treatment if an anaphylactic reaction occurs.
5.6
Liver Function
Discontinue Depo-Provera CI use if jaundice or acute or chronic disturbances of liver function develop. Do
not resume use until markers of liver function return to normal and Depo-Provera CI causation has been
excluded.
5.7
Convulsions
There have been a few reported cases of convulsions in patients who were treated with Depo-Provera CI.
Association with drug use or pre-existing conditions is not clear.
4
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.8
Depression
Monitor patients who have a history of depression and do not readminister Depo-Provera CI if depression
recurs.
5.9 Bleeding Irregularities
Most women using Depo-Provera CI experience disruption of menstrual bleeding patterns. Altered
menstrual bleeding patterns include amenorrhea, irregular or unpredictable bleeding or spotting,
prolonged spotting or bleeding, and heavy bleeding. Rule out the possibility of organic pathology if
abnormal bleeding persists or is severe, and institute appropriate treatment.
As women continue using Depo-Provera CI, fewer experience irregular bleeding and more experience
amenorrhea. In clinical studies of Depo-Provera CI, by month 12 amenorrhea was reported by 55% of
women, and by month 24, amenorrhea was reported by 68% of women using Depo-Provera CI.
5.10
Weight Gain
Women tend to gain weight while on therapy with Depo-Provera CI. From an initial average body weight of
136 lb, women who completed 1 year of therapy with Depo-Provera CI gained an average of 5.4 lb. Women
who completed 2 years of therapy gained an average of 8.1 lb. Women who completed 4 years gained an
average of 13.8 lb. Women who completed 6 years gained an average of 16.5 lb. Two percent of women
withdrew from a large-scale clinical trial because of excessive weight gain.
5.11
Carbohydrate Metabolism
A decrease in glucose tolerance has been observed in some patients on Depo-Provera CI treatment. Monitor
diabetic patients carefully while receiving Depo-Provera CI.
5.12
Lactation
Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. In
nursing mothers treated with Depo-Provera CI, milk composition, quality, and amount are not adversely
affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for
developmental and behavioral effects through puberty. No adverse effects have been noted.
5.13
Fluid Retention
Because progestational drugs including Depo-Provera CI may cause some degree of fluid retention, monitor
patients with conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and
cardiac or renal dysfunction.
5.14
Return of Fertility
Return to ovulation and fertility is likely to be delayed after stopping Depo-Provera CI. In a large US study
of women who discontinued use of Depo-Provera CI to become pregnant, data are available for 61% of
them. Of the 188 women who discontinued the study to become pregnant, 114 became pregnant. Based on
Life-Table analysis of these data, it is expected that 68% of women who do become pregnant may conceive
within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the
last injection. The median time to conception for those who do conceive is 10 months following the last
injection with a range of 4 to 31 months, and is unrelated to the duration of use. No data are available for
39% of the patients who discontinued Depo-Provera CI to become pregnant and who were lost to follow-up
or changed their mind.
5
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.15
Sexually Transmitted Diseases
Patients should be counseled that Depo-Provera CI does not protect against HIV infection (AIDS) and other
sexually transmitted diseases.
5.16
Pregnancy
Although Depo-Provera CI should not be used during pregnancy, there appears to be little or no increased
risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate
injections in early pregnancy. Neonates exposed to medroxyprogesterone acetate in-utero and followed to
adolescence showed no evidence of any adverse effects on their health including their physical, intellectual,
sexual or social development.
5.17
Monitoring
A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a
blood pressure check and for other indicated healthcare.
5.18
Interference with Laboratory Tests
The use of Depo-Provera CI may change the results of some laboratory tests, such as coagulation factors,
lipids, glucose tolerance, and binding proteins. [See Drug Interactions (7.2).]
6 ADVERSE REACTIONS
The following important adverse reactions observed with the use of Depo-Provera CI are discussed in greater
detail in the Warnings and Precautions section (5):
•
Loss of Bone Mineral Density [see Warnings and Precautions (5.1)]
•
Thromboembolic disease [see Warnings and Precautions (5.2)]
•
Breast Cancer [see Warnings and Precautions (5.3)]
•
Anaphylaxis and Anaphylactoid Reactions [see Warnings and Precautions (5.5)]
•
Bleeding Irregularities[see Warnings and Precautions (5.9)]
•
Weight Gain [see Warnings and Precautions (5.10)]
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 trials of another drug and may
not reflect the rates observed in practice.
In the two clinical trials with Depo-Provera CI, over 3,900 women, who were treated for up to 7 years,
reported the following adverse reactions, which may or may not be related to the use of Depo-Provera CI.
The population studied ranges in age from 15 to 51 years, of which 46% were White, 50% Non-White, and
4.9% Unknown race. The patients received 150 mg Depo-Provera CI every 3-months (90 days). The
median study duration was 13 months with a range of 1-84 months. Fifty eight percent of patients remained
in the study after 13 months and 34% after 24 months.
6
Reference ID: 2980748
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 that Were Reported by More than 5% of Subjects
Body System*
Adverse Reactions (Incidence (%))
Body as a Whole
Headache (16.5%)
Abdominal pain/discomfort (11.2%)
Metabolic/Nutritional
Increased weight> 10 lbs at 24 months (37.7%)
Nervous
Nervousness (10.8%)
Dizziness (5.6%)
Libido decreased (5.5%)
Urogenital
Menstrual irregularities:
(bleeding (57.3% at 12 months, 32.1% at 24 months)
amenorrhea (55% at 12 months, 68% at 24 months)
* Body System represented from COSTART medical dictionary.
Table 2 Adverse Reactions that Were Reported by between 1 and 5% of Subjects
Body System*
Adverse Reactions (Incidence (%))
Body as a Whole
Asthenia/fatigue (4.2%)
Backache (2.2%)
Dysmenorrhea (1.7%)
Hot flashes (1.0%)
Digestive
Nausea (3.3%)
Bloating (2.3%)
Metabolic/Nutritional
Edema (2.2%)
Musculoskeletal
Leg cramps (3.7%)
Arthralgia (1.0%)
Nervous
Depression (1.5%)
Insomnia (1.0%)
Skin and Appendages
Acne (1.2%)
No hair growth/alopecia (1.1%)
Rash (1.1%)
Urogenital
Leukorrhea (2.9%)
Breast pain (2.8%)
Vaginitis (1.2%)
* Body System represented from COSTART medical dictionary.
Adverse reactions leading to study discontinuation in ≥ 2% of subjects: bleeding (8.2%), amenorrhea
(2.1%), weight gain (2.0%)
6.2
Post-marketing Experience
The following adverse reactions have been identified during post approval use of Depo-Provera CI.
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.
There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients
taking Depo-Provera CI.
7
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3 Adverse Reactions Reported during Post-Marketing Experience
Body System
Adverse Reactions
Body as a Whole
Chest pain, Allergic reactions, Fever, Pain at injection site, Chills,
Axillary swelling
Cardiovascular
Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis,
Pulmonary embolus, Varicose veins
Digestive
Changes in appetite, Gastrointestinal disturbances, Jaundice,
Excessive thirst, Rectal bleeding
Hematologic and Lymphatic
Anemia, Blood dyscrasia
Musculoskeletal
Osteoporosis
Nervous
Paralysis, Facial palsy, Paresthesia, Drowsiness
Respiratory
Dyspnea and asthma, Hoarseness
Skin and Appendages
Hirsutism, Excessive sweating and body odor, Dry skin,
Scleroderma
Urogenital
Cervical cancer, Breast cancer, Lack of return to fertility,
Unexpected pregnancy, Prevention of lactation, Changes in breast
size, Breast lumps or nipple bleeding, Galactorrhea, Melasma,
Chloasma, Increased libido, Uterine hyperplasia, Genitourinary
infections, Vaginal cysts, Dyspareunia
* Body System represented from COSTART medical dictionary.
7 DRUG INTERACTIONS
7.1
Changes in Contraceptive Effectiveness Associated with Co-Administration of
Other Products
If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including
CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different
method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma
concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives.
Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include:
• barbiturates
• bosentan
• carbamazepine
• felbamate
• griseofulvin
• oxcarbazepine
• phenytoin
• rifampin
• St. John’s wort
• topiramate
HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or
decrease) in the plasma levels of progestin have been noted in some cases of co-administration of HIV
8
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
protease inhibitors. Significant changes (increase or decrease) in the plasma levels of the progestin have
been noted in some cases of co-administration with non-nucleoside reverse transcriptase inhibitors.
Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but
clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations
of synthetic steroids.
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with
hormonal contraceptives or the potential for enzyme alterations.
7.2
Laboratory Test Interactions
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
The following laboratory tests may be affected by progestins including Depo-Provera CI:
(a)
Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol,
testosterone, cortisol).
(b)
Gonadotropin levels are decreased.
(c)
Sex-hormone-binding-globulin concentrations are decreased.
(d)
Protein-bound iodine and butanol extractable protein-bound iodine may increase.
T3-uptake values may decrease.
(e)
Coagulation test values for prothrombin (Factor II), and
Factors VII, VIII, IX, and X may increase.
(f)
Sulfobromophthalein and other liver function test values may be increased.
(g)
The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both
increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL)
cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Depo-Provera CI should not be administered during pregnancy. [See Contraindications (4) and Warnings
and Precautions (5.16).]
8.3
Nursing Mothers
Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. [See
Warnings and Precautions (5.12).]
8.4
Pediatric Use
Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI is associated with significant
loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a critical
period of bone accretion. In adolescents, interpretation of BMD results should take into account patient
age and skeletal maturity. It is unknown if use of Depo-Provera CI by younger women will reduce peak
bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of
BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult
women.
8.5
Geriatric Use
This product has not been studied in post-menopausal women and is not indicated in this population.
9
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
s
truc
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8.6
Renal Impairment
The effect of renal impairment on Depo-Provera CI pharmacokinetics has not been studied.
8.7
Hepatic Impairment
The effect of hepatic impairment on Depo-Provera CI pharmacokinetics has not been studied. Depo-
Provera CI should not be used by women with significant liver disease and should be discontinued if
jaundice or disturbances of liver function occur. [See Contraindications (4) and Warnings and Precautions
(5.6).]
11 DESCRIPTION
Depo-Provera CI contains medroxyprogesterone acetate, a derivative of progesterone, as its active
ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a
white to off-white; odorless crystalline powder that is stable in air and that melts between 200°C and 210°C.
It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol,
slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-,
(6α-).
The structural formula is as follows:
Depo-Provera CI for intramuscular (IM) injection is available in vials and prefilled syringes, each
containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL.
Each mL contains:
Medroxyprogesterone acetate
Polyethylene glycol 3350
Polysorbate 80
Sodium chloride
Methylparaben
Propylparaben
Water for injection
150 mg
28.9 mg
2.41 mg
8.68 mg
1.37 mg
0.150 mg
quantity sufficient
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
10
Reference ID: 2980748
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
Depo-Provera CI (medroxyprogesterone acetate [MPA]), when administered at the recommended dose to
women every 3 months, inhibits the secretion of gonadotropins which, in turn, prevents follicular
maturation and ovulation and results in endometrial thinning. These actions produce its contraceptive
effect.
12.2
Pharmacodynamics
No specific pharmacodynamic studies were conducted with Depo-Provera CI.
12.3
Pharmacokinetics
Absorption
Following a single 150 mg IM dose of Depo-Provera CI in eight women between the ages of 28 and 36
years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay
procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL.
Distribution
Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No
binding of MPA occurs with sex-hormone-binding globulin (SHBG).
Metabolism
MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A
and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a
combination of these positions, resulting in more than 10 metabolites.
Excretion
The concentrations of medroxyprogesterone acetate decrease exponentially until they become
undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted
radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life
for medroxyprogesterone acetate following IM administration of Depo-Provera CI is approximately 50
days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates
with only minor amounts excreted as sulfates.
Specific Populations
The effect of hepatic and/or renal impairment on the pharmacokinetics of Depo-Provera CI is unknown.
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
[See Warnings and Precautions, (5.3, 5.14, and 5.16).]
14 CLINICAL STUDIES
14.1
Contraception
In five clinical studies using Depo-Provera CI, the 12-month failure rate for the group of women treated
with Depo-Provera CI was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of
Depo-Provera CI is dependent on the patient returning every 3 months (13 weeks) for reinjection.
11
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14.2 Bone Mineral Density (BMD) Changes in Adult Women
In a controlled, clinical study, adult women using Depo-Provera CI for up to 5 years showed spine and hip
BMD mean decreases of 5–6%, compared to no significant change in BMD in the control group. The
decline in BMD was more pronounced during the first two years of use, with smaller declines in
subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38%
after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and
femoral neck were similar.
After stopping use of Depo-Provera CI (150 mg), there was partial recovery of BMD toward baseline
values during the 2-year post-therapy period. Longer duration of treatment was associated with less
complete recovery during this 2-year period following the last injection. Table 4 shows the change in
BMD in women after 5 years of treatment with Depo-Provera CI and in women in a control group, as well
as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were
available.
Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort
(5 Years of Treatment and 2 Years of Follow-Up)
Time in
Study
Spine
Total Hip
Femoral Neck
Depo-Provera*
Control**
Depo-Provera*
Control**
Depo-Provera*
Control**
5 years
-5.38%
n=33
0.43%
n=105
-5.16%
n=21
0.19%
n=65
-6.12%
n=34
-0.27%
n=106
7 years
-3.13%
n=12
0.53%
n=60
-1.34%
n=7
0.94%
n=39
-5.38%
n=13
-0.11%
n=63
*The treatment group consisted of women who received Depo-Provera CI for 5 years and were then followed for 2
years post-use (total time in study of 7 years).
**The control group consisted of women who did not use hormonal contraception and were followed for 7 years.
14.3 Bone Mineral Density Changes in Adolescent Females (12-18 years of age)
The impact of Depo-Provera CI (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-
label non-randomized clinical study in 389 adolescent females (12-18 years). Use of Depo-Provera CI was
associated with a significant decline from baseline in BMD.
Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections
per Depo-Provera CI user was 9.3. The decline in BMD at total hip and femoral neck was greater with
longer duration of use (see Table 5). The mean decrease in BMD at 240 weeks was more pronounced at
total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).
In general, adolescents increase bone density during the period of growth following menarche, as seen in
the untreated cohort. However, the two cohorts were not matched at baseline for age, gynecologic age,
race, BMD and other factors that influence the rate of acquisition of bone mineral density.
12
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. Mean Percent Change from Baseline in BMD in Adolescents Receiving ≥4
Injections per 60-week Period, by Skeletal Site and Cohort
Duration of
Treatment
Depo-Provera CI
(150 mg IM)
Unmatched, Untreated
Cohort
N
Mean % Change
N
Mean % Change
Total Hip BMD
Week 60 (1.2 years)
Week 120 (2.3 years)
Week 240 (4.6 years)
113
73
28
-2.75
-5.40
-6.40
166
109
84
1.22
2.19
1.71
Femoral Neck BMD
Week 60
Week 120
Week 240
113
73
28
-2.96
-5.30
-5.40
166
108
84
1.75
2.83
1.94
Lumbar Spine BMD
Week 60
Week 120
Week 240
114
73
27
-2.47
-2.74
-2.11
167
109
84
3.39
5.28
6.40
BMD recovery post-treatment in adolescent women
Longer duration of treatment and smoking were associated with less recovery of BMD following the last
injection of Depo-Provera CI. Table 6 shows the extent of recovery of BMD up to 60 months post
treatment for adolescent women who received Depo-Provera CI for two years or less compared to more
than two years. Post-treatment follow-up showed that, in women treated for more than two years, only
lumbar spine BMD recovered to baseline levels after treatment was discontinued. Subjects treated with
Depo-Provera for more than two years did not recover to their baseline BMD level at femoral neck and
total hip even up to 60 months post-treatment. Adolescent women in the untreated cohort gained BMD
throughout the trial period (data not shown).
13
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6: Extent of BMD Recovery (Months Post-Treatment) in Adolescents by Years of
Depo Provera CI Use (2 Years or Less vs. More than 2 Years)
Duration of
Treatment
2 years or less
More than 2 years
N
Mean % Change
from baseline
N
Mean % Change from
baseline
Total Hip BMD
End of Treatment
49
-1.5%
49
-6.2%
12 M post-treatment
33
-1.4%
24
-4.6%
24 M post-treatment
18
0.3%
17
-3.6%
36 M post-treatment
12
2.1%
11
-4.6%
48 M post-treatment
10
1.3%
9
-2.5%
60 M post-treatment
3
0.2%
2
-1.0%
Femoral Neck BMD
End of Treatment
49
-1.6%
49
-5.8%
12 M post-treatment
33
-1.4%
24
-4.3%
24 M post-treatment
18
0.5%
17
-3.8%
36 M post-treatment
12
1.2%
11
-3.8%
48 M post-treatment
10
2.0%
9
-1.7%
60 M post-treatment
3
1.0%
2
-1.9%
Lumbar Spine BMD
End of Treatment
49
-0.9%
49
-3.5%
12 M post-treatment
33
0.4%
23
-1.1%
24 M post-treatment
18
2.6%
17
1.9%
36 M post-treatment
12
2.4%
11
0.6%
48 M post-treatment
10
6.5%
9
3.5%
60 M post-treatment
3
6.2%
2
5.7%
14.4
Relationship of fracture incidence to use of DMPA 150 mg IM or non-use by
women of reproductive age
A retrospective cohort study to assess the association between DMPA injection and the incidence of bone
fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture
were compared between DMPA users and contraceptive users who had no recorded use of DMPA. The
Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95%
CI 1.35, 1.47). It is not known if this is due to DMPA use or to other related lifestyle factors that have a
bearing on fracture rate.
In the study, when cumulative exposure to DMPA was calculated, the fracture rate in users who received
fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is
not clear that cumulative exposure, which may include periods of intermittent use separated by periods of
non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.
There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study
overall, and the incidence of osteoporotic fractures was not found to be higher in DMPA users compared
to non-users. Importantly, this study could not determine whether use of DMPA has an effect on fracture
rate later in life.
14
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
16 HOW SUPPLIED/STORAGE AND HANDLING
Depo-Provera CI is supplied in the following strengths and package configurations:
Package
Configuration
Strength
NDC
Depo-Provera CI (medroxyprogesterone acetate sterile aqueous
suspension 150 mg/mL)
1 mL vial
150 mg/mL
NDC 0009-0746-30
25 x 1 mL vials
150 mg/mL
NDC 0009-0746-35
1 mL prefilled
syringe
150 mg/mL
NDC 0009-7376-01
6 x 1 mL prefilled
syringes
150 mg/mL
NDC 0009-7376-02
24 x 1 mL prefilled
syringes
150 mg/mL
NDC 0009-7376-03
Depo-Provera CI prefilled syringes packaged with 22 gauge x 1 1/2
inch BD SafetyGlideTM Needles
1 mL prefilled
syringe
150 mg/mL
NDC 0009-7376-04
6 x 1 mL prefilled
syringes
150 mg/mL
NDC 0009-7376-05
24 x 1 mL prefilled
syringes
150 mg/mL
NDC 0009-7376-06
Vials MUST be stored upright at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
17 PATIENT COUNSELING INFORMATION
“See FDA-approved patient labeling (Patient Information).”
• Advise patients at the beginning of treatment that their menstrual cycle may be disrupted and that irregular
and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea
as treatment with Depo-Provera CI continues, without other therapy being required.
• Counsel patients that this product does not protect against HIV infection (AIDS) and other sexually
transmitted diseases.
• Counsel patients on Warnings and Precautions associated with use of Depo-Provera CI.
• Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers
are used with Depo-Provera CI.
LAB-0149-6.1
Revised July 2011
15
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
Depo-Provera® (DEP-po pro-VAIR-ah) CI
(medroxyprogesterone acetate injectable suspension)
Contraceptive Injection
Read this Patient Information carefully before you decide if Depo-Provera CI is right for
you. This information does not take the place of talking with your gynecologist or other
healthcare provider who specializes in women’s health. If you have any questions about
Depo-Provera CI, ask your healthcare provider. You should also learn about other birth
control methods to choose the one that is best for you.
What is the most important information I should know about Depo-Provera CI?
Depo-Provera CI can cause serious side effects, including:
• Use of Depo-Provera CI may cause you to lose calcium stored in your bone
and decrease your bone mass. The longer you use Depo-Provera CI, the
greater your loss of calcium from your bones. Your bones may not
recover completely when you stop using Depo-Provera CI.
• If you use Depo-Provera CI continuously for a long time (for more than 2
years), it may increase the risk of weak, porous bones (osteoporosis) that
could increase the risk of broken bones, especially after menopause.
• You should not use Depo-Provera CI for more than two years unless you
cannot use other birth control methods.
• It is not known if your risk of developing osteoporosis is greater if you are
a teenager or young adult when you start to use Depo-Provera CI. (See
“What are the possible side effects of Depo-Provera CI?”).
Depo-Provera CI is intended to prevent pregnancy. Depo-Provera CI does not
protect against HIV infection (AIDS) and other sexually transmitted diseases
(STDs).
What is Depo-Provera CI?
Depo-Provera CI is a progestin hormone birth control method that is given by injection
(a shot) to prevent pregnancy.
How well does Depo-Provera CI work?
Your chance of getting pregnant depends on how well you follow the directions for taking
your Depo-Provera CI. The more carefully you follow the directions (such as returning
every 3 months for your next injection), the less chance you have of getting pregnant.
In clinical studies, about 1 out of 100 women got pregnant during the first year that
they used Depo-Provera CI.
The following chart shows the chance of getting pregnant for women who use different
16
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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. flow chart
How should I take Depo-Provera CI?
• Depo-Provera CI is given by your healthcare provider as a shot into your muscle
(intramuscular injection). The shot is given in your buttock or upper arm 1 time
every 3 months. At the end of the 3 months, you will need to return to your
healthcare provider for your next injection in order to continue your protection
against pregnancy.
17
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• To make sure that you are not pregnant before you take Depo-Provera CI,
the first injection should be given only:
o during the first 5 days of a normal menstrual period, or
o within the first 5 days after giving birth, if you are not breastfeeding, or
o at the 6th week after giving birth, if you are feeding your baby only
breastmilk.
• Depo-Provera CI may be given at other times than those listed above, but you will
likely need to have a pregnancy test first to show that you are not pregnant.
• During treatment with Depo-Provera CI, you should see your healthcare provider
every year for a blood pressure check and other healthcare needs.
Who Should Not Use Depo-Provera CI?
Do not use Depo-Provera CI if you:
• are pregnant or think you might be pregnant
• have bleeding from your vagina that has not been explained
• have breast cancer now or in the past, or think you have breast cancer
• have had a stroke
• ever had blood clots in your arms, legs or lungs
• have problems with your liver or liver disease
• are allergic to medroxyprogesterone acetate or any of the other ingredients in
Depo-Provera CI. See the end of this leaflet for a complete list of ingredients in
Depo-Provera CI.
What should I tell my healthcare provider before taking Depo-Provera CI?
Before taking Depo-Provera CI, tell your healthcare provider if you have:
• risk factors for weak bones (osteoporosis) such as bone disease, use alcohol or
smoke regularly, anorexia nervosa, or a strong family history of osteoporosis
• irregular or lighter than usual menstrual periods
• breast cancer now or in the past, or think you have breast cancer
• a family history of breast cancer
• an abnormal mammogram (breast X-ray), fibrocystic breast disease, breast
nodules or lumps, or bleeding from your nipples
• kidney problems
• high blood pressure
• had a stroke
• had blood clots in your arms, legs or lungs
• migraine headaches
• asthma
• epilepsy (convulsions or seizures)
• diabetes
• depression or a history of depression
• any other medical conditions
If you are breastfeeding or plan to breastfeed, Depo-Provera CI can pass into your
breast milk. Talk to your healthcare provider about the best way to feed your baby if
you take Depo-Provera CI.
18
Reference ID: 2980748
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all of the medicines you take, including prescription
and nonprescription medicines, vitamins, and herbal supplements.
Depo-Provera CI and certain other medicines may affect each other, causing serious side
effects. Sometimes the doses of other medicines may need to be changed while you are
taking Depo-Provera CI.
Some medicines may make Depo-Provera CI less effective at preventing pregnancy,
including those listed below.
Especially tell your healthcare provider if you take:
• medicine to help you sleep
• bosentan
• medicine for seizures
• griseofulvin
• an antibiotic
• medicine for HIV (AIDS)
• St. John’s wort
Know the medicines you take. Keep a list of your medicines with you to show your
healthcare provider or pharmacist before you first start taking Depo-Provera CI or when
you get a new medicine.
Follow your healthcare provider’s instructions about using a back-up method of
birth control if you are taking medicines that may make Depo-Provera CI less
effective.
What are the possible side effects of Depo-Provera CI?
Depo-Provera CI can cause serious side effects, including:
• Effect on the bones: See “What is the most important information I should know
about Depo-Provera CI?”.
Teenage years are the most important years to gain bone strength. The decrease
in calcium in your bones is of most concern if you are a teenager or have the
following problems:
• bone disease
• an eating disorder (anorexia nervosa)
• a strong family history of osteoporosis
• you take a drug that can lower the amount of calcium in your bones (drugs for
epilepsy or steroid drugs)
• you drink a lot of alcohol (more than 2 drinks a day)
• you smoke
If you need a birth control method for more than 2 years, your healthcare provider
may switch you to another birth control method instead of using Depo-Provera CI.
19
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If you continue using Depo-Provera CI, your healthcare provider may ask you to
have a bone test, especially if you have other risks for weak bones.
When Depo-Provera CI is stopped, your bones may start to regain calcium.
However, in a study of teenage girls who used Depo-Provera CI for more than 2
years, their hip bones did not completely recover by 5 years after they stopped
using Depo-Provera CI. Taking calcium and Vitamin D and exercising daily may
lessen the loss of calcium from your bones.
• increased risk of breast cancer. Studies of women who have used different forms
of contraception found that women under 35 years of age who first used Depo-
Provera CI within the previous 4 to 5 years may have a slightly increased risk of
developing breast cancer.
• blood clots in your arms, legs, lungs, and eyes
• stroke
• a pregnancy outside of your uterus (ectopic pregnancy). Ectopic pregnancy is a
medical emergency that often requires surgery. Ectopic pregnancy can cause
internal bleeding, infertility, and even death.
• allergic reactions. Severe allergic reactions have been reported in some women
using Depo-Provera CI.
• loss of vision or other eye problems
• migraine headaches
• depression
• convulsions or seizures
• liver problems
Call your healthcare provider right away if you have:
• sharp chest pain, coughing up blood, or sudden shortness of breath (indicating a
possible clot in the lung)
• sudden severe headache or vomiting, dizziness or fainting, problems with your
eyesight or speech, weakness, or numbness in an arm or leg (indicating a possible
stroke)
• severe pain or swelling in the calf (indicating a possible clot in the leg)
• sudden blindness, partial or complete (indicating a possible clot in the blood
vessels of the eye)
• unusually heavy vaginal bleeding
• severe pain or tenderness in the lower abdominal area
• persistent pain, pus, or bleeding at the injection site
• yellowing of the eyes or skin
• hives or difficulty breathing
The most common side effects of Depo-Provera CI include:
• irregular vaginal bleeding, such as lighter or heavier menstrual bleeding, or
continued spotting
• weight gain. You may experience weight gain while you are using Depo-Provera
CI. About two-thirds of the women who used Depo-Provera CI in the clinical trials
20
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
reported a weight gain of about 5 pounds during the first year of use. You may
continue to gain weight after the first year. Women who used Depo-Provera CI for
2 years gained an average of 8 pounds over those 2 years.
• abdominal pain
• headache
• weakness
• tiredness
• nervousness
• dizziness
Tell your healthcare provider if you have any side effect that bothers you or does not go
away.
These are not all the possible side effects of Depo-Provera CI. 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.
What other information should I know before choosing Depo-Provera CI?
• Pregnancy. When you take Depo-Provera CI every 3 months, your chance of
getting pregnant is very low. You could miss a period or have a light period and
not be pregnant. If you miss 1 or 2 periods and think you might be pregnant, see
your healthcare provider as soon as possible. You should not use Depo-Provera CI
if you are pregnant. However, Depo-Provera CI taken by accident during
pregnancy does not seem to cause birth defects.
• Nursing Mothers. Although Depo-Provera CI can be passed to the nursing baby
in the breast milk, no harmful effects on babies have been found. Depo-Provera CI
does not stop the breasts from producing milk, so it can be used by nursing
mothers. However, to minimize the amount of Depo-Provera CI that is passed to
the baby in the first weeks after birth, you should wait until your baby is 6 weeks
old before you start using Depo-Provera CI for birth control.
How will Depo-Provera CI change my periods?
• Change in normal menstrual cycle. The side effect reported most frequently
by women who use Depo-Provera CI for birth controls is a change in their normal
menstrual cycle. During the first year of using Depo-Provera CI, you might have
one or more of the following changes:
o irregular or unpredictable bleeding or spotting
o an increase or decrease in menstrual bleeding
o no bleeding at all. In clinical studies of Depo-Provera CI, 55% of women
reported no menstrual bleeding (amenorrhea) after one year of use and
68% of women reported no menstrual bleeding after two years of use.
• Missed period. During the time you are using Depo-Provera CI for birth controls,
you may skip a period, or your periods may stop completely. If you have been
receiving your shot of Depo-Provera CI regularly every 3 months, then you are
21
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
probably not pregnant. However, if you think that you may be pregnant, see your
healthcare provider.
Unusually heavy or continuous bleeding is not a usual effect of Depo-Provera CI and if
this happens you should see your healthcare provider right away.
With continued use of Depo-Provera CI, bleeding usually decreases and many women
stop having periods completely. When you stop using Depo-Provera CI your menstrual
period will usually, in time, return to its normal cycle.
What if I want to become pregnant?
Because Depo-Provera CI is a long-acting birth control method, it takes some time after
your last shot for its effect to wear off. Most women who try to get pregnant after using
Depo-Provera CI get pregnant within 18 months after their last shot. The length of time
you use Depo-Provera CI has no effect on how long it takes you to become pregnant
after you stop using it.
General Information about Depo-Provera CI
Medicines are sometimes prescribed for conditions that are not mentioned in patient
information leaflets. This leaflet summarizes the most important information about
Depo-Provera CI. If you would like more information, talk with your healthcare provider.
You can ask your healthcare provider for information about Depo-Provera CI that is
written for healthcare providers.
What are the ingredients in Depo-Provera CI?
Active ingredient: medroxyprogesterone acetate
Inactive ingredients: polyethylene glycol 3350, polysorbate 80, sodium chloride,
methylparaben, propylparaben, and water for injection. When necessary, pH is adjusted
with sodium hydroxide or hydrochloric acid, or both. company logo
LAB-0148-6.1
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised July 2011
22
Reference ID: 2980748
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020246s035lbl.pdf', 'application_number': 20246, 'submission_type': 'SUPPL ', 'submission_number': 35}
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NDA 20-258/S-019
Page 3
IOPIDINE® 0.5%
(apraclonidine ophthalmic solution)
0.5% As Base
DESCRIPTION: IOPIDINE® 0.5% Ophthalmic Solution contains apraclonidine hydrochloride, an
alpha adrenergic agonist, in a sterile isotonic solution for topical application to the eye. Apraclonidine
hydrochloride is a white to off-white powder and is highly soluble in water. Its chemical name is 2-[(4-
amino-2,6 dichlorophenyl) imino]imidazolidine-, monohydrochloride with an empirical formula of
C9H11Cl3N4 and a molecular weight of 281.57. The chemical structure of apraclonidine hydrochloride
is:
[Structure]
Each mL of IOPIDINE 0.5% Ophthalmic Solution Contains: Active: apraclonidine hydrochloride
5.75 mg equivalent to apraclonidine base 5 mg; Preservative: benzalkonium chloride 0.01%.
Inactives: sodium chloride, sodium acetate, sodium hydroxide and/or hydrochloric acid (pH 4.4-7.8)
and purified water.
CLINICAL PHARMACOLOGY: Apraclonidine hydrochloride is a relatively selective alpha-2-
adrenergic agonist. When instilled in the eye, IOPIDINE 0.5% Ophthalmic Solution, has the action of
reducing elevated, as well as normal, intraocular pressure (IOP), whether or not accompanied by
glaucoma. Ophthalmic apraclonidine has minimal effect on cardiovascular parameters.
Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the
greater the likelihood of optic nerve damage and visual field loss. IOPIDINE 0.5% Ophthalmic
Solution has the action of reducing IOP. The onset of action of apraclonidine can usually be noted
within one hour, and maximum IOP reduction occurs about three hours after instillation. Aqueous
fluorophotometry studies demonstrate that apraclonidine’s predominant mechanism of action is
reduction of aqueous flow via stimulation of the alpha-adrenergic system.
Repeated dose-response and comparative studies (0.125% - 1.0% apraclonidine) demonstrate that 0.5%
apraclonidine is at the top of the dose/response IOP reduction curve.
The clinical utility of IOPIDINE 0.5% Ophthalmic Solution is most apparent for those glaucoma
patients on maximally tolerated medical therapy. Patients on maximally tolerated medical therapy with
uncontrolled IOP and scheduled to undergo laser trabeculoplasty or trabeculectomy surgery were
enrolled into a double-masked, placebo-controlled, multi-center clinical trial to determine if IOPIDINE
0.5% Ophthalmic Solution, dosed three times daily (TID), could delay the need for surgery for up to
three months.
All patients enrolled into this trial had advanced glaucoma and were undergoing maximally tolerated
medical therapy, i.e., patients were using combinations of a topical beta blocker, sympathomimetics,
parasympathomimetics and oral carbonic anhydrase inhibitors. Patients were considered to be
treatment failures in this study if, in the opinion of the investigators, their IOP was uncontrolled by the
masked study medication or there was evidence of further optic nerve damage or visual field loss, and
surgery was indicated. Of 171 patients receiving masked medication, 84 were treated with IOPIDINE
0.5% Ophthalmic Solution and 87 were treated with placebo (apraclonidine vehicle).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-258/S-019
Page 4
Apraclonidine treatment resulted in a significantly greater percentage of treatment successes compared
to patients treated with placebo. In this placebo-controlled maximum therapy trial, 14.3% of patients
treated with IOPIDINE 0.5% Ophthalmic Solution were discontinued due to adverse events, primarily
allergic-like reactions (12.9%).
The IOP lowering efficacy of IOPIDINE 0.5% Ophthalmic Solution diminishes over time in some
patients. This loss of effect, or tachyphylaxis, appears to be an individual occurrence with a variable
time of onset and should be closely monitored.
An unpredictable decrease of IOP control in some patients and incidence of ocular allergic responses
and systemic side effects may limit the utility of IOPIDINE 0.5% Ophthalmic Solution. However,
patients on maximally tolerated medical therapy may still benefit from the additional IOP reduction
provided by the short-term use of IOPIDINE 0.5% Ophthalmic Solution.
Topical use of IOPIDINE 0.5% Ophthalmic Solution leads to systemic absorption. Studies of
IOPIDINE 0.5% Ophthalmic Solution dosed one drop three times a day in both eyes for 10 days in
normal volunteers yielded mean peak and trough concentrations of 0.9 ng/mL and 0.5 ng/mL,
respectively. The half-life of IOPIDINE® 0.5% (apraclonidine ophthalmic solution) was calculated to
be 8 hours.
IOPIDINE 0.5% Ophthalmic Solution, because of its alpha adrenergic activity, is a vasoconstrictor.
Single dose ocular blood flow studies in monkeys, using the microsphere technique, demonstrated a
reduced blood flow for the anterior segment; however, no reduction in blood flow was observed in the
posterior segment of the eye after a topical dose of IOPIDINE 0.5% Ophthalmic Solution. Ocular
blood flow studies have not been conducted in humans.
INDICATIONS AND USAGE: IOPIDINE 0.5% Ophthalmic Solution is indicated for short-term
adjunctive therapy in patients on maximally tolerated medical therapy who require additional IOP
reduction. Patients on maximally tolerated medical therapy who are treated with IOPIDINE 0.5%
Ophthalmic Solution to delay surgery should have frequent followup examinations and treatment
should be discontinued if the intraocular pressure rises significantly.
The addition of IOPIDINE 0.5% Ophthalmic Solution to patients already using two aqueous
suppressing drugs (i.e., beta-blocker plus carbonic anhydrase inhibitor) as part of their maximally
tolerated medical therapy may not provide additional benefit. This is because IOPIDINE 0.5%
Ophthalmic Solution is an aqueous suppressing drug and the addition of a third aqueous suppressant
may not significantly reduce IOP.
The IOP lowering efficacy of IOPIDINE 0.5% Ophthalmic Solution diminishes over time in some
patients. This loss of effect, or tachyphylaxis, appears to be an individual occurrence with a variable
time of onset and should be closely monitored. The benefit for most patients is less than one month.
CONTRAINDICATIONS: IOPIDINE 0.5% Ophthalmic Solution is contraindicated in patients with
hypersensitivity to apraclonidine or any other component of this medication, as well as systemic
clonidine. It is also contraindicated in patients receiving monoamine oxidase inhibitors (MAO
inhibitors).
WARNINGS: Not for injection or oral ingestion. FOR TOPICAL OPHTHALMIC USE ONLY.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-258/S-019
Page 5
PRECAUTIONS: General: Glaucoma patients on maximally tolerated medical therapy who are
treated with IOPIDINE 0.5% Ophthalmic Solution to delay surgery should have their visual fields
monitored periodically.
Although the topical use of IOPIDINE 0.5% Ophthalmic Solution has not been studied in renal failure
patients, structurally related clonidine undergoes a significant increase in half-life in patients with
severe renal impairment. Close monitoring of cardiovascular parameters in patients with impaired
renal function is advised if they are candidates for topical apraclonidine therapy. Close monitoring of
cardiovascular parameters in patients with impaired liver function is also advised as the systemic
dosage form of clonidine is partly metabolized in the liver.
While the topical administration of IOPIDINE 0.5% Ophthalmic Solution had minimal effect on heart
rate or blood pressure in clinical studies evaluating glaucoma patients, the preclinical pharmacology
profile of this drug suggests that caution should be observed in treating patients with severe,
uncontrolled cardiovascular disease, including hypertension.
IOPIDINE 0.5% Ophthalmic Solution should be used with caution in patients with coronary
insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, Raynaud’s
disease, or thromboangiitis obliterans. Caution and monitoring of depressed patients are advised since
apraclonidine has been infrequently associated with depression.
Apraclonidine can cause dizziness and somnolence. Patients who engage in hazardous activities
requiring mental alertness should be warned of the potential for a decrease in mental alertness while
using apraclonidine.
Topical ocular administration of two drops of 0.5, 1.0 and 1.5% apraclonidine ophthalmic solution to
New Zealand albino rabbits three times daily for one month resulted in sporadic and transient instances
of minimal corneal edema in the 1.5% group only; no histopathological changes were noted in those
eyes.
Use of IOPIDINE 0.5% Ophthalmic Solution can lead to an allergic-like reaction characterized wholly
or in part by the symptoms of hyperemia, pruritus, discomfort, tearing, foreign body sensation, and
edema of the lids and conjunctiva. If ocular allergic-like symptoms occur, IOPIDINE® 0.5%
(apraclonidine ophthalmic solution) therapy should be discontinued.
Patient Information: Do not touch dropper tip to any surface as this may contaminate the contents.
Drug Interactions: Apraclonidine should not be used in patients receiving MAO inhibitors. (See
CONTRAINDICATIONS). Although no specific drug interactions with topical glaucoma drugs or
systemic medications were identified in clinical studies of IOPIDINE 0.5% Ophthalmic Solution, the
possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates,
sedatives, anesthetics) should be considered. Tricyclic antidepressants have been reported to blunt the
hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents
with apraclonidine can lead to a reduction in IOP lowering effect. No data on the level of circulating
catecholamines after apraclonidine withdrawal are available. Caution, however, is advised in patients
taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-258/S-019
Page 6
An additive hypotensive effect has been reported with the combination of systemic clonidine and
neuroleptic therapy. Systemic clonidine may inhibit the production of catecholamines in response to
insulin-induced hypoglycemia and mask the signs and symptoms of hypoglycemia.
Since apraclonidine may reduce pulse and blood pressure, caution in using drugs such as beta-blockers
(ophthalmic and systemic), antihypertensives, and cardiac glycosides is advised. Patients using
cardiovascular drugs concurrently with IOPIDINE 0.5% Ophthalmic Solution should have pulse and
blood pressures frequently monitored. Caution should be exercised with simultaneous use of clonidine
and other similar pharmacologic agents.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No significant change in tumor incidence or
type was observed following two years of oral administration of apraclonidine HCl to rats and mice at
dosages of 1.0 and 0.6 mg/kg, up to 20 and 12 times, respectively, the maximum dose recommended
for human topical ocular use.
Apraclonidine HCl was not mutagenic in a series of in vitro mutagenicity tests, including the Ames
test, a mouse lymphoma forward mutation assay, a chromosome aberration assay in cultured Chinese
hamster ovary (CHO) cells, a sister chromatid exchange assay in CHO cells, and a cell transformation
assay. An in vivo mouse micronucleus assay conducted with apraclonidine HCl also provided no
evidence of mutagenicity.
Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at a dose
of 0.5 mg/kg (5 to 10 times the maximum recommended human dose).
Pregnancy: Pregnancy Category C: Apraclonidine HCl has been shown to have an embryocidal
effect in rabbits when given in an oral dose of 3.0 mg/kg (60 times the maximum recommended human
dose). Dose related maternal toxicity was observed in pregnant rats at 0.3 mg/kg (6 times the
maximum recommended human dose). There are no adequate and well-controlled studies in pregnant
women. IOPIDINE 0.5% Ophthalmic Solution should be used during pregnancy only if the potential
benefit justifies the potential risk to the 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 IOPIDINE 0.5% Ophthalmic Solution is
administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly
and younger patients.
ADVERSE REACTIONS:
In clinical studies the overall discontinuation rate related to IOPIDINE 0.5% Ophthalmic Solution was
15%. The most commonly reported events leading to discontinuation included (in decreasing order of
frequency) hyperemia, pruritus, tearing, discomfort, lid edema, dry mouth, and foreign body sensation.
The following adverse reactions (incidences) were reported in clinical studies of IOPIDINE 0.5%
(apraclonidine ophthalmic solution) as being possibly, probably, or definitely related to therapy:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-258/S-019
Page 7
Ocular
The following adverse reactions were reported in 5 to 15% of patients: discomfort, hyperemia, and
pruritus.
The following adverse reactions were reported in 1 to 5% of the patients: blanching, blurred vision,
conjunctivitis, discharge, dry eye, foreign body sensation, lid edema, and tearing.
The following adverse reactions were reported in less than 1% of the patients: abnormal vision,
blepharitis, blepharoconjunctivitis, conjunctival edema, conjunctival follicles, corneal erosion, corneal
infiltrate, corneal staining, edema, irritation, keratitis, keratopathy, lid disorder, lid erythema, lid
margin crusting, lid retraction, lid scales, pain, photophobia.
Nonocular
Dry mouth occurred in approximately 10% of the patients.
The following adverse reactions were reported in less than 3% of the patients: abnormal coordination,
asthenia, arrhythmia, asthma, chest pain, constipation, contact dermatitis, depression, dermatitis,
dizziness, dry nose, dyspnea, facial edema, headache, insomnia, malaise, myalgia, nausea,
nervousness, paresthesia, parosmia, peripheral edema, pharyngitis, rhinitis, somnolence, and taste
perversion.
Clinical practice: The following events have been identified during postmarketing use of IOPIDINE
0.5% Ophthalmic Solution in clinical practice. Because they are reported voluntarily from a
population of unknown size, estimates of frequency cannot be made. The events, which have been
chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection
to IOPIDINE 0.5% Ophthalmic Solution, or a combination of these factors, include: bradycardia.
OVERDOSAGE: Ingestion of IOPIDINE 0.5% Ophthalmic Solution has been reported to cause
bradycardia, drowsiness, and hypothermia.
Accidental or intentional ingestion of oral clonidine has been reported to cause apnea, arrhythmias,
asthenia, bradycardia, conduction defects, diminished or absent reflexes, dryness of the mouth,
hypotension, hypothermia, hypoventilation, irritability, lethargy, miosis, pallor, respiratory depression,
sedation or coma, seizure, somnolence, transient hypertension, and vomiting.
Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be
maintained. Hemodialysis is of limited value since a maximum of 5% of circulating drug is removed.
DOSAGE AND ADMINISTRATION: One to two drops of IOPIDINE 0.5% Ophthalmic Solution
should be instilled in the affected eye(s) three times daily. Since IOPIDINE 0.5% Ophthalmic Solution
will be used with other ocular glaucoma therapies, an approximate 5 minute interval between
instillation of each medication should be practiced to prevent washout of the previous dose. NOT
FOR INJECTION INTO THE EYE. NOT FOR ORAL INGESTION.
HOW SUPPLIED: IOPIDINE 0.5% Ophthalmic Solution as base in a sterile, isotonic, aqueous
solution containing apraclonidine hydrochloride.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-258/S-019
Page 8
Supplied in plastic ophthalmic DROP-TAINER® dispenser as follows:
5
mL
NDC 0065-0665-05
10
mL
NDC 0065-0665-10
Storage:
Store between 2 - 27°C (36 - 80°F).
Protect from freezing and light.
Rx Only
Alcon
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
August 2002
Printed in USA
©2002 Alcon Laboratories, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20258slr019_iopidine_lbl.pdf', 'application_number': 20258, 'submission_type': 'SUPPL ', 'submission_number': 19}
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company logo
Voltaren®-XR
(diclofenac sodium extended-release) tablets, USP
Tablets of 100 mg
Rx only
Prescribing Information
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.)
• Voltaren®-XR (diclofenac sodium extended-release) tablets, USP are contraindicated for
the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG)
surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach or intestines, which can
be fatal. These events can occur at any time during use and without warning symptoms.
Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.)
DESCRIPTION
Voltaren®-XR (diclofenac sodium extended-release) tablets, USP is a benzeneacetic acid
derivative. Voltaren-XR is available as extended-release tablets of 100 mg (light pink) for oral
administration. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid,
monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2,
and it has the following structural formula
Reference ID: 2909345
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2 structural formula
The inactive ingredients in Voltaren-XR include: cetyl alcohol, hydroxypropyl
methylcellulose, iron oxide, magnesium stearate, polyethylene glycol, polysorbate, povidone,
silicon dioxide, sucrose, talc, titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Voltaren®-XR (diclofenac sodium extended-release) tablets, USP is a non-steroidal
anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic
activities in animal models. The mechanism of action of Voltaren-XR, like that of other
NSAIDs, is not completely understood but may be related to prostaglandin synthetase
inhibition.
Pharmacokinetics
Absorption
Diclofenac is 100% absorbed after oral administration compared to IV administration as
measured by urine recovery. However, due to first-pass metabolism, only about 50% of the
absorbed dose is systemically available (see Table 1). When Voltaren-XR is taken with food,
there is a delay of 1 to 2 hours in the Tmax and a two-fold increase in Cmax values. The extent
of absorption of diclofenac, however, is not significantly affected by food intake.
Table 1. Pharmacokinetic Parameters for Diclofenac
PK Parameter
Normal Healthy Adults
(18-48 yrs.)
Coefficient of
Absolute
Mean
55
Variation (%)
40
Bioavailability (%)
[N = 7]
Tmax (hr)
[N = 12]
5.3
28
Oral Clearance (CL/F;
895
56
Reference ID: 2909345
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3
mL/min) [N = 12]
Renal Clearance
<1
—
(% unchanged drug in
urine) [N = 7]
Apparent Volume of
1.4
58
Distribution (V/F; L/kg)
[N = 56]
Terminal Half-life (hr)
2.3
48
[N = 56]
Distribution
The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg. Diclofenac is
more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding
is constant over the concentration range (0.15-105 μg/mL) achieved with recommended
doses.
Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs
when plasma levels are higher than those in the synovial fluid, after which the process
reverses and synovial fluid levels are higher than plasma levels. It is not known whether
diffusion into the joint plays a role in the effectiveness of diclofenac.
Metabolism
Five diclofenac metabolites have been identified in human plasma and urine. The metabolites
include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy
diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak
pharmacologic activity. The formation of 4’-hydroxy diclofenac is primarily mediated by
CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation
followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation
mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible
for the formation of minor metabolites, 5-hydroxy- and 3’-hydroxy-diclofenac. In patients
with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy
diclofenac were approximately 50% and 4% of the parent compound after single oral dosing
compared to 27% and 1% in normal healthy subjects.
Excretion
Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of
the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged
diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and
approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites.
Because renal elimination is not a significant pathway of elimination for unchanged
diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not
necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.
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Drug Interactions
When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the
Cmax and AUC of diclofenac increased by 114% and 78%, respectively (see
PRECAUTIONS, Drug Interactions).
Special Populations
Pediatric: The pharmacokinetics of Voltaren-XR has not been investigated in pediatric
patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of Voltaren-XR
elimination, so patients with hepatic disease may require reduced doses of Voltaren-XR
compared to patients with normal hepatic function.
Renal Insufficiency: Diclofenac pharmacokinetics has been investigated in subjects with
renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected
in studies of patients with renal impairment. In patients with renal impairment (inulin
clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination
rate were comparable to those in healthy subjects.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of Voltaren®-XR (diclofenac sodium
extended-release) tablets, USP and other treatment options before deciding to use Voltaren-
XR. Use the lowest effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).
Voltaren-XR is indicated:
• For relief of the signs and symptoms of osteoarthritis
• For relief of the signs and symptoms of rheumatoid arthritis
CONTRAINDICATIONS
Voltaren®-XR (diclofenac sodium extended-release) tablets, USP is contraindicated in
patients with known hypersensitivity to diclofenac.
Voltaren-XR 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,
Anaphylactic Reactions, and PRECAUTIONS, Preexisting Asthma).
Voltaren-XR is contraindicated for the treatment of perioperative pain in the setting of
coronary artery bypass graft (CABG) surgery (see WARNINGS).
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WARNINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years
duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,
myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and
nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV
disease may be at greater risk. To minimize the potential risk for an adverse CV event in
patients treated with an NSAID, the lowest effective dose should be used for the shortest
duration possible. Physicians and patients should remain alert for the development of such
events, even in the absence of previous CV symptoms. Patients should be informed about the
signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased
risk of serious CV thrombotic events associated with NSAID use. The concurrent use of
aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, GI
Effects).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of
pain in the first 10-14 days following CABG surgery found an increased incidence of
myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs 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 Voltaren®-XR (diclofenac sodium extended-release) tablets,
USP, should be used with caution in patients with hypertension. Blood pressure (BP) should
be monitored closely during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. Voltaren-XR
should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and
Perforation
NSAIDs, including Voltaren-XR, can cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine,
or large intestine, which can be fatal. These serious adverse events can occur at any time,
with or without warning symptoms, in patients treated with NSAIDs. Only one in five
patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1%
of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These
trends continue with longer duration of use, increasing the likelihood of developing a serious
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GI event at some time during the course of therapy. However, even short-term therapy is not
without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of
ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease
and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk
for developing a GI bleed compared to patients with neither of these risk factors. Other
factors that increase the risk for GI bleeding in patients treated with NSAIDs include
concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy,
smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports
of fatal GI events are in elderly or debilitated patients and therefore special care should be
taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an
NSAID, the lowest effective dose should be used for the shortest possible duration. Patients
and physicians should remain alert for signs and symptoms of GI ulceration and bleeding
during NSAID therapy and promptly initiate additional evaluation and treatment if a serious
GI adverse event is suspected. This should include discontinuation of the NSAID until a
serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not
involve NSAIDs should be considered.
Renal Effects
Caution should be used when initiating treatment with Voltaren-XR in patients with
considerable dehydration.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other
renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients, administration of a
nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin
formation and, secondarily, in renal blood flow, which may precipitate overt renal
decompensation. Patients at greatest risk of this reaction are those with impaired renal
function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly. Discontinuation of non-steroidal anti-inflammatory drug (NSAID) therapy is usually
followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of Voltaren-XR
in patients with advanced renal disease. Therefore, treatment with Voltaren-XR is not
recommended in these patients with advanced renal disease. If Voltaren-XR therapy must be
initiated, close monitoring of the patient's renal function is advisable.
Hepatic Effects
Elevations of one or more liver tests may occur during therapy with Voltaren-XR. These
laboratory abnormalities may progress, may remain unchanged, or may be transient with
continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper
limit of the normal range]) or greater elevations of transaminases occurred in about 15% of
diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended
for the monitoring of liver injury.
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In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST
(GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700
patients at some time during diclofenac treatment. In a large, open-label, controlled trial of
3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200
patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST
occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the
ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of
borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times
the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when
compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients
with osteoarthritis than in those with rheumatoid arthritis.
Almost all meaningful elevations in transaminases were detected before patients
became symptomatic. Abnormal tests occurred during the first 2 months of therapy with
diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.
In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in
the first month, and in some cases, the first 2 months of therapy, but can occur at any time
during treatment with diclofenac. Postmarketing surveillance has reported cases of severe
hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without
jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver
transplantation.
Physicians should measure transaminases periodically in patients receiving long-term
therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of
distinguishing symptoms. The optimum times for making the first and subsequent
transaminase measurements are not known. Based on clinical trial data and postmarketing
experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment
with diclofenac. However, severe hepatic reactions can occur at any time during treatment
with diclofenac.
If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent
with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash,
abdominal pain, diarrhea, dark urine, etc.), Voltaren-XR should be discontinued immediately.
To minimize the possibility that hepatic injury will become severe between
transaminase measurements, physicians should inform patients of the warning signs and
symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right
upper quadrant tenderness, and "flu-like" symptoms), and the appropriate action patients
should take if these signs and symptoms appear.
To minimize the potential risk for an adverse liver related event in patients treated
with Voltaren-XR, the lowest effective dose should be used for the shortest duration possible.
Caution should be exercised in prescribing Voltaren-XR with concomitant drugs that are
known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).
Anaphylactic Reactions
As with other NSAIDs, anaphylactic reactions may occur both in patients with the aspirin
triad and in patients without known sensitivity to NSAIDs or known prior exposure to
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Voltaren-XR. Voltaren-XR 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.) Anaphylaxis-type reactions have been reported with NSAID products, including
with diclofenac products, such as Voltaren-XR. Emergency help should be sought in cases
where an anaphylactic reaction occurs.
Skin Reactions
NSAIDs, including Voltaren-XR, can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which
can be fatal. These serious events may occur without warning. Patients should be informed
about the signs and symptoms of serious skin manifestations and use of the drug should be
discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, Voltaren-XR should be avoided because it may
cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
Voltaren®-XR (diclofenac sodium extended-release) tablets, USP 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 Voltaren-XR in reducing fever and inflammation may
diminish the utility of these diagnostic signs in detecting complications of presumed
noninfectious, painful conditions.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including Voltaren-XR. 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 Voltaren-XR,
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 Voltaren-XR 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.
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Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal
anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Voltaren-XR
should not be administered to patients with this form of aspirin sensitivity and should be used
with caution in all patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating therapy with
an NSAID and periodically during the course of ongoing therapy. Patients should also
be encouraged to read the NSAID Medication Guide that accompanies each prescription
dispensed.
1. Voltaren-XR, 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. Voltaren-XR, like other NSAIDs, can cause GI discomfort and, rarely, more 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. Voltaren-XR, like other NSAIDs, can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even
death. Although serious skin reactions may occur without warning, patients should be
alert for the signs and symptoms of skin rash and blisters, fever, or other signs of
hypersensitivity such as itching, and should ask for medical advice when observing
any indicative signs or symptoms. Patients should be advised to stop the drug
immediately if they develop any type of rash and contact their physicians as soon as
possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or
edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity
(e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and
“flu-like” symptoms). If these occur, patients should be instructed to stop therapy and
seek immediate medical therapy (see WARNINGS, Hepatic Effects).
6. Patients should be informed of the signs of an anaphylactic reaction (e.g., difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed
to seek immediate emergency help (see WARNINGS, Anaphylactic Reactions).
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7. In late pregnancy, as with other NSAIDs, Voltaren-XR 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. In patients on long-term
treatment with NSAIDs, including Voltaren-XR, the CBC and a chemistry profile (including
transaminase levels) should be 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, Voltaren-XR should be discontinued.
Drug Interactions
Aspirin: When Voltaren-XR is administered with aspirin, its protein binding is reduced. The
clinical significance of this interaction is not known; however, as with other NSAIDs,
concomitant administration of diclofenac and aspirin is not generally recommended because
of the potential of increased adverse effects.
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.
Cyclosporine: Voltaren-XR, like other NSAIDs, may affect renal prostaglandins and increase
the toxicity of certain drugs. Therefore, concomitant therapy with Voltaren-XR may increase
cyclosporine’s nephrotoxicity. Caution should be used when Voltaren-XR is administered
concomitantly with cyclosporine.
ACE Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of
ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs
concomitantly with ACE inhibitors.
Furosemide: Clinical studies, as well as postmarketing observations, have shown that
Voltaren-XR 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.
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.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
users of both drugs together have a risk of serious GI bleeding higher than users of either drug
alone.
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CYP2C9 Inhibitors or Inducers: Diclofenac is metabolized by cytochrome P450 enzymes,
predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g.
voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration
with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Use
caution when dosing diclofenac with CYP2C9 inhibitors or inducers, a dosage adjustment
may be warranted (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug
Interactions).
Pregnancy
Teratogenic Effects: Pregnancy Category C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of
developmental abnormalities. However, animal reproduction studies are not always
predictive of human response. There are no adequate and well-controlled studies in pregnant
women.
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.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an
increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The
effects of Voltaren-XR on labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing
infants from Voltaren-XR, 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.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
ADVERSE REACTIONS
In patients taking Voltaren®-XR (diclofenac sodium extended-release) tablets, USP or other
NSAIDs, the most frequently reported adverse experiences occurring in approximately
1%-10% of patients are:
Gastrointestinal experiences including: abdominal pain, constipation, diarrhea,
dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers
(gastric/duodenal) and vomiting.
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Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes,
headaches, increased bleeding time, pruritus, rashes and tinnitus.
Additional adverse experiences reported occasionally include:
Body as a Whole: fever, infection, sepsis
Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope
Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal
bleeding, glossitis, hematemesis, hepatitis, jaundice
Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal
bleeding, stomatitis, thrombocytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo
Respiratory System: asthma, dyspnea
Skin and Appendages: alopecia, photosensitivity, sweating increased
Special Senses: blurred vision
Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria,
proteinuria, renal failure.
Other adverse reactions, which occur rarely are:
Body as a Whole: anaphylactic reactions, appetite changes, death
Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations,
vasculitis
Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice,
liver failure, liver necrosis, pancreatitis
Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia,
lymphadenopathy, pancytopenia
Metabolic and Nutritional: hyperglycemia
Nervous System: convulsions, coma, hallucinations, meningitis
Respiratory System: respiratory depression, pneumonia
Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme,
exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
Special Senses: conjunctivitis, hearing impairment.
OVERDOSAGE
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
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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 NSAID
overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g 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.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of Voltaren®-XR (diclofenac sodium
extended-release) tablets, USP and other treatment options before deciding to use
Voltaren-XR. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with Voltaren-XR, the dose and
frequency should be adjusted to suit an individual patient’s needs.
For the relief of osteoarthritis, the recommended dosage is 100 mg q.d.
For the relief of rheumatoid arthritis, the recommended dosage is 100 mg q.d. In the
rare patient where Voltaren-XR 100 mg/day is unsatisfactory, the dose may be increased to
100 mg b.i.d. if the benefits outweigh the clinical risks of increased side effects.
Different formulations of diclofenac [Voltaren® (diclofenac sodium enteric-coated
tablets); Voltaren®-XR (diclofenac sodium extended-release) tablets, USP; Cataflam®
(diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the
milligram strength is the same.
HOW SUPPLIED
Voltaren®-XR (diclofenac sodium extended-release) tablets, USP
100 mg
Light pink, film-coated, round, biconvex with beveled edges (imprinted Voltaren XR on one
side and 100 on the other side in black ink)
Bottles of 100……………………………………………………..NDC 0078-0446-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
MEDICATION GUIDE FOR NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDs)
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(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can
lead to death.
This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery
called a "coronary artery bypass graft (CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines
at any time during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called "corticosteroids" and "anticoagulants"
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
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What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any
other NSAID medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all 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 Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
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(fluid retention)
• kidney problems including kidney
failure
• bleeding and ulcers in the stomach
and intestine
• heartburn
• nausea
• vomiting
• dizziness
• 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
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 pains
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
Reference ID: 2909345
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Page 17
• 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 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart
attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can
also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription
(over the counter). Talk to your healthcare provider before using over the counter
NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
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
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan,
Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
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Page 18
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.
The brands listed are the trademarks or register marks of their respective owners and
are not all trademarks or register marks of Novartis.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
REV: February 2011 .
T2009-40/T2009-31 company logo
Manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland for
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
©Novartis
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:14.677466
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020254s019s020lbl.pdf', 'application_number': 20254, 'submission_type': 'SUPPL ', 'submission_number': 20}
|
12,377
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structural formula
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tructu
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fo
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*BAR CODE POSITION ONLY
07-19-69-716
07-19-71-235
Baxter
DOBUTamine Hydrochloride in 5% Dextrose Injection
in Plastic Container
VIAFLEX Plus Container
DESCRIPTION
Dobutamine Hydrochloride in 5% Dextrose Injection is a sterile, nonpyrogenic solution
of Dobutamine Hydrochloride, USP and Dextrose, USP in Water for Injection, USP.
Dobutamine hydrochloride is chemically designated as (±)-4-[2-[[3-(p-hydroxyphenyl)-1
methylpropyl]amino]ethyl]-pyrocatechol hydrochloride. It is a synthetic catecholamine.
Dextrose Hydrous, USP is chemically designated as D-Glucopyranose monohydrate.
Structural formulas are shown below:
Dobutamine Hydrochloride, USP
(D-Glucopyranose monohydrate)
Dextrose Hydrous, USP
Dobutamine Hydrochloride in 5% Dextrose Injection is intended for intravenous use
only. It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide
and/or hydrochloric acid. Sodium bisulfite is added as a stabilizer. The solution is
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intended for single use only. When smaller doses are required, the unused portion should
be discarded. Composition, osmolarity, pH and caloric content are given in Table 1.
Table 1.
Composition†
Dobutamine Hydrochloride
in 5% Dextrose Injection.
Dobutamine
(mg/Container)
Dobutamine
(mcg/mL)
Dextrose
Hydrous, USP
(g/L)
Osmolarity
(mOsmol/L)
(calc)*
pH
kcal/L
250 mg/500 mL
500
50
256
3.5
170
250 mg/250 mL
1000
50
259
(2.5 to 5.5)
170
500 mg/500 mL
1000
50
259
3.5
170
500 mg/250 mL
2000
50
266
(2.5 to 5.5)
170
1000 mg/250 mL
4000
50
280
3.5
(2.5 to 5.5)
170
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
†Approximately 5 mEq/L sodium bisulfite is added as a stabilizer.
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
Dobutamine hydrochloride is a direct-acting inotropic agent whose primary activity
results from stimulation of the ß-receptors of the heart while producing comparatively
mild chronotropic, hypertensive, arrhythmogenic, and vasodilative effects. It does not
cause the release of endogenous norepinephrine, as does dopamine. In animal studies,
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dobutamine produces less increase in heart rate and less decrease in peripheral vascular
resistance for a given inotropic effect than does isoproterenol.
In patients with depressed cardiac function, both dobutamine and isoproterenol increase
the cardiac output to a similar degree. In the case of dobutamine, this increase is usually
not accompanied by marked increases in heart rate (although tachycardia is occasionally
observed), and the cardiac stroke volume is usually increased. In contrast, isoproterenol
increases the cardiac index primarily by increasing the heart rate while stroke volume
changes little or declines.
Facilitation of atrioventricular conduction has been observed in human electrophysiologic
studies and in patients with atrial fibrillation.
Systemic vascular resistance is usually decreased with administration of dobutamine.
Occasionally, minimum vasoconstriction has been observed.
Most clinical experience with dobutamine is short-term - not more than several hours in
duration. In the limited number of patients who were studied for 24, 48, and 72 hours, a
persistent increase in cardiac output occurred in some, whereas output returned toward
baseline values in others.
The onset of action of dobutamine is within one to two minutes; however, as much as ten
minutes may be required to obtain the peak effect of a particular infusion rate.
The plasma half-life of dobutamine in humans is two minutes. The principal routes of
metabolism are methylation of the catechol and conjugation. In human urine, the major
excretion products are the conjugates of dobutamine and 3-O-methyl dobutamine. The 3
O-methyl derivative of dobutamine is inactive.
Alteration of synaptic concentrations of catecholamines with either reserpine or tricyclic
antidepressants does not alter the actions of dobutamine in animals, which indicates that
the actions of dobutamine are not dependent on presynaptic mechanisms.
The effective infusion rate of dobutamine varies widely from patient to patient, and
titration is always necessary (see Dosage and Administration). At least in pediatric
patients, dobutamine-induced increases in cardiac output and systemic pressure are
generally seen, in any given patient, at lower infusion rates than those that cause
substantial tachycardia (see Pediatric Use under Precautions).
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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
Dobutamine in 5% Dextrose Injection is indicated when parenteral therapy is necessary
for inotropic support in the short-term treatment of patients with cardiac decompensation
due to depressed contractility resulting either from organic heart disease or from cardiac
surgical procedures. Experience with intravenous dobutamine in controlled trials does not
extend beyond 48 hours of repeated boluses and/or continuous infusions.
Whether given orally, continuously intravenously, or intermittently intravenously, neither
dobutamine nor any other cyclic-AMP-dependent inotrope has been shown in controlled
trials to be safe or effective in the long-term treatment of congestive heart failure. In
controlled trials of chronic oral therapy with various such agents, symptoms were not
consistently alleviated, and the cyclic-AMP-dependent inotropes were consistently
associated with increased risks of hospitalization and death. Patients with NYHA Class
IV symptoms appeared to be at particular risk.
CONTRAINDICATIONS
Dobutamine Hydrochloride in 5% Dextrose Injection is contraindicated in patients with
idiopathic hypertrophic subaortic stenosis and in patients who have shown previous
manifestations of hypersensitivity to dobutamine.
Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products.
WARNINGS
Increase in Heart Rate or Blood Pressure
Dobutamine Hydrochloride in 5% Dextrose Injection may cause a marked increase in
heart rate or blood pressure, especially systolic pressure. Approximately 10% of adult
patients in clinical studies have had rate increases of 30 beats/minute or more, and about
7.5% have had a 50-mm Hg or greater increase in systolic pressure. Usually, reduction of
dosage reverses these effects. Because dobutamine facilitates atrioventricular conduction,
patients with atrial fibrillation are at risk of developing rapid ventricular response.
Patients with preexisting hypertension appear to face an increased risk of developing an
exaggerated pressor response. In patients who have atrial fibrillation with rapid
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ventricular response, a digitalis preparation should be used prior to institution of therapy
with Dobutamine in D5W.
Ectopic Activity
Dobutamine Hydrochloride in 5% Dextrose Injection may precipitate or exacerbate
ventricular ectopic activity, but it rarely has caused ventricular tachycardia.
Hypersensitivity
Reactions suggestive of hypersensitivity associated with administration of dobutamine
including skin rash, fever, eosinophilia, and bronchospasm, have been reported
occasionally.
Dobutamine Hydrochloride in 5% Dextrose Injection 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.
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. The risk of dilutional states is inversely proportional to the electrolyte
concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentration
of the injections.
Excess administration of potassium-free solutions may result in significant hypokalemia.
PRECAUTIONS
General
During the administration of Dobutamine Hydrochloride in 5% Dextrose Injection,
as with any adrenergic agent, ECG and blood pressure should be continuously
monitored. In addition, pulmonary wedge pressure and cardiac output should be
monitored whenever possible to aid in the safe and effective infusion of dobutamine.
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Hypovolemia should be corrected with suitable volume expanders before treatment with
dobutamine is instituted.
Animal studies indicate that dobutamine may be ineffective if the patient has recently
received a ß-blocking drug. In such a case, the peripheral vascular resistance may
increase.
No improvement may be observed in the presence of marked mechanical obstruction,
such as severe valvular aortic stenosis.
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.
Usage Following Acute Myocardial Infarction
Clinical experience with dobutamine following myocardial infarction has been
insufficient to establish the safety of the drug for this use. There is concern that any agent
that increases contractile force and heart rate may increase the size of an infarction by
intensifying ischemia, but it is not known whether dobutamine does so.
Drug Interactions
There was no evidence of drug interactions in clinical studies in which dobutamine was
administered concurrently with other drugs, including digitalis preparations, furosemide,
spironolactone, lidocaine, glyceryl trinitrate, isosorbide dinitrate, morphine, atropine,
heparin, protamine, potassium chloride, folic acid, and acetaminophen. Preliminary
studies indicate that the concomitant use of dobutamine and nitroprusside results in a
higher cardiac output and, usually, a lower pulmonary wedge pressure than when either
drug is used alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies to evaluate the carcinogenic or mutagenic potential of dobutamine or the potential
of the drug to affect fertility adversely have not been performed.
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Pregnancy
Pregnancy Category B
Reproduction studies performed in rats and rabbits have revealed no evidence of harm to
the fetus due to dobutamine. The drug, however, has not been administered to pregnant
women and should be used only when the expected benefits clearly outweigh the
potential risks to the fetus.
Pediatric Use
Dobutamine has been shown to increase cardiac output and systemic pressure in pediatric
patients of every age group. In premature neonates, however, dobutamine is less effective
than dopamine in raising systemic blood pressure without causing undue tachycardia, and
dobutamine has not been shown to provide any added benefit when given to such infants
already receiving optimal infusions of dopamine.
Geriatric Use
Clinical studies of dobutamine 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
drug therapy.
ADVERSE REACTIONS
Increased Heart Rate, Blood Pressure, and Ventricular Ectopic Activity
A 10 to 20-mm Hg increase in systolic blood pressure and an increase in heart rate of 5 to
15 beats/minute have been noted in most patients (see Warnings regarding exaggerated
chronotropic and pressor effects). Approximately 5% of adult patients have had increased
premature ventricular beats during infusions. These effects are dose related.
Hypotension
Precipitous decreases in blood pressure have occasionally been described in association
with dobutamine therapy. Decreasing the dose or discontinuing the infusion typically
results in rapid return of blood pressure to baseline values. In rare cases, however,
intervention may be required and reversibility may not be immediate.
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Reactions at Sites of Intravenous Infusion
Phlebitis has occasionally been reported. Local inflammatory changes have been
described following inadvertent infiltration.
Miscellaneous Uncommon Effects
The following adverse effects have been reported in 1% to 3% of adult patients: nausea,
headache, anginal pain, nonspecific chest pain, palpitations, and shortness of breath.
Administration of dobutamine, like other catecholamines, has been associated with
decreases in serum potassium concentrations, rarely to hypokalemic values.
OVERDOSAGE
Overdoses of dobutamine have been reported rarely. The following is provided to serve
as a guide if such an overdose is encountered.
Signs and Symptoms
Toxicity from dobutamine is usually due to excessive cardiac ß-receptor stimulation. The
duration of action of dobutamine is generally short (T1/2 = two minutes) because it is
rapidly metabolized by catechol-O-methyltransferase. The symptoms of toxicity may
include anorexia, nausea, vomiting, tremor, anxiety, palpitations, headache, shortness of
breath, and anginal and nonspecific chest pain. The positive inotropic and chronotropic
effects of dobutamine on the myocardium may cause hypertension, tachyarrhythmias,
myocardial ischemia, and ventricular fibrillation. Hypotension may result from
vasodilation.
If the product is ingested, unpredictable absorption may occur from the mouth and the
gastrointestinal tract.
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.
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The initial actions to be taken in a dobutamine overdose are discontinuing administration,
establishing an airway, and ensuring oxygenation and ventilation. Resuscitative measures
should be initiated promptly. Severe ventricular tachyarrhythmias may be successfully
treated with propranolol or lidocaine. Hypertension usually responds to a reduction in
dose or discontinuation of therapy.
Protect the patient’s airway and support ventilation and perfusion. If needed,
meticulously monitor and maintain, within acceptable limits, the patient’s vital signs,
blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract
may be decreased by giving activated charcoal, which, in many cases, is more effective
than emesis or lavage; consider charcoal instead of or in addition to gastric emptying.
Repeated doses of charcoal over time may hasten elimination of some drugs that have
been absorbed. Safeguard the patient’s airway when employing gastric emptying or
charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not
been established as beneficial for an overdose of dobutamine.
DOSAGE AND ADMINISTRATION
Recommended Dosage
Dobutamine Hydrochloride in 5% Dextrose Injection is administered intravenously
through a suitable intravenous catheter or needle. A calibrated electronic infusion device
is recommended for controlling the rate of flow in mL/hour or drops/minute.
Infusion of dobutamine should be started at a low rate (0.5-1.0 µg/kg/min) and titrated at
intervals of a few minutes, guided by the patient’s response, including systemic blood
pressure, urine flow, frequency of ectopic activity, heart rate, and (whenever possible)
measurements of cardiac output, central venous pressure, and/or pulmonary capillary
wedge pressure. In reported trials, the optimal infusion rates have varied from patient to
patient, usually 2-20 µg/kg/min but sometimes slightly outside of this range. On rare
occasions, infusion rates up to 40 µg/kg/min have been required to obtain the desired
effect.
Rates of infusion in mL/hour for dobutamine hydrochloride concentrations of 500, 1,000,
2,000 and 4,000 mg/L are in Table 2.
This container system may be inappropriate for the dosage requirements of pediatric
patients under 30 kg. Other dosage forms may be more appropriate.
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Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
Dobutamine Hydrochloride in 5% Dextrose Injection solutions may exhibit a pink color
that, if present, will increase with time. This color change is due to slight oxidation of the
drug, but there is no significant loss of potency.
The rate of administration and the duration of therapy should be adjusted according to the
patient’s response, as determined by heart rate, presence of ectopic activity, blood
pressure, urine flow, and, whenever possible, measurement of central venous or
pulmonary wedge pressure and cardiac output.
Do not add supplementary medications to Dobutamine Hydrochloride in 5% Dextrose
Injection. Do not administer Dobutamine Hydrochloride in 5% Dextrose Injection
simultaneously with solutions containing sodium bicarbonate or strong alkaline solutions.
HOW SUPPLIED
Dobutamine Hydrochloride in 5% Dextrose Injection in VIAFLEX Plus plastic
containers is available as follows:
2B0791
Dobutamine 250 mg/250 mL
NDC 0338-1073-02
2B0792
Dobutamine 500 mg/250 mL
NDC 0338-1075-02
2B0793
Dobutamine 1000 mg/250 mL
NDC 0338-1077-02
2B0795
Dobutamine 250 mg/500 mL
NDC 0338-1071-03
2B0796
Dobutamine 500 mg/500 mL
NDC 0338-1073-03
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.
Directions for use of VIAFLEX Plus Plastic Container
Do not remove unit from overwrap until ready for use.
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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
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.
Table 2.
Infusion Rate (mL/hr)
of Dobutamine Hydrochloride in 5% Dextrose Injection.
500 mcg/mL
Patient's Weight (Kg)
Drug
Delivery
Rate
(mcg/Kg/
min)
5
10
20
30
40
50
60
70
80
90
100
110
0.5
0.30
0.60
1.2
1.8
2.4
3.0
3.6
4.2
4.8
5.4
6.0
6.6
1
0.60
1.2
2.4
3.6
4.8
6.0
7.2
8.4
9.6
11
12
13
2.5
1.5
3.0
6.0
9.0
12
15
18
21
24
27
30
33
5
3.0
6.0
12
18
24
30
36
42
48
54
60
66
7.5
4.5
9.0
18
27
36
45
54
63
72
81
90
99
10
6.0
12
24
36
48
60
72
84
96
108
120
132
12.5
7.5
15
30
45
60
75
90
105
120
135
150
165
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15
9.0
18
36
54
72
90
108
126
144
162
180
198
17.5
11
21
42
63
84
105
126
147
168
189
210
231
20
12
24
48
72
96
120
144
168
192
216
240
264
1000 mcg/mL
Patient's Weight (Kg)
Drug
Delivery
Rate
(mcg/Kg/
min)
5
10
20
30
40
50
60
70
80
90
100
110
0.5
0.15
0.30
0.60
0.90
1.2
1.5
1.8
2.1
2.4
2.7
3.0
3.3
1
0.30
0.60
1.2
1.8
2.4
3.0
3.6
4.2
4.8
5.4
6.0
6.6
2.5
0.75
1.5
3.0
4.5
6.0
7.5
9.0
11
12
14
15
17
5
1.5
3.0
6.0
9.0
12
15
18
21
24
27
30
33
7.5
2.3
4.5
9.0
14
18
23
27
32
36
41
45
50
10
3.0
6.0
12
18
24
30
36
42
48
54
60
66
12.5
3.8
7.5
15
23
30
38
45
53
60
68
75
83
15
4.5
9.0
18
27
36
45
54
63
72
81
90
99
17.5
5.3
11
21
32
42
53
63
74
84
95
105
116
20
6.0
12
24
36
48
60
72
84
96
108
120
132
2000 mcg/mL
Patient's Weight (Kg)
Drug
Delivery
Rate
(mcg/Kg/
min)
5
10
20
30
40
50
60
70
80
90
100
110
0.5
0.08
0.15
0.30
0.45
0.60
0.75
0.90
1.1
1.2
1.4
1.5
1.7
1
0.15
0.30
0.60
0.90
1.2
1.5
1.8
2.1
2.4
2.7
3.0
3.3
2.5
0.38
0.75
1.5
2.3
3.0
3.8
4.5
5.3
6.0
6.8
7.5
8.3
5
0.75
1.5
3.0
4.5
6.0
7.5
9.0
11
12
14
15
17
7.5
1.1
2.3
4.5
6.8
9.0
11
14
16
18
20
23
25
10
1.5
3.0
6.0
9.0
12
15
18
21
24
27
30
33
12.5
1.9
3.8
7.5
11
15
19
23
26
30
34
38
41
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15
2.3
4.5
9.0
14
18
23
27
32
36
41
45
50
17.5
2.6
5.3
11
16
21
26
32
37
42
47
53
58
20
3.0
6.0
12
18
24
30
36
42
48
54
60
66
4000 mcg/mL
Patient's Weight (Kg)
Drug
Delivery
Rate
(mcg/Kg/
min)
5
10
20
30
40
50
60
70
80
90
100
110
0.5
0.04
0.08
0.15
0.23
0.30
0.38
0.45
0.53
0.60
0.68
0.75
0.83
1
0.08
0.15
0.30
0.45
0.60
0.75
0.90
1.1
1.2
1.4
1.5
1.7
2.5
0.19
0.38
0.75
1.1
1.5
1.9
2.3
2.6
3.0
3.4
3.8
4.1
5
0.38
0.75
1.5
2.3
3.0
3.8
4.5
5.3
6.0
6.8
7.5
8.3
7.5
0.56
1.1
2.3
3.4
4.5
5.6
6.8
7.9
9.0
10
11
12
10
0.75
1.5
3.0
4.5
6.0
7.5
9.0
11
12
14
15
17
12.5
0.94
1.9
3.8
5.6
7.5
9.4
11
13
15
17
19
21
15
1.1
2.3
4.5
6.8
9.0
11
14
16
18
20
23
25
17.5
1.3
2.6
5.3
7.9
11
13
16
18
21
24
26
29
20
1.5
3.0
6.0
9.0
12
15
18
21
24
27
30
33
BAXTER, AND VIAFLEX ARE TRADEMARKS OF BAXTER INTERNATIONAL
INC.
©Copyright 1991, 1993, Baxter Healthcare Corporation. All rights reserved.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
7-19-69-716
Revised September 2012
*BAR CODE POSITION ONLY
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07-19-71-235
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Reference ID: 3294594
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Reference ID: 3294594
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:14.717331
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020255s016lbl.pdf', 'application_number': 20255, 'submission_type': 'SUPPL ', 'submission_number': 16}
|
12,380
|
89011105
89011105
89011105
Lescol
®
(fluvastatin sodium)
Capsules
Lescol
® XL
(fluvastatin sodium)
Extended-Release Tablets
Rx only
Prescribing Information
DESCRIPTION
Lescol® (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through the inhi-
bition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
Fluvastatin sodium is [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H -indol-2-yl]-3,5-
dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is
C24H25FNO4•Na, its molecular weight is 433.46 and its structural formula is:
This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part struc-
turally distinct from the fungal derivatives of this therapeutic class.
Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and
methanol. Lescol is supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of
fluvastatin, for oral administration. Lescol® XL (fluvastatin sodium) is supplied as extended-release
tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral administration.
Active Ingredient: fluvastatin sodium
Inactive Ingredients in capsules: gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized
starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, and other
ingredients.
Capsules may also include: benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose
sodium, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide and sodium propionate.
Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, iron oxide
yellow, titanium dioxide and polyethylene glycol 8000.
CLINICAL PHARMACOLOGY
A variety of clinical studies have demonstrated that elevated levels of total cholesterol (Total-C), low den-
sity lipoprotein cholesterol (LDL-C), triglycerides (TG) and apolipoprotein B (a membrane transport
complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol
(HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atheroscle-
rosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary
directly with the level of Total-C and LDL-C and inversely with the level of HDL-C.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL and remnants, can
also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low
HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for
coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent
risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of
coronary and cardiovascular morbidity and mortality has not been determined.
In patients with hypercholesterolemia and mixed dyslipidemia, treatment with Lescol® (fluvastatin sodium)
or Lescol® XL (fluvastatin sodium) reduced Total-C, LDL-C, apolipoprotein B, and triglycerides while
producing an increase in HDL-C. Increases in HDL-C are greater in patients with low HDL-C
(<35 mg/dL). Neither agent had a consistent effect on either Lp(a) or fibrinogen. The effect of Lescol or
Lescol XL induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovas-
cular morbidity or mortality has not been determined.
Mechanism of Action
Lescol is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including
cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which
stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end
result of these biochemical processes is a reduction of the plasma cholesterol concentration.
Pharmacokinetics/Metabolism
Oral Absorption
Fluvastatin is absorbed rapidly and completely following oral administration of the capsule, with peak
concentrations reached in less than 1 hour. Following administration of a 10 mg dose, the absolute
bioavailability is 24% (range 9%-50%). Administration with food reduces the rate but not the extent of
absorption. At steady-state, administration of fluvastatin with the evening meal results in a two-fold
decrease in Cmax and more than two-fold increase in tmax as compared to administration 4 hours after the
evening meal. No significant differences in extent of absorption or in the lipid-lowering effects were
observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin
exhibits saturable first-pass metabolism resulting in higher-than-expected plasma fluvastatin concentrations.
Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form. In vivo studies
showed that stereo-selective hepatic binding of the active form occurs during the first pass resulting in a
difference in the peak levels of the two enantiomers, with the active to inactive peak concentration ratio
being about 0.7. The approximate ratio of the active to inactive approaches unity after the peak is seen
and thereafter the two enantiomers decline with the same half-life. After an intravenous administration,
bypassing the first-pass metabolism, the ratios of the enantiomers in plasma were similar throughout
the concentration-time profiles.
Fluvastatin administered as Lescol XL 80 mg tablets reaches peak concentration in approximately
3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean rela-
tive bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the
Lescol immediate release capsule administered under fasting conditions. Administration of a high fat
meal delayed the absorption (Tmax: 6H) and increased the bioavailability of the XL tablet by approximately
50%. Once Lescol XL begins to be absorbed, fluvastatin concentrations rise rapidly. The maximum
concentration seen after a high fat meal is much less than the peak concentration following a single
dose or twice daily dose of the 40 mg Lescol capsule. Overall variability in the pharmacokinetics of
Lescol XL is large (42%-64% CV for Cmax and AUC), and especially so after a high fat meal (63%-89%
for Cmax and AUC). Intrasubject variability in the pharmacokinetics of Lescol XL under fasting conditions
(about 25% for Cmax and AUC) tends to be much smaller as compared to the overall variability. Multiple
peaks in plasma fluvastatin concentrations have been observed after Lescol XL administration.
Distribution
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at
0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are present systemically.
At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid
and glyburide.
Metabolism
Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and
6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites
have some pharmacologic activity, but do not circulate in the blood. Both enantiomers of fluvastatin are
metabolized in a similar manner.
In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via
2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%)
and 3A4 (~20%). (See PRECAUTIONS: Drug Interactions Section).
Elimination
Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2% present as
unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of fluvastatin, the clearance
was 0.8 L/h/kg. Following multiple oral doses of radiolabeled compound, there was no accumulation of
fluvastatin; however, there was a 2.3 fold accumulation of total radioactivity.
Steady-state plasma concentrations show no evidence of accumulation of fluvastatin following
immediate release capsule administration of up to 80 mg daily, as evidenced by a beta-elimination half-
life of less than 3 hours. However, under conditions of maximum rate of absorption (i.e., fasting) sys-
temic exposure to fluvastatin is increased 33% to 53% compared to a single 20 mg or 40 mg dose of
the immediate release capsule. Following once daily administration of the 80 mg Lescol XL tablet for 7
days, systemic exposure to fluvastatin is increased (20%-30%) compared to a single dose of the 80 mg
Lescol XL tablet. Terminal half-life of Lescol XL was about 9 hours as a result of the slow-release formulation.
Single-dose and steady-state pharmacokinetic parameters in 33 subjects with hypercholesterolemia for the
capsules and in 35 healthy subjects for the extended-release tablets are summarized below:
Table 1
Single-dose and steady-state pharmacokinetic parameters
Cmax
AUC
tmax
CL/F
t1/2
(ng/mL)
(ng?h/mL)
(hr)
(L/hr)
(hr)
mean6 SD
mean6 SD mean6 SD
mean6 SD
mean6 SD
(range)
(range)
(range)
(range)
(range)
Capsules
20 mg single
1666 106
2076 65
0.96 0.4
1076 38.1
2.56 1.7
dose (n=17)
(48.9-517)
(111-288)
(0.5-2.0)
(69.5-181)
(0.5-6.6)
20 mg twice daily
2006 86
2756 111
1.26 0.9
87.86 45
2.86 1.7
(n=17)
(71.8-366)
(91.6-467)
(0.5-4.0)
(42.8-218)
(0.9-6.0)
40 mg single
2736 189
4566 259
1.26 0.7
1086 44.7
2.76 1.3
dose (n=16)
(72.8-812)
(207-1221)
(0.75-3.0)
(32.8-193)
(0.8-5.9)
40 mg twice daily
4326 236
6976 275
1.26 0.6
64.26 21.1
2.76 1.3
(n=16)
(119-990)
(359-1559)
(0.5-2.5)
(25.7-111)
(0.7-5.0)
Extended-Release Tablets 80 mg single dose (n=24)
80 mg single dose,
1266 53
5796 341
3.26 2.6
-
-
fasting (n=24)
(37-242)
(144-1760)
(1-12)
80 mg single dose,
fed-state high fat
1836 163
8616 632
6
-
-
meal (n=24)
(21-733)
(199-3132)
(2-24)
Extended-Release Tablets 80 mg following 7 days dosing (steady-state) (n=11)
80 mg once daily,
1026 42
6306 326
2.66 0.91
-
-
fasting (n=11)
(43.9-181)
(247-1406)
(1.5-4)
Special Populations
Renal Insufficiency: No significant (<6%) renal excretion of fluvastatin occurs in humans.
Hepatic Insufficiency: Fluvastatin is subject to saturable first-pass metabolism/sequestration by the
liver and is eliminated primarily via the biliary route. Therefore, the potential exists for drug accumula-
tion in patients with hepatic insufficiency. Caution should therefore be exercised when fluvastatin sodium
is administered to patients with a history of liver disease or heavy alcohol ingestion (see WARNINGS).
Fluvastatin AUC and Cmax values increased by about 2.5 fold in hepatic insufficiency patients. This
result was attributed to the decreased presystemic metabolism due to hepatic dysfunction. The enan-
tiomer ratios of the two isomers of fluvastatin in hepatic insufficiency patients were comparable to those
observed in healthy subjects.
Age: Plasma levels of fluvastatin are not affected by age.
Gender: Women tend to have slightly higher (but statistically insignificant) fluvastatin concentrations
than men for the immediate release capsule. This is most likely due to body weight differences, as
adjusting for body weight decreases the magnitude of the differences seen. For Lescol XL, there are 67%
and 77% increases in systemic availability for women over men under fasted and high fat meal conditions.
Pediatric: No data are available. Fluvastatin is not indicated for use in the pediatric population.
CLINICAL STUDIES
Hypercholesterolemia (heterozygous familial and non familial) and Mixed Dyslipidemia
In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinemia, Lescol®
(fluvastatin sodium) alone was administered to 1621 patients in daily dose regimens of 20 mg, 40 mg,
and 80 mg (40 mg twice daily) for at least 6 weeks duration. After 24 weeks of treatment, daily doses of
20 mg, 40 mg, and 80 mg (40 mg twice daily) resulted in median LDL-C reductions of 22% (n=747),
25% (n=748) and 36% (n=257), respectively. Lescol treatment produced dose-related reductions in
Apo B and in triglycerides and increases in HDL-C. The median (25th, 75th percentile) percent changes
from baseline in HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and
80 mg (40 mg twice daily) were +2 (-4,+10), +5 (-2,+12), and +4 (-3,+12), respectively. In a subgroup of
patients with primary mixed dyslipidemia, defined as baseline TG levels ≥200 mg/dL, treatment with
Lescol also produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in
HDL-C. The median (25th, 75th percentile) percent changes from baseline in HDL-C after 12 weeks of
treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice daily) in this population
were +4 (-2,+12), +8 (+1,+15), and +4 (-3,+13), respectively.
In a long-term open-label free titration study, after 96 weeks LDL-C decreases of 25% (20 mg, n=68),
31% (40 mg, n=298) and 34% (80 mg, n=209) were seen. No consistent effect on Lp(a) was observed.
Lescol® XL (fluvastatin sodium) Extended-Release Tablets have been studied in five controlled stud-
ies of patients with Type IIa or IIb hyperlipoproteinemia. Lescol XL was administered to over 900
patients in trials from 4 to 26 weeks in duration. In the three largest of these studies, Lescol XL given as
a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG and Apo B. Therapeutic response
is well established within two weeks, and a maximum response is achieved within four weeks. After
four weeks of therapy, the median decrease in LDL-C was 38% and at week 24 endpoint the median
LDL-C decrease was 35%. Significant increases in HDL-C were also observed. The median (25th and 75th
percentile) percent changes from baseline in HDL-C for Lescol XL were +7(+0,+15) after 24 weeks of
treatment.
Table 2
Median Percent Change in Lipid Parameters from Baseline to Week 24 Endpoint
All Placebo-Controlled Studies (Lescol) and Active Controlled Trials (Lescol XL)
Total Chol.
TG
LDL
Apo B
HDL
Dose
N
% ∆
N
% ∆
N
% ∆
N
% ∆
N
% ∆
All Patients
Lescol 20 mg1
747
-17
747
-12
747
-22
114
-19
747
+3
Lescol 40 mg1
748
-19
748
-14
748
-25
125
-18
748
+4
Lescol 40 mg twice daily1
257
-27
257
-18
257
-36
232
-28
257
+6
Lescol XL 80 mg2
750
-25
750
-19
748
-35
745
-27
750
+7
Baseline TG ≥200 mg/dL
Lescol 20 mg1
148
-16
148
-17
148
-22
23
-19
148
+6
Lescol 40 mg1
179
-18
179
-20
179
-24
47
-18
179
+7
Lescol 40 mg twice daily1
76
-27
76
-23
76
-35
69
-28
76
+9
Lescol XL 80 mg2
239
-25
239
-25
237
-33
235
-27
239 +11
1 Data for Lescol from 12 placebo controlled trials
2 Data for Lescol XL 80 mg tablet from three 24 week controlled trials
In patients with primary mixed dyslipidemia (Fredrickson Type IIb) as defined by baseline plasma
triglycerides levels ≥200 mg/dL, Lescol XL 80 mg produced a median reduction in triglycerides of 25%.
In these patients, Lescol XL 80 mg produced median (25th and 75th percentile) percent change from
baseline in HDL-C of +11(+3,+20). Significant decreases in Total-C, LDL-C, and Apo B were also
achieved. In these studies, patients with triglycerides >400 mg/dL were excluded.
Atherosclerosis
In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of Lescol therapy on coronary
atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with coronary
artery disease and mild to moderate hypercholesterolemia (baseline LDL-C range 115-190 mg/dL). In
this randomized double-blind, placebo controlled trial, 429 patients were treated with conventional mea-
sures (Step 1 AHA Diet) and either Lescol 40 mg/day or placebo. In order to provide treatment to
patients receiving placebo with LDL-C levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyra-
mine was added after week 12 to all patients in the study with baseline LDL-C values of ≥160 mg/dL.
These baseline levels were present in 25% of the study population. Quantitative coronary angiograms
were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients.
Lescol significantly slowed the progression of coronary atherosclerosis. Compared to placebo,
Lescol significantly slowed the progression of lesions as measured by within-patient per-lesion change
in minimum lumen diameter (MLD), the primary endpoint (see Figure 1 below), percent diameter steno-
sis (Figure 2), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all place-
bo patients). Additionally, a significant difference in favor of Lescol was found between all fluvastatin
and all placebo patients in the distribution among the three categories of definite progression, definite
regression, and mixed or no change. Beneficial angiographic results (change in MLD) were independent
of patients' gender and consistent across a range of baseline LDL-C levels.
INDICATIONS AND USAGE
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals at significantly increased risk for atherosclerosis vascular disease due to hypercholes-
terolemia.
Hypercholesterolemia (heterozygous familial and non familial) and Mixed Dyslipidemia
Lescol® (fluvastatin sodium) and Lescol® XL (fluvastatin sodium) are indicated as an adjunct to diet to
reduce elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase HDL-C in
patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb) whose
response to dietary restriction of saturated fat and cholesterol and other nonpharmacological measures
has not been adequate.
Atherosclerosis
Lescol and Lescol XL are also indicated to slow the progression of coronary atherosclerosis in patients with
coronary heart disease as part of a treatment strategy to lower total and LDL cholesterol to target levels.
Therapy with lipid-altering agents should be considered only after secondary causes for hyperlipi-
demia such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias,
obstructive liver disease, other medication, or alcoholism, have been excluded. Prior to initiation of
fluvastatin sodium, a lipid profile should be performed to measure Total-C, HDL-C and TG. For patients
with TG <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:
LDL-C = Total-C - HDL-C - 1/5 TG
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 many hypertriglyceridemic patients LDL-C may be low or
normal despite elevated Total-C. In such cases, Lescol is not indicated.
Lipid determinations should be performed at intervals of no less than 4 weeks and dosage adjusted
according to the patient's response to therapy.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
Table 3
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 Consider
LDL Goal
Initiate Therapeutic
Drug
Lifestyle Changes
Therapy
Risk Category
(mg/dL)
(mg/dL)
(mg/dL)
CHD† or CHD risk
<100
≥100
≥130
equivalents
(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 pri-
marily modify triglycerides and HDL-C, e.g. nicotinic acid or fibrate. Clinical judgement also may call
for deferring drug therapy in this subcategory.
†††Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in peo-
ple 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 level is ≥130 mg/dL (NCEP-ATP II).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that the 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.
Table 4
Classification of Hyperlipoproteinemias
Lipid Elevations
Lipoproteins
Type
Elevated
Major
Minor
I (rare)
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
C = cholesterol, TG = triglycerides, LDL = low density lipoprotein, VLDL = very low density lipoprotein,
IDL = intermediate density lipoprotein
Neither Lescol nor Lescol XL have been studied in conditions where the major abnormality is eleva-
tion of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV, or V).
CONTRAINDICATIONS
Hypersensitivity to any component of this medication. Lescol® (fluvastatin sodium) and Lescol® XL
(fluvastatin sodium) are contraindicated in patients with active liver disease or unexplained, persistent
elevations in serum transaminases (see WARNINGS).
Pregnancy and Lactation
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy
should have little impact on the outcome of long-term therapy of primary hypercholesterolemia.
Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development
(including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cho-
lesterol synthesis and possibly the synthesis of other biologically active substances derived from choles-
terol, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase
inhibitors are contraindicated during pregnancy and in nursing mothers. Fluvastatin sodium should be
administered to women of childbearing age only when such patients are highly unlikely to conceive and
have been informed of the potential hazards. If the patient becomes pregnant while taking this class of
drug, therapy should be discontinued and the patient apprised of the potential hazard to the fetus.
WARNINGS
Liver Enzymes
Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors
and other lipid-lowering agents. Approximately 1.1% of patients treated with Lescol® (fluvastatin sodium)
capsules in worldwide trials developed dose-related, persistent elevations of transaminase levels to more
than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy.
In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an
average fluvastatin exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued.
The majority of patients with these abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which Lescol capsules were used, persistent
transaminase elevations (>3 times the upper limit of normal [ULN] on two consecutive weekly measure-
ments) occurred in 0.2%, 1.5%, and 2.7% of patients treated with 20, 40, and 80 mg (titrated to 40 mg
twice daily) Lescol capsules, respectively. Ninety-one percent of the cases of persistent liver function
test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with per-
sistent liver function test abnormalities there was an abnormal liver function test present at baseline or by
week 8.
In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in
1.9%, 1.8% and 4.9% of patients treated with Lescol® XL (fluvastatin sodium) 80 mg, Lescol 40 mg and
Lescol 40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol XL the abnormality
occurred within 12 weeks of initiation of treatment with Lescol XL 80 mg.
C24H25FNO4 • Na
Mol. wt. 433.46
H3C
CH3
OH
OH
O
O
Na
F
+
N
T2002-76
89011105
-0.12
-0.10
-0.08
-0.06
-0.04
-0.02
Lescol®
(n=129)
Placebo
(n=132)
-0.094
-0.028
-0.024
-0.100
-0.117
p=0.016
Monotherapy
All Patients
Combination
Therapy
-0.041
0
Change in Minimum Lumen Diameter (mm)
Lescol®
(n=171)
Placebo
(n=169)
Lescol®
+ CME*
(n=42)
*CME=cholestyramine
Placebo
+ CME*
(n=37)
p=0.005
p=0.139
Figure 1
Change in Minimum Lumen Diameter (mm)
0.00%
1.50%
2.00%
2.50%
3.00%
3.50%
Lescol®
(n=129)
Placebo
(n=132)
2.52%
0.59%
0.45%
2.79%
3.65%
p=0.043
Monotherapy
All Patients
Combination
Therapy
0.96%
4.00%
Change in % Diameter Stenosis
1.00%
0.50%
Lescol®
(n=171)
Placebo
(n=169)
Lescol®
+ CME*
(n=42)
*CME=cholestyramine
Placebo
+ CME*
(n=37)
p=0.014
p=0.138
Figure 2
Change in % Diameter Stenosis
©Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
It is recommended that liver function tests be performed before the initiation of therapy and at
12 weeks following initiation of treatment or elevation in dose. Patients who develop transaminase
elevations or signs and symptoms of liver disease should be monitored to confirm the finding and
should be followed thereafter with frequent liver function tests until the levels return to normal. Should
an increase in AST or ALT of three times the upper limit of normal or greater persist (found on two con-
secutive occasions) withdrawal of fluvastatin sodium therapy is recommended.
Active liver disease or unexplained transaminase elevations are contraindications to the use of
Lescol and Lescol XL (see CONTRAINDICATIONS). Caution should be exercised when fluvastatin sodium
is administered to patients with a history of liver disease or heavy alcohol ingestion (see CLINICAL
PHARMACOLOGY: Pharmacokinetics/Metabolism). Such patients should be closely monitored.
Skeletal Muscle
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported with
fluvastatin and with other drugs in this class. Myopathy, defined as muscle aching or muscle weakness
in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper
limit of normal, has been reported.
Myopathy should be considered in any patients with diffuse myalgias, muscle tenderness or
weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unex-
plained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Fluvastatin sodium therapy should be discontinued if markedly elevated CPK levels occur or myopa-
thy is diagnosed or suspected. Fluvastatin sodium therapy should also be temporarily withheld in
any patient experiencing an acute or serious condition predisposing to the development of renal fail-
ure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabol-
ic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy and or rhabdomyolysis during treatment with HMG-CoA reductase inhibitors
has been reported to be increased if therapy with either cyclosporine, gemfibrozil, erythromycin, or
niacin is administered concurrently. Myopathy was not observed in a clinical trial in 74 patients involving
patients who were treated with fluvastatin sodium together with niacin.
Uncomplicated myalgia has been observed infrequently in patients treated with Lescol at rates indis-
tinguishable from placebo.
The use of fibrates alone may occasionally be associated with myopathy. The combined use of
HMG-CoA reductase inhibitors and fibrates should generally be avoided.
PRECAUTIONS
General
Before instituting therapy with Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin sodium), an attempt
should be made to control hypercholesterolemia with appropriate diet, exercise, and weight reduction in
obese patients, and to treat other underlying medical problems (see INDICATIONS AND USAGE).
The HMG-CoA reductase inhibitors may cause elevation of 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 fluvastatin sodium.
Homozygous Familial Hypercholesterolemia
HMG-CoA reductase inhibitors are reported to be less effective in patients with rare homozygous familial
hypercholesterolemia, possibly because these patients have few functional LDL receptors.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness,
particularly if accompanied by malaise or fever.
Women should be informed that if they become pregnant while receiving Lescol or Lescol XL the
drug should be discontinued immediately to avoid possible harmful effects on a developing fetus from a
relative deficit of cholesterol and biological products derived from cholesterol. In addition, Lescol or
Lescol XL should not be taken during nursing. (See CONTRAINDICATIONS.)
Drug Interactions
The below listed drug interaction information is derived from studies using immediate release fluvastatin.
Similar studies have not been conducted using the Lescol XL tablet.
Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin (See WARNINGS:
Skeletal Muscle).
In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP)
isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (~75%), while
CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e. ~5% and ~20%, respectively. If
one pathway is inhibited in the elimination process of fluvastatin other pathways may compensate.
In vivo drug interaction studies with CYP3A4 inhibitors/substrates such as cyclosporine, ery-
thromycin, and itraconazle result in minimal changes in the pharmacokinetics of fluvastatin, confirming
less involvement of CYP3A4 isozyme. Concomitant administration of fluvastatin and phenytoin increased
the levels of phenytoin and fluvastatin, suggesting predominant involvement of CYP2C9 in fluvastatin
metabolism.
Niacin/Propranolol: Concomitant administration of immediate release fluvastatin sodium with niacin or
propranolol has no effect on the bioavailability of fluvastatin sodium.
Cholestyramine: Administration of immediate release fluvastatin sodium concomitantly with, or up to
4 hours after cholestyramine, results in fluvastatin decreases of more than 50% for AUC and 50%-80%
for Cmax. However, administration of immediate release fluvastatin sodium 4 hours after cholestyramine
resulted in a clinically significant additive effect compared with that achieved with either component drug.
Cyclosporine: Plasma cyclosporine levels remain unchanged when fluvastatin (20 mg daily) was
administered concurrently in renal transplant recipients on stable cyclosporine regimens. Fluvastatin
AUC increased 1.9 fold, and Cmax increased 1.3 fold compared to historical controls.
Digoxin: In a crossover study involving 18 patients chronically receiving digoxin, a single 40 mg dose
of immediate release fluvastatin had no effect on digoxin AUC, but had an 11% increase in digoxin Cmax
and small increase in digoxin urinary clearance.
Erythromycin: Erythromycin (500 mg, single dose) did not affect steady-state plasma levels of fluvastatin
(40 mg daily).
Itraconazole: Concomitant administration of fluvastatin (40 mg) and itraconazole (100 mg daily x 4 days)
does not affect plasma itraconazole or fluvastatin levels.
Gemfibrozil: There is no change in either fluvastatin (20 mg twice daily) or gemfibrozil (600 mg twice daily)
plasma levels when these drugs are co-administered.
Phenytoin: Single morning dose administration of phenytoin (300 mg extended release) increased
mean steady-state fluvastatin (40 mg) Cmax by 27% and AUC by 40% whereas fluvastatin increased the
mean phenytoin Cmax by 5% and AUC by 20%. Patients on phenytoin should continue to be monitored
appropriately when fluvastatin therapy is initiated or when the fluvastatin dosage is changed.
Diclofenac: Concurrent administration of fluvastatin (40 mg) increased the mean Cmax and AUC of
diclofenac by 60% and 25% respectively.
Tolbutamide: In healthy volunteers, concurrent administration of either single or multiple daily doses of
fluvastatin sodium (40 mg) with tolbutamide (1 g) did not affect the plasma levels of either drug to a
clinically significant extent.
Glibenclamide (Glyburide): In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin
(40 mg twice daily for 14 days) increased the mean Cmax, AUC, and t1/2 of glibenclamide approximately
50%, 69% and 121%, respectively. Glibenclamide (5-20 mg daily) increased the mean Cmax and AUC of
fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin and
C-peptide levels. However, patients on concomitant therapy with glibenclamide (glyburide) and fluvastatin
should continue to be monitored appropriately when their fluvastatin dose is increased to 40 mg twice
daily.
Losartan: Concomitant administration of fluvastatin with losartan has no effect on the bioavailability of
either losartan or its active metabolite.
Cimetidine/Ranitidine/Omeprazole: Concomitant administration of immediate release fluvastatin
sodium with cimetidine, ranitidine and omeprazole results in a significant increase in the fluvastatin Cmax
(43%, 70% and 50%, respectively) and AUC (24%-33%), with an 18%-23% decrease in plasma clearance.
Rifampicin: Administration of immediate release fluvastatin sodium to subjects pretreated with
rifampicin results in significant reduction in Cmax (59%) and AUC (51%), with a large increase (95%) in
plasma clearance.
Warfarin: In vitro protein binding studies demonstrated no interaction at therapeutic concentrations.
Concomitant administration of a single dose of warfarin (30 mg) in young healthy males receiving
immediate release fluvastatin sodium (40 mg/day x 8 days) resulted in no elevation of racemic warfarin
concentration. There was also no effect on prothrombin complex activity when compared to concomitant
administration of placebo and warfarin. However, bleeding and/or increased prothrombin times have
been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase
inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times
closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating cholesterol
levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production.
Fluvastatin exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon
thyroid metabolism as assessed by TSH. Small declines in total testosterone have been noted in treated
groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to
a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited
number of premenopausal females studied to date, no conclusions regarding the effect of fluvastatin
upon female sex hormones may be made.
Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to
28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical
study evaluated the effect of fluvastatin at doses up to 80 mg daily for 28 weeks upon the gonadal
response to HCG stimulation. Although the mean total testosterone response was significantly reduced
(p<0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes
noted in groups receiving either 40 mg of fluvastatin or placebo.
Patients treated with fluvastatin sodium who develop clinical evidence of endocrine dysfunction
should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or
other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., keto-
conazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones.
CNS Toxicity
CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in
the following animal studies: the 18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month
dog study at 36 mg/kg/day, the 6-month hamster study at 40 mg/kg/day, and in acute, high-dose studies
in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute
high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns
of the spinal cord at a dose of 5000 mg/kg and (in rat) by edema with separation of myelinated fibers of
the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periax-
onal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with
48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to
36 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononu-
clear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of
this class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin
in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).
Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with
1, 8, and 16 mg/kg/day for 2 years.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day.
These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the
mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach
squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was consid-
ered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather
than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adeno-
mas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of
thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with find-
ings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no
hepatic adenomas or carcinomas were observed.
The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as
in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females
at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels
of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral
dose.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in
the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or
Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat
primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese
Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse
micronucleus test.
In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2,
10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.
Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approxi-
mately three times the 40 milligram human daily dose based on surface area, mg/m2). There was tubular
degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of
seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day
(approximately 4 times the human Cmax achieved with a 40 milligram daily dose).
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rab-
bits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that
produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at
10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. A study in which female rats were
dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term
and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus
occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings
in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was per-
formed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementa-
tion with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol
biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and
neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on days 0 and 7 postpar-
tum. Therefore, the maternal and neonatal lethality observed with fluvastatin sodium reflect its exagger-
ated pharmacologic effect during pregnancy. There are no data with fluvastatin sodium in pregnant
women. However, rare reports of congenital anomalies have been received following intrauterine expo-
sure to other HMG-CoA reductase inhibitors. There has been one report of severe congenital bony defor-
mity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who
took another HMG-CoA reductase inhibitor with dextroamphetamine sulfate during the first trimester of
pregnancy. Lescol or Lescol XL 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.
If a woman becomes pregnant while taking Lescol or Lescol XL, the drug should be discontinued and
the patient advised again as to the potential hazards to the fetus.
Nursing Mothers
Based on preclinical data, drug is present in breast milk in a 2:1 ratio (milk:plasma). Because of the
potential for serious adverse reactions in nursing infants, nursing women should not take Lescol or
Lescol XL (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in individuals less than 18 years old have not been established. Treatment in
patients less than 18 years of age is not recommended at this time.
Geriatric Use
The effect of age on the pharmacokinetics of immediate release fluvastatin sodium was evaluated.
Results indicate that for the general patient population plasma concentrations of fluvastatin sodium do
not vary as a function of age. (See also CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism.)
Elderly patients (≥65 years of age) demonstrated a greater treatment response in respect to LDL-C,
Total-C and LDL/HDL ratio than patients <65 years of age.
ADVERSE REACTIONS
In all clinical studies of Lescol® (fluvastatin sodium), 1.0% (32/2969) of fluvastatin-treated patients were
discontinued due to adverse experiences attributed to study drug (mean exposure approximately
16 months ranging in duration from 1 to >36 months). This results in an exposure adjusted rate of 0.8%
(32/4051) per patient year in fluvastatin patients in controlled studies compared to an incidence of 1.1%
(4/355) in placebo patients. Adverse reactions have usually been of mild to moderate severity.
In controlled clinical studies, 3.9% (36/912) of patients treated with Lescol® XL (fluvastatin sodium)
80 mg discontinued due to adverse events (causality not determined).
Adverse experiences occurring in the Lescol and Lescol XL controlled studies with a frequency >2%,
regardless of causality, include the following:
Table 5
Adverse experiences occurring in >2% patients
in Lescol and Lescol XL controlled studies
Lescol1
Placebo1
Lescol XL2
(%)
(%)
(%)
Adverse Event
(N=2326)
(N=960)
(N = 912)
Integumentary
Rash
2.3
2.4
1.6
Musculoskeletal
Back Pain
5.7
6.6
4.7
Myalgia
5.0
4.5
3.8
Arthralgia
4.0
4.1
1.3
Arthritis
2.1
2.0
1.3
Arthropathy
NA
NA
3.2
Respiratory
Upper Respiratory
Tract Infection
16.2
16.5
12.5
Pharyngitis
3.8
3.8
2.4
Rhinitis
4.7
4.9
1.5
Sinusitis
2.6
1.9
3.5
Coughing
2.4
2.9
1.9
Bronchitis
1.8
1.0
2.6
Gastrointestinal
Dyspepsia
7.9
3.2
3.5
Diarrhea
4.9
4.2
3.3
Abdominal Pain
4.9
3.8
3.7
Nausea
3.2
2.0
2.5
Constipation
3.1
3.3
2.3
Flatulence
2.6
2.5
1.4
Misc. Tooth Disorder
2.1
1.7
1.4
Central Nervous System
Dizziness
2.2
2.5
1.9
Psychiatric Disorders
Insomnia
2.7
1.4
0.8
Genitourinary
Urinary Tract Infection
1.6
1.1
2.7
Miscellaneous
Headache
8.9
7.8
4.7
Influenza-Like Symptoms
5.1
5.7
7.1
Accidental Trauma
5.1
4.8
4.2
Fatigue
2.7
2.3
1.6
Allergy
2.3
2.2
1.0
1 Controlled trials with Lescol Capsules (20 and 40 mg daily and 40 mg twice daily)
2 Controlled trials with Lescol XL 80 mg Tablets
The following effects have been reported with drugs in this class. Not all the effects listed below
have necessarily been associated with fluvastatin sodium 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 neu-
ropathy, 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 erythematosus-like
syndrome, polymyalgia rheumatica, 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, g-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
Concomitant Therapy
Fluvastatin sodium has been administered concurrently with cholestyramine and nicotinic acid. No
adverse reactions unique to the combination or in addition to those previously reported for this class of
drugs alone have been reported. Myopathy and rhabdomyolysis (with or without acute renal failure)
have been reported when another HMG-CoA reductase inhibitor was used in combination with immuno-
suppressive drugs, gemfibrozil, erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant
therapy with HMG-CoA reductase inhibitors and these agents is generally not recommended. (See
WARNINGS: Skeletal Muscle.)
OVERDOSAGE
The approximate oral LD50 is greater than 2 g/kg in mice and greater than 0.7 g/kg in rats.
The maximum single oral dose of Lescol® (fluvastatin sodium) capsules received by healthy volun-
teers was 80 mg. No clinically significant adverse experiences were seen at this dose. The maximum
dose administered with an extended-release formulation was 640 mg for two weeks. This dose was not
well tolerated and produced a variety of GI complaints and an increase in transaminase values (i.e.,
SGOT and SGPT).
There has been a single report of 2 children, one 2 years old and the other 3 years of age, either of
whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that
could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both
children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms
and both recovered from the incident without problems.
Should an accidental overdose occur, treat symptomatically and institute supportive measures as
required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present.
Information about the treatment of overdose can often be obtained from a certified Regional Poison
Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the
Physicians' Desk Reference®.*
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving Lescol®
(fluvastatin sodium) or Lescol® XL (fluvastatin sodium) and should continue on this diet during treat-
ment with Lescol or Lescol XL. (See NCEP Treatment Guidelines for details on dietary therapy.)
For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting dose is
40 mg as one capsule, 80 mg as one Lescol XL tablet administered as a single dose in the evening or
80 mg in divided doses of the 40 mg capsule given twice daily. For patients requiring LDL-C reduction
to a goal of <25% a starting dose of 20 mg may be used. The recommended dosing range is 20-80 mg/day.
Lescol or Lescol XL may be taken without regard to meals, since there are no apparent differences in the
lipid-lowering effects of fluvastatin sodium administered with the evening meal or 4 hours after the
evening meal. Since the maximal reductions in LDL-C of a given dose are seen within 4 weeks, periodic
lipid determinations should be performed and dosage adjustment made according to the patient's
response to therapy and established treatment guidelines. The therapeutic effect of Lescol or Lescol XL
is maintained with prolonged administration.
Concomitant Therapy
Lipid-lowering effects on total cholesterol and LDL cholesterol are additive when immediate release
Lescol is combined with a bile-acid binding resin or niacin. When administering a bile-acid resin (e.g.,
cholestyramine) and fluvastatin sodium, Lescol should be administered at bedtime, at least 2 hours fol-
lowing the resin to avoid a significant interaction due to drug binding to resin. (See also ADVERSE
REACTIONS: Concomitant Therapy.)
Dosage in Patients with Renal Insufficiency
Since fluvastatin sodium is cleared hepatically with less than 6% of the administered dose excreted into
the urine, dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has
not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore caution
should be exercised when treating such patients at higher doses.
HOW SUPPLIED
Lescol® (fluvastatin sodium) Capsules
20 mg
Brown and light brown imprinted twice with "
" and "20" on one half and "LESCOL" and the Lescol®
(fluvastatin sodium) logo twice on the other half of the capsule.
Bottles of 30 capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(NDC 0078-0176-15)
Bottles of 100 capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(NDC 0078-0176-05)
40 mg
Brown and gold imprinted twice with "
" and "40" on one half and "LESCOL" and the Lescol®
(fluvastatin sodium) logo twice on the other half of the capsule.
Bottles of 30 capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(NDC 0078-0234-15)
Bottles of 100 capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(NDC 0078-0234-05)
Lescol® XL (fluvastatin sodium) Extended-Release Tablets
80 mg
Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with "Lescol XL" on one
side and "80" on the other.
Bottles of 30 tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(NDC 0078-0354-15)
Bottle of 100 tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(NDC 0078-0354-05)
Store and Dispense
Store at 25˚C (77˚F); excursions permitted to 15˚C-30˚C (59˚F-86˚F). [See USP Controlled Room
Temperature]. Dispense in a tight container. Protect from light.
*Trademark of Medical Economics Company, Inc.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
T2002-76
REV: AUGUST 2002 Printed in U.S.A. 89011105
Lescol® (fluvastatin sodium) Capsules
Lescol® XL (fluvastatin sodium) Extended-Release Tablets
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.
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/s/
---------------------
David Orloff
9/6/02 01:45:33 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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PATIENT INFORMATION
LESCOL® [ lĕs-cŏl]
(fluvastatin sodium)
Capsules
and
LESCOL® [ lĕs-cŏl] XL
(fluvastatin sodium)
Extended-release tablets
Read the Patient Information that comes with
LESCOL or LESCOL XL before you start taking it,
and each time you get a refill. There may be new
information. This leaflet does not take the place of
talking with your doctor about your condition or
treatment.
If you have any questions about LESCOL or LESCOL
XL, ask your doctor or pharmacist.
What are LESCOL and LESCOL XL?
LESCOL and LESCOL XL are prescription medicines
called "statins" that lower cholesterol in your blood.
They lower the "bad" cholesterol and triglycerides in
your blood. They can raise your "good" cholesterol as
well.
LESCOL and LESCOL XL are for people whose
cholesterol does not come down enough with exercise
and a low-fat diet alone.
LESCOL and LESCOL XL may be used in patients
with heart disease (coronary artery disease) to:
• lower the chances of heart problems which would
require procedures to help restore blood flow to
the heart.
• slow the buildup of too much cholesterol in the
arteries of the heart.
Treatment with LESCOL or LESCOL XL has not
been shown to prevent heart attacks or stroke.
LESCOL and LESCOL XL have the same active
ingredient, fluvastatin. However, LESCOL is a
capsule that is taken one or two times a day and
LESCOL XL is an extended-release tablet that is only
taken one time a day.
Who should not take LESCOL or LESCOL XL?
Do not take LESCOL or LESCOL XL if you:
• are pregnant or think you may be
pregnant, or are planning to become
pregnant. LESCOL and LESCOL XL may
harm your unborn baby. If you get pregnant,
stop taking LESCOL or LESCOL XL and
call your doctor right away.
• are breast-feeding. LESCOL and LESCOL
XL can pass into your breast milk and may
harm your baby
• have liver problems
• are allergic to LESCOL or LESCOL XL
or any of its ingredients. The active
ingredient in LESCOL and LESCOL XL is
fluvastatin. See the end of this leaflet for a
complete list of ingredients in LESCOL and
LESCOL XL.
LESCOL and LESCOL XL have not been
studied in children under 18 years of age.
LESCOL and LESOL XL are not recommended
for use in children.
Before taking LESCOL or LESCOL XL,
tell your doctor if you:
• have muscle aches or weakness
• drink more than 2 glasses of alcohol
daily
• have diabetes
• have a thyroid problem
• have kidney problems
Some medicines should not be taken with
LESCOL or LESCOL XL. Tell your doctor
about all the medicines you take, including
prescription and non-prescription medicines,
vitamins and herbal supplements. LESCOL and
LESCOL XL and certain other medicines can
interact causing serious side effects. Especially
tell your doctor if you take medicines for:
• your immune system
• cholesterol
• infections
• heart failure
• seizures
• diabetes
• heartburn or stomach ulcers
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know all the medicines you take. Keep a list of all
the medicines you take with you to show your doctor
and pharmacist.
How should I take LESCOL or LESCOL XL?
• Take LESCOL or LESCOL XL exactly as
prescribed. Your doctor will prescribe the one that
is right for you. Do not change your dose or stop
LESCOL or LESCOL XL without talking to your
doctor. Your doctor may do blood tests to check
your cholesterol levels during treatment with
LESCOL and LESCOL XL. Your dose of
LESCOL or LESCOL XL may be changed based
on these blood test results.
• Take LESCOL capsules or LESCOL XL tablets at
the same time every evening. Sometimes
LESCOL capsules are also taken every morning.
LESCOL and LESCOL XL can be taken with or
without food.
• LESCOL XL tablets must be swallowed whole
with a liquid. Do not break, crush or chew
LESCOL XL tablets or open Lescol capsules.
Tell your doctor if you cannot swallow tablets
whole. You may need LESCOL capsules or a
different medicine instead of LESCOL XL tablets.
• Your doctor should start you on a low-fat and low-
cholesterol diet before giving you LESCOL or
LESCOL XL. Stay on this low-fat and low-
cholesterol diet while taking LESCOL or
LESCOL XL.
• If you miss a dose of LESCOL or LESCOL XL,
take it as soon as you remember. Do not take
Lescol or Lescol XL if it has been more than 12
hours since your last dose. Wait and take the next
dose at your regular time. Do not take 2 doses of
Lescol or Lescol XL at the same time.
• If you take too much LESCOL or LESCOL XL or
overdose, call your doctor or Poison Control
Center right away. Or, go to the nearest emergency
room.
What should I avoid while taking LESCOL or
LESCOL XL?
• Talk to your doctor before you start any new
medicines. This includes prescription and non-
prescription medicines, vitamins and herbal
supplements. LESCOL and LESCOL XL and
certain other medicines can interact causing
serious side effects.
• Do not get pregnant. If you get pregnant,
stop taking LESCOL or LESCOL XL right
away and call your doctor.
What are the possible side effects of
LESCOL and LESCOL XL?
When taking LESCOL and LESCOL XL, some
patients may develop serious side effects,
including:
• muscle problems. These serious muscle
problems can sometimes lead to kidney
problems, including kidney failure. You
have a higher chance for muscle problems if
you are taking certain other medicines with
LESCOL or LESCOL XL.
• liver problems. Your doctor may do blood
tests to check your liver before you start
taking LESCOL or LESCOL XL, and while
you are taking one of them.
Call your doctor right away if you have:
• muscle problems like weakness, tenderness,
or pain that happen without a good reason,
especially if you also have a fever or feel
more tired than usual
• nausea and vomiting
• passing brown or dark-colored urine
• you feel more tired than usual
• your skin and whites of your eyes get yellow
• stomach pain
The most common side effects of LESCOL or
LESCOL XL are headache, upset stomach and
stomach pain, diarrhea, flu-like symptoms,
muscle pain, sinus infection, tiredness, or trouble
sleeping. These side effects are usually mild and
may go away.
Talk to your doctor or pharmacist if you have
side effects that bother you or that will not go
away.
These are not all the side effects of LESCOL and
LESCOL XL. Ask your doctor or pharmacist for
a complete list.
How should I store LESCOL and LESCOL
XL?
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store LESCOL and LESCOL XL at room
temperature, 59° to 86° F (15° to 30° C).
• Do not keep medicine that is out of date or that
you no longer need.
• Keep LESCOL and LESCOL XL out of the
reach of children. Be sure that if you throw
medicines away, it is out of the reach of children.
General information about LESCOL and
LESCOL XL
Medicines are sometimes prescribed for conditions
that are not mentioned in patient information leaflets.
Do not use LESCOL or LESCOL XL for a condition
for which it was not prescribed. Do not give
LESCOL or LESCOL XL to other people, even if they
have the same problem you have. It may harm them.
This leaflet summarizes the most important
information about LESCOL and LESCOL XL. If you
would like more information, talk with your doctor.
For information that is written for health
professionals, ask your doctor or pharmacist or call 1-
888-669-6682.
What are the ingredients in LESCOL and
LESCOL XL?
Active Ingredient: fluvastatin sodium
Inactive Ingredients:
LESCOL Capsules: gelatin, magnesium
stearate, microcrystalline cellulose, pregelatinized
starch (corn), red iron oxide, sodium lauryl sulfate,
talc, titanium dioxide, yellow iron oxide, and other
ingredients. The capsules may also contain benzyl
alcohol, black iron oxide, butylparaben,
carboxymethylcellulose sodium, edetate calcium
disodium, methylparaben, propylparaben, silicon
dioxide, and sodium propionate.
LESCOL XL Tablets: microcrystalline
cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, potassium bicarbonate, povidone,
magnesium stearate, yellow iron oxide, titanium
dioxide and polyethylene glycol 8000.
Rx only
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
August 2004
89023001
T2004-60
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Lescol
®
(fluvastatin sodium)
Capsules
Lescol
® XL
(fluvastatin sodium)
Extended-Release Tablets
Rx only
Prescribing Information
DESCRIPTION
Lescol® (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through
the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
Fluvastatin sodium is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-
indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of
fluvastatin sodium is C24H25FNO4•Na, its molecular weight is 433.46 and its structural
formula is:
This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and
is in part structurally distinct from the fungal derivatives of this therapeutic class.
Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water,
ethanol and methanol. Lescol is supplied as capsules containing fluvastatin sodium,
equivalent to 20 mg or 40 mg of fluvastatin, for oral administration. Lescol® XL (fluvastatin
sodium) is supplied as extended-release tablets containing fluvastatin sodium, equivalent to
80 mg of fluvastatin, for oral administration.
Active Ingredient: fluvastatin sodium
Inactive Ingredients in capsules: gelatin, magnesium stearate, microcrystalline cellulose,
pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide,
yellow iron oxide, and other ingredients.
Capsules may also include: benzyl alcohol, black iron oxide, butylparaben,
carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben,
silicon dioxide and sodium propionate.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2
Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium
stearate, iron oxide yellow, titanium dioxide and polyethylene glycol 8000.
CLINICAL PHARMACOLOGY
A variety of clinical studies have demonstrated that elevated levels of total cholesterol
(Total-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and apolipoprotein
B (a membrane transport complex for LDL-C) promote human atherosclerosis. Similarly,
decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A,
are associated with the development of atherosclerosis. Epidemiologic investigations have
established that cardiovascular morbidity and mortality vary directly with the level of Total-C
and LDL-C and inversely with the level of HDL-C.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL
and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently
found in a triad with low HDL-C levels and small LDL particles, as well as in association
with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has
not consistently been shown to be an independent risk factor for CHD. Furthermore, the
independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular
morbidity and mortality has not been determined.
In patients with hypercholesterolemia and mixed dyslipidemia, treatment with Lescol®
(fluvastatin sodium) or Lescol® XL (fluvastatin sodium) reduced Total-C, LDL-C,
apolipoprotein B, and triglycerides while producing an increase in HDL-C. Increases in
HDL-C are greater in patients with low HDL-C (<35 mg/dL). Neither agent had a consistent
effect on either Lp(a) or fibrinogen. The effect of Lescol or Lescol XL induced changes in
lipoprotein levels, including reduction of serum cholesterol, on cardiovascular mortality has
not been determined.
Mechanism of Action
Lescol is a competitive inhibitor of HMG-CoA reductase, which is responsible for the
conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a
precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces
the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby
increases the uptake of LDL particles. The end result of these biochemical processes is a
reduction of the plasma cholesterol concentration.
Pharmacokinetics/Metabolism
Oral Absorption
Fluvastatin is absorbed rapidly and completely following oral administration of the capsule,
with peak concentrations reached in less than 1 hour. Following administration of a 10 mg
dose, the absolute bioavailability is 24% (range 9%-50%). Administration with food reduces
the rate but not the extent of absorption. At steady-state, administration of fluvastatin with the
evening meal results in a two-fold decrease in Cmax and more than two-fold increase in tmax as
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3
compared to administration 4 hours after the evening meal. No significant differences in
extent of absorption or in the lipid-lowering effects were observed between the two
administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable
first-pass metabolism resulting in higher-than-expected plasma fluvastatin concentrations.
Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form.
In vivo studies showed that stereo-selective hepatic binding of the active form occurs during
the first pass resulting in a difference in the peak levels of the two enantiomers, with the
active to inactive peak concentration ratio being about 0.7. The approximate ratio of the active
to inactive approaches unity after the peak is seen and thereafter the two enantiomers decline
with the same half-life. After an intravenous administration, bypassing the first-pass
metabolism, the ratios of the enantiomers in plasma were similar throughout the
concentration-time profiles.
Fluvastatin administered as Lescol XL 80 mg tablets reaches peak concentration in
approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a
low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range:
9%-66%) compared to that of the Lescol immediate release capsule administered under
fasting conditions. Administration of a high fat meal delayed the absorption (Tmax: 6H) and
increased the bioavailability of the XL tablet by approximately 50%. Once Lescol XL begins
to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after
a high fat meal is much less than the peak concentration following a single dose or twice daily
dose of the 40 mg Lescol capsule. Overall variability in the pharmacokinetics of Lescol XL is
large (42%-64% CV for Cmax and AUC), and especially so after a high fat meal (63%-89% for
Cmax and AUC). Intrasubject variability in the pharmacokinetics of Lescol XL under fasting
conditions (about 25% for Cmax and AUC) tends to be much smaller as compared to the
overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed
after Lescol XL administration.
Distribution
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is
estimated at 0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are
present systemically. At therapeutic concentrations, the protein binding of fluvastatin is not
affected by warfarin, salicylic acid and glyburide.
Metabolism
Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the
5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The
hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood.
Both enantiomers of fluvastatin are metabolized in a similar manner.
In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism,
predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin
metabolism are 2C8 (~5%) and 3A4 (~20%). (See PRECAUTIONS: Drug Interactions
Section).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4
Elimination
Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2%
present as unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of
fluvastatin, the clearance was 0.8 L/h/kg. Following multiple oral doses of radiolabeled
compound, there was no accumulation of fluvastatin; however, there was a 2.3 fold
accumulation of total radioactivity.
Steady-state plasma concentrations show no evidence of accumulation of fluvastatin
following immediate release capsule administration of up to 80 mg daily, as evidenced by a
beta-elimination half-life of less than 3 hours. However, under conditions of maximum rate of
absorption (i.e., fasting) systemic exposure to fluvastatin is increased 33% to 53% compared
to a single 20 mg or 40 mg dose of the immediate release capsule. Following once daily
administration of the 80 mg Lescol XL tablet for 7 days, systemic exposure to fluvastatin is
increased (20%-30%) compared to a single dose of the 80 mg Lescol XL tablet. Terminal
half-life of Lescol XL was about 9 hours as a result of the slow-release formulation.
Single-dose and steady-state pharmacokinetic parameters in 33 subjects with
hypercholesterolemia for the capsules and in 35 healthy subjects for the extended-release
tablets are summarized below:
Table 1
Single-Dose and Steady-State Pharmacokinetic Parameters
Cmax
(ng/mL)
mean±SD
(range)
AUC
(ng·h/mL)
mean±SD
(range)
tmax
(hr)
mean±SD
(range)
CL/F
(L/hr)
mean±SD
(range)
t1/2
(hr)
mean±SD
(range)
Capsules
166±106
207±65
0.9±0.4
107±38.1
2.5±1.7
20 mg single
dose (n=17)
(48.9-517)
(111-288)
(0.5-2.0)
(69.5-181)
(0.5-6.6)
200±86
275±111
1.2±0.9
87.8±45
2.8±1.7
20 mg twice daily
(n=17)
(71.8-366)
(91.6-467)
(0.5-4.0)
(42.8-218)
(0.9-6.0)
273±189
456±259
1.2±0.7
108±44.7
2.7±1.3
40 mg single
dose (n=16)
(72.8-812)
(207-1221)
(0.75-3.0)
(32.8-193)
(0.8-5.9)
432±236
697±275
1.2±0.6
64.2±21.1
2.7±1.3
40 mg twice daily
(n=16)
(119-990)
(359-1559)
(0.5-2.5)
(25.7-111)
(0.7-5.0)
Extended-Release Tablets 80 mg single dose (n=24)
126±53
579±341
3.2± 2.6
-
-
80 mg single dose,
fasting (n=24)
(37-242)
(144-1760)
(1-12)
183±163
861±632
6
-
-
80 mg single dose,
fed-state high fat
meal (n=-24)
(21-733)
(199-3132)
(2-24)
Extended-Release Tablets 80 mg following 7 days dosing (steady-state) (n-11)
102±42
630±326
2.6±0.91
-
-
80 mg once daily,
fasting (n=11)
(43.9-181)
(247-1406)
(1.5-4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5
Special Populations
Renal Insufficiency:
No significant (<6%) renal excretion of fluvastatin occurs in humans.
Hepatic Insufficiency:
Fluvastatin is subject to saturable first-pass metabolism/sequestration by the liver and is
eliminated primarily via the biliary route. Therefore, the potential exists for drug
accumulation in patients with hepatic insufficiency. Caution should therefore be exercised
when fluvastatin sodium is administered to patients with a history of liver disease or heavy
alcohol ingestion (see WARNINGS).
Fluvastatin AUC and Cmax values increased by about 2.5 fold in hepatic insufficiency
patients. This result was attributed to the decreased presystemic metabolism due to hepatic
dysfunction. The enantiomer ratios of the two isomers of fluvastatin in hepatic insufficiency
patients were comparable to those observed in healthy subjects.
Age:
Plasma levels of fluvastatin are not affected by age.
Gender:
Women tend to have slightly higher (but statistically insignificant) fluvastatin concentrations
than men for the immediate release capsule. This is most likely due to body weight
differences, as adjusting for body weight decreases the magnitude of the differences seen. For
Lescol XL, there are 67% and 77% increases in systemic availability for women over men
under fasted and high fat meal conditions.
Pediatric:
Pharmacokinetic data in the pediatric population are not available.
CLINICAL STUDIES
Hypercholesterolemia (heterozygous familial and non familial) and Mixed
Dyslipidemia
In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinemia,
Lescol® (fluvastatin sodium) alone was administered to 1621 patients in daily dose regimens
of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration. After 24 weeks
of treatment, daily doses of 20 mg, 40 mg, and 80 mg (40 mg twice daily) resulted in median
LDL-C reductions of 22% (n=747), 25% (n=748) and 36% (n=257), respectively. Lescol
treatment produced dose-related reductions in Apo B and in triglycerides and increases in
HDL-C. The median (25th, 75th percentile) percent changes from baseline in HDL-C after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6
12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice
daily) were +2 (-4,+10), +5 (-2,+12), and +4 (-3,+12), respectively. In a subgroup of patients
with primary mixed dyslipidemia, defined as baseline TG levels ≥200 mg/dL, treatment with
Lescol also produced significant decreases in Total-C, LDL-C, TG and Apo B and variable
increases in HDL-C. The median (25th, 75th percentile) percent changes from baseline in
HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg
(40 mg twice daily) in this population were +4 (-2,+12), +8 (+1,+15), and +4 (-3,+13),
respectively.
In a long-term open-label free titration study, after 96 weeks LDL-C decreases of 25%
(20 mg, n=68), 31% (40 mg, n=298) and 34% (80 mg, n=209) were seen. No consistent effect
on Lp(a) was observed.
Lescol® XL (fluvastatin sodium) Extended-Release Tablets have been studied in five
controlled studies of patients with Type IIa or IIb hyperlipoproteinemia. Lescol XL was
administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest
of these studies, Lescol XL given as a single daily dose of 80 mg significantly reduced
Total-C, LDL-C, TG and Apo B. Therapeutic response is well established within two weeks,
and a maximum response is achieved within four weeks. After four weeks of therapy, the
median decrease in LDL-C was 38% and at week 24 endpoint the median LDL-C decrease
was 35%. Significant increases in HDL-C were also observed. The median (25th and 75th
percentile) percent changes from baseline in HDL-C for Lescol XL were +7(+0,+15) after 24
weeks of treatment.
Table 2
Median Percent Change in Lipid Parameters from Baseline to Week 24 Endpoint
All Placebo-Controlled Studies (Lescol®) and Active Controlled Trials (Lescol® XL)
Total Chol.
TG
LDL
Apo B
HDL
Dose
N
% ∆
N
% ∆
N
% ∆
N
% ∆
N
% ∆
All patients
Lescol 20 mg1
747
-17
747
-12
747
-22
114
-19
747
+3
Lescol 40 mg1
748
-19
748
-14
748
-25
125
-18
748
+4
Lescol 40 mg twice daily1
257
-27
257
-18
257
-36
232
-28
257
+6
Lescol XL 80 mg2
750
-25
750
-19
748
-35
745
-27
750
+7
Baseline TG ≥200 mg/dL
Lescol 20 mg1
148
-16
148
-17
148
-22
23
-19
148
+6
Lescol 40 mg1
179
-18
179
-20
179
-24
47
-18
179
+7
Lescol 40 mg twice daily1
76
-27
76
-23
76
-35
69
-28
76
+9
Lescol XL 80 mg2
239
-25
239
-25
237
-33
235
-27
239
+11
1 Data for Lescol from 12 placebo controlled trials
2 Data for Lescol XL 80 mg tablet from three 24 week controlled trials
In patients with primary mixed dyslipidemia (Fredrickson Type IIb) as defined by
baseline plasma triglycerides levels ≥200 mg/dL, Lescol XL 80 mg produced a median
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 7
reduction in triglycerides of 25%. In these patients, Lescol XL 80 mg produced median
(25th and 75th percentile) percent change from baseline in HDL-C of +11(+3,+20). Significant
decreases in Total-C, LDL-C, and Apo B were also achieved. In these studies, patients with
triglycerides >400 mg/dL were excluded.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
Fluvastatin sodium was studied in two open-label, uncontrolled, dose-titration studies which
enrolled pediatric patients with heterozygous familial hypercholesterolemia. The first study
enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level > 90th percentile
for age and one parent with primary hypercholesterolemia and either a family history of
premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226
mg/dL (range: 137-354 mg/dL). All patients were started on Lescol capsules 20 mg daily
with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg bid) to achieve
an LDL-C goal of 96.7 to 123.7 mg/dL. Endpoint analyses were performed at Year 2. The
second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C
> 190 mg/dL or LDL-C > 160 mg/dL and one or more risk factors for coronary heart disease,
or LDL-C > 160 mg/dL and a proven LDL-receptor defect. The mean baseline LDL-C was
225 mg/dL (range: 148-343 mg/dL). All patients were started on Lescol capsules 20 mg daily
with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (Lescol 80 mg XL
tablet) to achieve an LDL-C goal of < 130 mg/dL. Endpoint analyses were performed at
Week 114.
In the first study, Lescol 20 to 80 mg daily doses decreased plasma levels of total-C
and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL
(range: 74-336 mg/dL). In the second study, Lescol 20 to 80 mg daily doses decreased
plasma levels of total-C and LDL-C by 22% and 28%, respectively. The mean achieved
LDL-C was 159 mg/dL (range: 90-295 mg/dL).
The majority of patients in both studies (83% in the first study and 89% in the second
study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26 to 30% of
patients in both studies achieved a targeted LDL-C goal of < 130 mg/dL. The long-term
efficacy of Lescol or Lescol XL therapy in childhood to reduce morbidity and mortality in
adulthood has not been established
Reduction in the Risk of Recurrent Cardiac Events
In the Lescol Intervention Prevention Study, the effect of Lescol 40 mg administered twice
daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal
myocardial infarction, or revascularization) was assessed in 1677 patients with coronary heart
disease who had undergone a percutaneous coronary intervention (PCI) procedure (mean time
from PCI to randomization=3 days). In this multicenter, randomized, double-blind, placebo-
controlled study, patients were treated with dietary/lifestyle counseling and either Lescol
40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. The study
population was 84% male, 98% Caucasian, with 37% >65 years of age. At baseline patients
had total cholesterol between 100 and 367 mg/dL (mean 201 mg/dL), LDL-C between 42 and
243 mg/dL (mean 132 mg/dL), triglycerides between 15 and 270 mg/dL (mean 70 mg/dL) and
HDL-C between 8 and 174 mg/dL (mean 39 mg/dL).
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Lescol significantly reduced the risk of recurrent cardiac events (Figure 1) by 22%
(p=0.013, 181 patients in the Lescol group vs. 222 patients in the placebo group).
Revascularization procedures comprised the majority of the initial recurrent cardiac events
(143 revascularization procedures in the Lescol group and 171 in the placebo group).
Consistent trends in risk reduction were observed in patients >65 years of age).
Figure 1.
Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal
MI or Revascularization Procedure) (ITT Population)
Outcome data for the Lescol Intervention Prevention Study are shown in Figure 2. After
exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6
months of the initial procedure involving the originally instrumental site, treatment with
Lescol was associated with a 32% (p=0.002) reduction in risk of late revascularization
procedures (CABG or PCI occurring at the original site >6 months after the initial procedure,
or at another site).
Figure 2.
Lescol® Intervention Prevention Study - Primary and Secondary
Endpoints
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Atherosclerosis
In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of Lescol therapy
on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in
patients with coronary artery disease and mild to moderate hypercholesterolemia (baseline
LDL-C range 115-190 mg/dL). In this randomized double-blind, placebo controlled trial,
429 patients were treated with conventional measures (Step 1 AHA Diet) and either Lescol
40 mg/day or placebo. In order to provide treatment to patients receiving placebo with LDL-C
levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after
week 12 to all patients in the study with baseline LDL-C values of ≥160 mg/dL. These
baseline levels were present in 25% of the study population. Quantitative coronary
angiograms were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable
patients.
Lescol significantly slowed the progression of coronary atherosclerosis. Compared to
placebo, Lescol significantly slowed the progression of lesions as measured by within-patient
per-lesion change in minimum lumen diameter (MLD), the primary endpoint (see Figure 3
below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all
fluvastatin patients versus 22% of all placebo patients). Additionally, a significant difference
in favor of Lescol was found between all fluvastatin and all placebo patients in the
distribution among the three categories of definite progression, definite regression, and mixed
or no change. Beneficial angiographic results (change in MLD) were independent of patients’
gender and consistent across a range of baseline LDL-C levels.
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INDICATIONS AND USAGE
Therapy with lipid-altering agents should be used in addition to a diet restricted in saturated
fat and cholesterol (see National Cholesterol Education Program (NCEP) Treatment
Guidelines, below).
Hypercholesterolemia (heterozygous familial and non familial) and Mixed
Dyslipidemia
Lescol® (fluvastatin sodium) and Lescol® XL (fluvastatin sodium) are indicated to reduce
elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase HDL-C in
patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa
and IIb) whose response to dietary restriction of saturated fat and cholesterol and other
nonpharmacological measures has not been adequate.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
Lescol® (fluvastatin sodium) and Lescol® XL (fluvastatin sodium) are indicated as an adjunct
to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at
least one year post-menarche, 10-16 years of age, with heterozygous familial
hypercholesterolemia whose response to dietary restriction has not been adequate and the
following findings are present:
1. LDL-C remains ≥ 190 mg/dL or
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2. LDL-C remains ≥ 160 mg/dL and:
• there is a positive family history of premature cardiovascular disease or
• two or more other cardiovascular disease risk factors are present
Therapy with lipid-altering agents should be considered only after secondary causes
for hyperlipidemia such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic
syndrome, dysproteinemias, obstructive liver disease, other medication, or alcoholism, have
been excluded. Prior to initiation of fluvastatin sodium, a lipid profile should be performed to
measure Total-C, HDL-C and TG. For patients with TG <400 mg/dL (<4.5 mmol/L), LDL-C
can be estimated using the following equation:
LDL-C = Total-C - HDL-C - 1/5 TG
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 many hypertriglyceridemic
patients LDL-C may be low or normal despite elevated Total-C. In such cases, Lescol is not
indicated.
Lipid determinations should be performed at intervals of no less than 4 weeks and
dosage adjusted according to the patient’s response to therapy.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are
summarized below:
Table 3
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%)
<100
≥100
≥130
(100-129: drug optional)††
2+ Risk factors
(10-year risk ≤20%)
<130
≥130
10-year risk 10%-20%: ≥130
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 <100mg/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 judgement also may call for deferring drug
therapy in this subcategory.
††† Almost all people with 0-1 risk factor have 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.
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At the time of hospitalization for an acute coronary event, consideration can be given
to initiating drug therapy at discharge if the LDL-C level is ≥130 mg/dL (NCEP-ATP II).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that the 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.
Table 4
Classification of Hyperlipoproteinemias
Lipid Elevations
Type
Lipoproteins
Elevated
Major
Minor
I (rare)
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
C = cholesterol, TG = triglycerides, LDL = low density lipoprotein, VLDL = very low density lipoprotein,
IDL = intermediate density lipoprotein
Neither Lescol nor Lescol XL have 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 fluvastatin in adolescence should be re-evaluated in adulthood
and appropriate changes made to their cholesterol-lowering regimen to achieve adult
treatment goals.
Secondary Prevention of Coronary Events
In patients with coronary heart disease, Lescol and Lescol XL are indicated to reduce the risk
of undergoing coronary revascularization procedures.
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Atherosclerosis
Lescol and Lescol XL are also indicated to slow the progression of coronary atherosclerosis in
patients with coronary heart disease as part of a treatment strategy to lower total and LDL
cholesterol to target levels.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication. Lescol® (fluvastatin sodium) and
Lescol® XL (fluvastatin sodium) are contraindicated in patients with active liver disease or
unexplained, persistent elevations in serum transaminases (see WARNINGS).
Pregnancy and Lactation
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during
pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential
components for fetal development (including synthesis of steroids and cell membranes). Since
HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of
other biologically active substances derived from cholesterol, they may cause fetal harm when
administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are
contraindicated during pregnancy and in nursing mothers. Fluvastatin sodium should be
administered to women of childbearing age only when such patients are highly unlikely
to conceive and have been informed of the potential hazards. If the patient becomes
pregnant while taking this class of drug, therapy should be discontinued and the patient
apprised of the potential hazard to the fetus.
WARNINGS
Liver Enzymes
Biochemical abnormalities of liver function have been associated with HMG-CoA reductase
inhibitors and other lipid-lowering agents. Approximately 1.1% of patients treated with
Lescol® (fluvastatin sodium) capsules in worldwide trials developed dose-related, persistent
elevations of transaminase levels to more than 3 times the upper limit of normal. Fourteen of
these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969
patients (1.1%) had persistent transaminase elevations with an average fluvastatin exposure of
approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of
patients with these abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which Lescol capsules were
used, persistent transaminase elevations (>3 times the upper limit of normal [ULN] on two
consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with
20, 40, and 80 mg (titrated to 40 mg twice daily) Lescol capsules, respectively. Ninety-one
percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred
within 12 weeks of therapy and in all patients with persistent liver function test abnormalities
there was an abnormal liver function test present at baseline or by week 8.
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In the pooled analysis of the 24-week controlled trials, persistent transaminase
elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with Lescol® XL (fluvastatin
sodium) 80 mg, Lescol 40 mg and Lescol 40 mg twice daily, respectively. In 13 of 16 patients
treated with Lescol XL the abnormality occurred within 12 weeks of initiation of treatment
with Lescol XL 80 mg.
It is recommended that liver function tests be performed before the initiation of
therapy and at 12 weeks following initiation of treatment or elevation in dose. Patients
who develop transaminase elevations or signs and symptoms of liver disease should be
monitored to confirm the finding and should be followed thereafter with frequent liver
function tests until the levels return to normal. Should an increase in AST or ALT of three
times the upper limit of normal or greater persist (found on two consecutive occasions)
withdrawal of fluvastatin sodium therapy is recommended.
Active liver disease or unexplained transaminase elevations are contraindications to
the use of Lescol and Lescol XL (see CONTRAINDICATIONS). Caution should be exercised
when fluvastatin sodium is administered to patients with a history of liver disease or heavy
alcohol ingestion (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism). Such
patients should be closely monitored.
Skeletal Muscle
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported
with fluvastatin and with other drugs in this class. Myopathy, defined as muscle aching or
muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to
greater than 10 times the upper limit of normal, has been reported.
Myopathy should be considered in any patients with diffuse myalgias, muscle
tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to
report promptly unexplained muscle pain, tenderness or weakness, particularly if
accompanied by malaise or fever. Fluvastatin sodium therapy should be discontinued if
markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin
sodium 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 and or rhabdomyolysis during treatment with HMG-CoA
reductase inhibitors has been reported to be increased if therapy with either cyclosporine,
gemfibrozil, erythromycin, or niacin is administered concurrently. Myopathy was not
observed in a clinical trial in 74 patients involving patients who were treated with fluvastatin
sodium together with niacin.
Uncomplicated myalgia has been observed infrequently in patients treated with Lescol
at rates indistinguishable from placebo.
The use of fibrates alone may occasionally be associated with myopathy. The
combined use of HMG-CoA reductase inhibitors and fibrates should generally be avoided.
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PRECAUTIONS
General
Before instituting therapy with Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin
sodium), an attempt should be made to control hypercholesterolemia with appropriate diet,
exercise, and weight reduction in obese patients, and to treat other underlying medical
problems (see INDICATIONS AND USAGE).
The HMG-CoA reductase inhibitors may cause elevation of 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 fluvastatin
sodium.
Homozygous Familial Hypercholesterolemia
HMG-CoA reductase inhibitors are reported to be less effective in patients with rare
homozygous familial hypercholesterolemia, possibly because these patients have few
functional LDL receptors.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever.
Women should be informed that if they become pregnant while receiving Lescol or
Lescol XL the drug should be discontinued immediately to avoid possible harmful effects on a
developing fetus from a relative deficit of cholesterol and biological products derived from
cholesterol. In addition, Lescol or Lescol XL should not be taken during nursing. (See
CONTRAINDICATIONS.)
Drug Interactions
The below listed drug interaction information is derived from studies using immediate release
fluvastatin. Similar studies have not been conducted using the Lescol XL tablet.
Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin
(See WARNINGS: Skeletal Muscle).
In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450
(CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin
(~75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e.
~5% and ~20%, respectively. If one pathway is inhibited in the elimination process of
fluvastatin other pathways may compensate.
In vivo drug interaction studies with CYP3A4 inhibitors/substrates such as
cyclosporine, erythromycin, and itraconazle result in minimal changes in the
pharmacokinetics of fluvastatin, confirming less involvement of CYP3A4 isozyme.
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Concomitant administration of fluvastatin and phenytoin increased the levels of phenytoin and
fluvastatin, suggesting predominant involvement of CYP2C9 in fluvastatin metabolism.
Niacin/Propranolol:
Concomitant administration of immediate release fluvastatin sodium with niacin or
propranolol has no effect on the bioavailability of fluvastatin sodium.
Cholestyramine:
Administration of immediate release fluvastatin sodium concomitantly with, or up to 4 hours
after cholestyramine, results in fluvastatin decreases of more than 50% for AUC and 50%-
80% for Cmax. However, administration of immediate release fluvastatin sodium 4 hours after
cholestyramine resulted in a clinically significant additive effect compared with that achieved
with either component drug.
Cyclosporine:
Plasma cyclosporine levels remain unchanged when fluvastatin (20 mg daily) was
administered concurrently in renal transplant recipients on stable cyclosporine regimens.
Fluvastatin AUC increased 1.9 fold, and Cmax increased 1.3 fold compared to historical
controls.
Digoxin:
In a crossover study involving 18 patients chronically receiving digoxin, a single 40 mg dose
of immediate release fluvastatin had no effect on digoxin AUC, but had an 11% increase in
digoxin Cmax and small increase in digoxin urinary clearance.
Erythromycin:
Erythromycin (500 mg, single dose) did not affect steady-state plasma levels of fluvastatin (40
mg daily).
Fluconazole:
Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with
fluconazole for 4 days results in an increase of fluvastatin Cmax (44%) and AUC (84%).
Based on this data, caution should be exercised when fluvastatin is co-administered with
fluconazole.
Itraconazole:
Concomitant administration of fluvastatin (40 mg) and itraconazole (100 mg daily x 4 days)
does not affect plasma itraconazole or fluvastatin levels.
Gemfibrozil:
There is no change in either fluvastatin (20 mg twice daily) or gemfibrozil (600 mg twice
daily) plasma levels when these drugs are co-administered.
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Phenytoin:
Single morning dose administration of phenytoin (300 mg extended release) increased mean
steady-state fluvastatin (40 mg) Cmax by 27% and AUC by 40% whereas fluvastatin increased
the mean phenytoin Cmax by 5% and AUC by 20%. Patients on phenytoin should continue to
be monitored appropriately when fluvastatin therapy is initiated or when the fluvastatin
dosage is changed.
Diclofenac:
Concurrent administration of fluvastatin (40 mg) increased the mean Cmax and AUC of
diclofenac by 60% and 25% respectively.
Tolbutamide:
In healthy volunteers, concurrent administration of either single or multiple daily doses of
fluvastatin sodium (40 mg) with tolbutamide (1 g) did not affect the plasma levels of either
drug to a clinically significant extent.
Glibenclamide (Glyburide):
In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice
daily for 14 days) increased the mean Cmax, AUC, and t1/2 of glibenclamide approximately
50%, 69% and 121%, respectively. Glibenclamide (5-20 mg daily) increased the mean Cmax
and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in
glucose, insulin and C-peptide levels. However, patients on concomitant therapy with
glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when
their fluvastatin dose is increased to 40 mg twice daily.
Losartan:
Concomitant administration of fluvastatin with losartan has no effect on the bioavailability of
either losartan or its active metabolite.
Cimetidine/Ranitidine/Omeprazole:
Concomitant administration of immediate release fluvastatin sodium with cimetidine,
ranitidine and omeprazole results in a significant increase in the fluvastatin Cmax (43%, 70%
and 50%, respectively) and AUC (24%-33%), with an 18%-23% decrease in plasma
clearance.
Rifampicin:
Administration of immediate release fluvastatin sodium to subjects pretreated with rifampicin
results in significant reduction in Cmax (59%) and AUC (51%), with a large increase (95%) in
plasma clearance.
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Warfarin:
In vitro protein binding studies demonstrated no interaction at therapeutic concentrations.
Concomitant administration of a single dose of warfarin (30 mg) in young healthy males
receiving immediate release fluvastatin sodium (40 mg/day x 8 days) resulted in no elevation
of racemic warfarin concentration. There was also no effect on prothrombin complex activity
when compared to concomitant administration of placebo and warfarin. However, bleeding
and/or increased prothrombin times have been reported in patients taking coumarin
anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients
receiving warfarin-type anticoagulants should have their prothrombin times closely monitored
when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating
cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone
production.
Fluvastatin exhibited no effect upon non-stimulated cortisol levels and demonstrated
no effect upon thyroid metabolism as assessed by TSH. Small declines in total testosterone
have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting
that the observation was not due to a direct effect upon testosterone production. No effect
upon FSH in males was noted. Due to the limited number of premenopausal females studied
to date, no conclusions regarding the effect of fluvastatin upon female sex hormones may be
made.
Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for
periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to
ACTH stimulation. A clinical study evaluated the effect of fluvastatin at doses up to 80 mg
daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total
testosterone response was significantly reduced (p<0.05) relative to baseline in the 80 mg
group, it was not significant in comparison to the changes noted in groups receiving either
40 mg of fluvastatin or placebo.
Patients treated with fluvastatin sodium who develop clinical evidence of endocrine
dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA
reductase inhibitor or other agent used to lower cholesterol levels is administered to patients
receiving other drugs (e.g., ketoconazole, spironolactone, or cimetidine) that may decrease the
levels of endogenous steroid hormones.
CNS Toxicity
CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis
were seen in the following animal studies: the 18-month mouse carcinogenicity study at
50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at
40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits
(300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was
characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal
cord at a dose of 5000 mg/kg and (in rat) by edema with separation of myelinated fibers of the
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ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by
periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for
5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the
dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular
hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been
observed in dogs treated with other members of this class. No CNS lesions have been
observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to
350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).
Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after
treatment with 1, 8, and 16 mg/kg/day for 2 years.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year)
mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and
26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low
incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the
24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by
direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In
addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was
recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid
follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with
findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase
inhibitors, no hepatic adenomas or carcinomas were observed.
The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and
30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous
cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These
treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the
mean human plasma drug concentration after a 40 mg oral dose.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests using mutant strains of
Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3
cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in
V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no
evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.
In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose
levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the
fertility or reproductive performance.
Seminal vesicles and testes were small in hamsters treated for 3 months at
20 mg/kg/day (approximately three times the 40 milligram human daily dose based on surface
area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as well as
vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were
also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax
achieved with a 40 milligram daily dose).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 20
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day
and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at
36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at
12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface
area. A study in which female rats were dosed during the third trimester at 12 and
24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal
and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day.
A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study
with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at
dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation
with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol
biosynthesis. The concurrent administration of mevalonic acid completely prevented the
maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on
days 0 and 7 postpartum. Therefore, the maternal and neonatal lethality observed with
fluvastatin sodium reflect its exaggerated pharmacologic effect during pregnancy. There are
no data with fluvastatin sodium in pregnant women. However, rare reports of congenital
anomalies have been received following intrauterine exposure to other HMG-CoA reductase
inhibitors. There has been one report of severe congenital bony deformity, tracheo-esophageal
fistula, and anal atresia (VATER association) in a baby born to a woman who took another
HMG-CoA reductase inhibitor with dextroamphetamine sulfate during the first trimester of
pregnancy. Lescol or Lescol XL 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. If a woman becomes pregnant while taking Lescol or
Lescol XL, the drug should be discontinued and the patient advised again as to the potential
hazards to the fetus.
Nursing Mothers
Based on preclinical data, drug is present in breast milk in a 2:1 ratio (milk:plasma). Because
of the potential for serious adverse reactions in nursing infants, nursing women should not
take Lescol or Lescol XL (see CONTRAINDICATIONS).
Pediatric Use
The safety and efficacy of Lescol and Lescol XL in children and adolescent patients 9-16
years of age with heterozygous familial hypercholesterolemia have been evaluated in open-
label, uncontrolled clinical trials of 2 years' duration. The most common adverse events
observed were influenza and infections. In these limited uncontrolled studies, there was no
detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle
length in girls. See CLINICAL STUDIES: Heterozygous Familial Hypercholesterolemia in
Pediatric Patients; ADVERSE REACTIONS: Pediatric Patients (9-17 years of age); and
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Page 21
DOSAGE AND ADMINISTRATION: Heterozygous Familial Hypercholesterolemia in
Pediatric Patients. Adolescent females should be counseled on appropriate contraceptive
methods while on fluvastatin therapy (see CONTRAINDICATIONS: Pregnancy and
Lactation).
Geriatric Use
The effect of age on the pharmacokinetics of immediate release fluvastatin sodium was
evaluated. Results indicate that for the general patient population plasma concentrations of
fluvastatin sodium do not vary as a function of age. (See also CLINICAL PHARMACOLOGY:
Pharmacokinetics/Metabolism.) Elderly patients (≥65 years of age) demonstrated a greater
treatment response in respect to LDL-C, Total-C and LDL/HDL ratio than patients <65 years
of age.
ADVERSE REACTIONS
In all clinical studies of Lescol® (fluvastatin sodium), 1.0% (32/2969) of fluvastatin-treated
patients were discontinued due to adverse experiences attributed to study drug (mean
exposure approximately 16 months ranging in duration from 1 to >36 months). This results in
an exposure adjusted rate of 0.8% (32/4051) per patient year in fluvastatin patients in
controlled studies compared to an incidence of 1.1% (4/355) in placebo patients. Adverse
reactions have usually been of mild to moderate severity.
In controlled clinical studies, 3.9% (36/912) of patients treated with Lescol® XL
(fluvastatin sodium) 80 mg discontinued due to adverse events (causality not determined).
Clinically relevant adverse experiences occurring in the Lescol and Lescol XL
controlled studies with a frequency >2%, regardless of causality, include the following:
Table 5
Clinically Relevant Adverse Experiences Occurring in >2% Patients
in Lescol® and Lescol XL® Controlled Studies
Lescol®1
(%)
Placebo1
(%)
Lescol® XL2
(%)
Adverse Event
(N=2326)
(N=960)
(N = 912)
Musculoskeletal
Myalgia
5.0
4.5
3.8
Arthritis
2.1
2.0
1.3
Arthropathy
NA
NA
3.2
Respiratory
Sinusitis
2.6
1.9
3.5
Bronchitis
1.8
1.0
2.6
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Page 22
Gastrointestinal
Dyspepsia
7.9
3.2
3.5
Diarrhea
4.9
4.2
3.3
Abdominal Pain
4.9
3.8
3.7
Nausea
3.2
2.0
2.5
Flatulence
2.6
2.5
1.4
Psychiatric Disorders
Insomnia
2.7
1.4
0.8
Genitourinary
Urinary Tract Infection
1.6
1.1
2.7
Miscellaneous
Headache
8.9
7.8
4.7
Influenza-Like Symptoms
5.1
5.7
7.1
Accidental Trauma
5.1
4.8
4.2
Fatigue
2.7
2.3
1.6
Allergy
2.3
2.2
1.0
1 Controlled trials with Lescol Capsules (20 and 40 mg daily and 40 mg twice daily)
2 Controlled trials with Lescol XL 80 mg Tablets
The following effects have been reported with drugs in this class. Not all the effects
listed below have necessarily been associated with fluvastatin sodium 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
erythematosus-like syndrome, polymyalgia rheumatica, 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 23
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl
transpeptidase, and bilirubin; thyroid function abnormalities.
Pediatric Patients
In two open-label, uncontrolled studies, 114 patients (66 boys and 48 girls) with heterozygous
familial hypercholesterolemia, 9-16 years of age, were treated for 2 years with fluvastatin
sodium administered as Lescol capsules 20 mg- 40 mg bid or Lescol XL 80 mg extended-
release tablets. The most common adverse events observed were influenza and infections.
See CLINICAL STUDIES: Heterozygous Familial Hyercholesterolemia in Pediatric Patients
and PRECAUTIONS: Pediatric Use).
Concomitant Therapy
Fluvastatin sodium has been administered concurrently with cholestyramine and nicotinic
acid. No adverse reactions unique to the combination or in addition to those previously
reported for this class of drugs alone have been reported. Myopathy and rhabdomyolysis (with
or without acute renal failure) have been reported when another HMG-CoA reductase
inhibitor was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin,
or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA reductase
inhibitors and these agents is generally not recommended. (See WARNINGS: Skeletal
Muscle.)
OVERDOSAGE
The approximate oral LD50 is greater than 2 g/kg in mice and greater than 0.7 g/kg in rats.
The maximum single oral dose of Lescol® (fluvastatin sodium) capsules received by
healthy volunteers was 80 mg. No clinically significant adverse experiences were seen at this
dose. The maximum dose administered with an extended-release formulation was 640 mg for
two weeks. This dose was not well tolerated and produced a variety of GI complaints and an
increase in transaminase values (i.e., SGOT and SGPT).
There has been a single report of 2 children, one 2 years old and the other 3 years of
age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of
fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting
was induced by ipecac in both children and no capsules were noted in their emesis. Neither
child experienced any adverse symptoms and both recovered from the incident without
problems.
Should an accidental overdose occur, treat symptomatically and institute supportive
measures as required. The dialyzability of fluvastatin sodium and of its metabolites in humans
is not known at present.
Information about the treatment of overdose can often be obtained from a certified
Regional Poison Control Center. Telephone numbers of certified Regional Poison Control
Centers are listed in the Physicians’ Desk Reference®.*
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 24
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving Lescol®
(fluvastatin sodium) or Lescol® XL (fluvastatin sodium) and should continue on this diet
during treatment with Lescol or Lescol XL. (See NCEP Treatment Guidelines for details on
dietary therapy.)
For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting
dose is 40 mg as one capsule in the evening, 80 mg as one Lescol XL tablet administered as a
single dose at any time of the day or 80 mg in divided doses of the 40 mg capsule given twice
daily. For patients requiring LDL-C reduction to a goal of <25% a starting dose of 20 mg may
be used. The recommended dosing range is 20-80 mg/day. Lescol or Lescol XL may be taken
without regard to meals, since there are no apparent differences in the lipid-lowering effects
of fluvastatin sodium administered with the evening meal or 4 hours after the evening meal.
Do not break, crush or chew Lescol XL tablets or open Lescol capsules prior to
administration.
Since the maximal reductions in LDL-C of a given dose are seen within 4 weeks,
periodic lipid determinations should be performed and dosage adjustment made according to
the patient’s response to therapy and established treatment guidelines. The therapeutic effect
of Lescol or Lescol XL is maintained with prolonged administration.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
The recommended starting dose is one 20 mg Lescol capsule. Dose adjustments, up to a
maximum daily dose administered either as Lescol capsules 40 mg twice daily or one Lescol
XL 80 mg tablet once daily, should be made at 6 week intervals. Doses should be
individualized according to the goal of therapy (see NCEP Pediatric Panel Guidelines and
INDICATIONS AND USAGE.)1.
Concomitant Therapy
Lipid-lowering effects on total cholesterol and LDL cholesterol are additive when immediate
release Lescol is combined with a bile-acid binding resin or niacin. When administering a
bile-acid resin (e.g., cholestyramine) and fluvastatin sodium, Lescol should be administered at
bedtime, at least 2 hours following the resin to avoid a significant interaction due to drug
binding to resin. (See also ADVERSE REACTIONS: Concomitant Therapy.)
Dosage in Patients with Renal Insufficiency
Since fluvastatin sodium is cleared hepatically with less than 6% of the administered dose
excreted into the urine, dose adjustments for mild to moderate renal impairment are not
necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe
renal impairment; therefore caution should be exercised when treating such patients at higher
doses.
1 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
Page 25
HOW SUPPLIED
Lescol® (fluvastatin sodium) Capsules
20 mg
Brown and light brown imprinted twice with “
” and “20” on one half and “LESCOL” and
the Lescol® (fluvastatin sodium) logo twice on the other half of the capsule.
Bottles of 30 capsules………………………………………………. (NDC 0078-0176-15)
Bottles of 100 capsules……………………………………………... (NDC 0078-0176-05)
40 mg
Brown and gold imprinted twice with “
” and “40” on one half and “LESCOL” and the
Lescol® (fluvastatin sodium) logo twice on the other half of the capsule.
Bottles of 30 capsules………………………………………………. (NDC 0078-0234-15)
Bottles of 100 capsules………………………………..……………. (NDC 0078-0234-05)
Lescol® XL (fluvastatin sodium) Extended-Release Tablets
80 mg
Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with
“Lescol XL” on one side and “80” on the other.
Bottles of 30 tablets………………………………………………… (NDC 0078-0354-15)
Bottle of 100 tablets………………………………………………… (NDC 0078-0354-05)
Store and Dispense
Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF). [See USP Controlled
Room Temperature]. Dispense in a tight container. Protect from light.
*Trademark of Medical Economics Company, Inc.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
LESCOL® [ lĕs-cŏl]
(fluvastatin sodium)
Capsules
and
LESCOL® [ lĕs-cŏl] XL
(fluvastatin sodium)
Extended-release tablets
Read the Patient Information that comes with
LESCOL or LESCOL XL before you start taking it,
and each time you get a refill. There may be new
information. This leaflet does not take the place of
talking with your doctor about your condition or
treatment.
If you have any questions about LESCOL or LESCOL
XL, ask your doctor or pharmacist.
What are LESCOL and LESCOL XL?
LESCOL and LESCOL XL are prescription medicines
called "statins" that lower cholesterol in your blood.
They lower the "bad" cholesterol and triglycerides in
your blood. They can raise your "good" cholesterol as
well.
LESCOL and LESCOL XL are for people whose
cholesterol does not come down enough with exercise
and a low-fat diet alone.
LESCOL and LESCOL XL may be used in patients
with heart disease (coronary artery disease) to:
• lower the chances of heart problems which would
require procedures to help restore blood flow to
the heart.
• slow the buildup of too much cholesterol in the
arteries of the heart.
Treatment with LESCOL or LESCOL XL has not
been shown to prevent heart attacks or stroke.
LESCOL and LESCOL XL have the same active
ingredient, fluvastatin. However, LESCOL is a
capsule that is taken one or two times a day and
LESCOL XL is an extended-release tablet that is only
taken one time a day.
Who should not take LESCOL or
LESCOL XL?
Do not take LESCOL or LESCOL XL if you:
•
•
are pregnant or think you may be
pregnant, or are planning to become
pregnant. LESCOL and LESCOL XL may
harm your unborn baby. If you get pregnant,
stop taking LESCOL or LESCOL XL and
call your doctor right away.
are breast-feeding. LESCOL and LESCOL
XL can pass into your breast milk and may
harm your baby
• have liver problems
• are allergic to LESCOL or LESCOL XL
or any of its ingredients. The active
ingredient in LESCOL and LESCOL XL is
fluvastatin. See the end of this leaflet for a
complete list of ingredients in LESCOL and
LESCOL XL.
LESCOL and LESCOL XL have not been
studied in children under 9 years of age.
Before taking LESCOL or LESCOL XL,
tell your doctor if you:
• have muscle aches or weakness
• drink more than 2 glasses of alcohol
daily
• have diabetes
• have a thyroid problem
• have kidney problems
Some medicines should not be taken with
LESCOL or LESCOL XL. Tell your doctor
about all the medicines you take, including
prescription and non-prescription medicines,
vitamins and herbal supplements. LESCOL and
LESCOL XL and certain other medicines can
interact causing serious side effects. Especially
tell your doctor if you take medicines for:
• your immune system
• cholesterol
• infections
• heart failure
• seizures
• diabetes
• heartburn or stomach ulcers
Know all the medicines you take. Keep a list of
all the medicines you take with you to show your
doctor and pharmacist.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I take LESCOL or LESCOL XL?
• Take LESCOL or LESCOL XL exactly as
prescribed. Your doctor will prescribe the one that
is right for you. Do not change your dose or stop
LESCOL or LESCOL XL without talking to your
doctor. Your doctor may do blood tests to check
your cholesterol levels during treatment with
LESCOL and LESCOL XL. Your dose of
LESCOL or LESCOL XL may be changed based
on these blood test results.
• LESCOL XL tablets may be taken at any time of
the day. Take LESCOL capsules at the same time
every evening. When LESCOL capsules are taken
twice daily, the capsules may be taken once in the
morning and once in the evening. LESCOL and
LESCOL XL can be taken with or without food.
• LESCOL XL tablets must be swallowed whole
with a liquid. Do not break, crush or chew
LESCOL XL tablets or open Lescol capsules.
Tell your doctor if you cannot swallow tablets
whole. You may need LESCOL capsules or a
different medicine instead of LESCOL XL tablets.
• Your doctor should start you on a low-fat and low-
cholesterol diet before giving you LESCOL or
LESCOL XL. Stay on this low-fat and low-
cholesterol diet while taking LESCOL or
LESCOL XL.
• If you miss a dose of LESCOL or LESCOL XL,
take it as soon as you remember. Do not take
Lescol or Lescol XL if it has been more than 12
hours since your last dose. Wait and take the next
dose at your regular time. Do not take 2 doses of
Lescol or Lescol XL at the same time.
• If you take too much LESCOL or LESCOL XL or
overdose, call your doctor or Poison Control
Center right away. Or, go to the nearest emergency
room.
What should I avoid while taking LESCOL or
LESCOL XL?
• Talk to your doctor before you start any new
medicines. This includes prescription and non-
prescription medicines, vitamins and herbal
supplements. LESCOL and LESCOL XL and
certain other medicines can interact causing
serious side effects.
• Do not get pregnant. If you get pregnant, stop
taking LESCOL or LESCOL XL right away and
call your doctor.
What are the possible side effects of
LESCOL and LESCOL XL?
When taking LESCOL and LESCOL XL, some
patients may develop serious side effects,
including:
• muscle problems. These serious muscle
problems can sometimes lead to kidney
problems, including kidney failure. You
have a higher chance for muscle problems if
you are taking certain other medicines with
LESCOL or LESCOL XL.
• liver problems. Your doctor may do blood
tests to check your liver before you start
taking LESCOL or LESCOL XL, and while
you are taking one of them.
Call your doctor right away if you have:
• muscle problems like weakness, tenderness,
or pain that happen without a good reason,
especially if you also have a fever or feel
more tired than usual
• nausea and vomiting
• passing brown or dark-colored urine
• you feel more tired than usual
• your skin and whites of your eyes get yellow
• stomach pain
The most common side effects of LESCOL or
LESCOL XL are headache, upset stomach and
stomach pain, diarrhea, flu-like symptoms,
muscle pain, sinus infection, tiredness, or trouble
sleeping. These side effects are usually mild and
may go away.
Talk to your doctor or pharmacist if you have
side effects that bother you or that will not go
away.
These are not all the side effects of LESCOL and
LESCOL XL. Ask your doctor or pharmacist for
a complete list.
How should I store LESCOL and LESCOL
XL?
• Store LESCOL and LESCOL XL at room
temperature, 59° to 86° F (15° to 30° C).
Protect from light.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not keep medicine that is out of date or that
you no longer need.
• Keep LESCOL and LESCOL XL out of the
reach of children. Be sure that if you throw
medicines away, it is out of the reach of children.
General information about LESCOL and
LESCOL XL
Medicines are sometimes prescribed for conditions
that are not mentioned in patient information leaflets.
Do not use LESCOL or LESCOL XL for a condition
for which it was not prescribed. Do not give
LESCOL or LESCOL XL to other people, even if they
have the same problem you have. It may harm them.
This leaflet summarizes the most important
information about LESCOL and LESCOL XL. If you
would like more information, talk with your doctor.
For information that is written for health
professionals, ask your doctor or pharmacist or call 1-
888-669-6682.
What are the ingredients in LESCOL and
LESCOL XL?
Active Ingredient: fluvastatin sodium
Inactive Ingredients:
LESCOL Capsules: gelatin, magnesium
stearate, microcrystalline cellulose, pregelatinized
starch (corn), red iron oxide, sodium lauryl sulfate,
talc, titanium dioxide, yellow iron oxide, and other
ingredients. The capsules may also contain benzyl
alcohol, black iron oxide, butylparaben,
carboxymethylcellulose sodium, edetate calcium
disodium, methylparaben, propylparaben, silicon
dioxide, and sodium propionate.
LESCOL XL Tablets: microcrystalline
cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, potassium bicarbonate, povidone,
magnesium stearate, yellow iron oxide, titanium
dioxide and polyethylene glycol 8000.
Rx only
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
January 2005
T2005-13
5000291
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:15.240983
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021192,s010,011,020261s035,s036lbl.pdf', 'application_number': 20261, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
12,386
|
1
Mead Johnson
ONCOLOGY PRODUCTS
CAUTION: FEDERAL LAW PROHIBITS
DISPENSING WITHOUT PRESCRIPTION
TAXOL7
(paclitaxel)
INJECTION
WARNING
TAXOL7 (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer
chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and
treatment facilities are readily available.
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment,
angioedema, and generalized urticaria have occurred in 2%-4% of patients receiving TAXOL in clinical trials. Fatal
reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids,
diphenhydramine, and H2 antagonists. (See DOSAGE AND ADMINISTRATION section.) Patients who experience severe
hypersensitivity reactions to TAXOL should not be rechallenged with the drug.
TAXOL therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1500
cells/mm
3 and should not be given to patients with AIDS-related Kaposi=s sarcoma if the baseline neutrophil count is less
than 1000 cells/mm
3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may
be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all
patients receiving TAXOL.
DESCRIPTION
TAXOL (paclitaxel) Injection is a clear colorless to slightly yellow viscous solution. It is supplied as a nonaqueous
solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. TAXOL is available in 30 mg
(5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6
mg paclitaxel, 527 mg of purified Cremophor7 EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol,
USP.
Paclitaxel is a natural product with antitumor activity. TAXOL (paclitaxel) is obtained via a semi-synthetic
process from Taxus baccata. The chemical name for paclitaxel is 5$,20-Epoxy-1,2",4,7$,10$,13"-hexahydroxytax-
11-en-9-one 4, 10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
_____________________________________
*Cremaphor7 EL is the registered trademark of BASF Aktiengesellschaft.
Cremaphor7 EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Paclitaxel has the following structural formula:
Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular
weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216-217NC.
CLINICAL PHARMACOLOGY
Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and
stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic
reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In
addition, paclitaxel induces abnormal arrays or Abundles@ of microtubules throughout the cell cycle and multiple
asters of microtubules during mitosis.
Following intravenous administration of TAXOL, paclitaxel plasma concentrations decline in a biphasic
manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug.
The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of TAXOL at dose levels of 135
and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in
the following table:
TABLE 1
Summary of Pharmacokinetic Parameters - Mean Values
Dose
(mg/m2)
Infusion
Duration (h)
N
(patients)
CMAX
(ng/mL)
AUC(0-4)
(ng@h/mL)
T-HALF
(h)
CLT
(L/h/m2)
135
175
135
175
24
24
3
3
2
4
7
5
195
365
2170
3650
6300
7993
7952
15007
52.7
15.7
13.1
20.2
21.7
23.8
17.7
12.2
CMAX=Maximum plasma concentration
AUC(0-4) = Area under the plasma concentration-time curve from time 0 to infinity
CLT = Total body clearance
It appeared that with the 24-hour infusion of TAXOL, a 30% increase in dose (135 mg/m2 versus 175 mg/m2)
increased the CMAX by 87%, whereas the AUC(0-4) remained proportional. However, with a 3-hour infusion, for a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
30% increase in dose, the CMAX and AUC(0-4) were increased by 68% and 89%, respectively. The mean apparent
volume of distribution at steady state, with the 24-hour infusion of TAXOL, ranged from 227 to 688 L/m2, indicating
extensive extravascular distribution and/or tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses
of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275
mg/m2 given by 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CLT and volume of distribution were
consistent with the findings in the Phase 3 study. The pharmacokinetics of TAXOL in patients with AIDS-related
Kaposi=s sarcoma have not been studied.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50
:g/mL, indicate that between 89-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or
diphenhydramine did not affect protein binding of paclitaxel.
After intravenous administration of 15-275 mg/m2 doses of TAXOL as 1-, 6-, or 24-hour infusions, mean
values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating
extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radiolabeled TAXOL as a 3-
hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in
the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5%
of the administered radioactivity recovered in the feces, while metabolites, primarily 6"-hydroxypaclitaxel, accounted
for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was
metabolized primarily to 6"-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor
metabolites, 3'-p-hydroxypaclitaxel and 6",3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel
to 6"-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine,
dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those
found in vivo following normal therapeutic doses. Testosterone, 17"-ethinyl estradiol, retinoic acid, and quercetin, a
specific inhibitor of CYP2C8, also inhibited the formation of 6"-hydroxypaclitaxel in vitro. The pharmacokinetics of
paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or
inhibitors of CYP2C8 and/or CYP3A4. (See PRECAUTIONS: Drug Interactions section.) The effect of renal or
hepatic dysfunction on the disposition of paclitaxel has not been investigated.
Possible interactions of paclitaxel with concomitantly administered medications have not been formally
investigated.
CLINICAL STUDIES
Ovarian Carcinoma
First-Line Data: The safety and efficacy of TAXOL (135 mg/m2 over 24 hr) in combination with cisplatin (75 mg/m2) in
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patients with advanced ovarian cancer and no prior chemotherapy were evaluated in a Phase 3 multicenter,
randomized, controlled (vs. cyclophosphamide 750 mg/m2 plus cisplatin 75 mg/m2) clinical trial conducted by the
Gynecologic Oncology Group (GOG). A total of 410 patients with Stage III or IV disease (>1 cm residual disease after
staging laparotomy or distant metastases) were randomized. Patients treated with TAXOL in combination with
cisplatin had significantly longer time to progression (median 16.6 vs. 13.0 months, p=0.0008) and nearly a year
longer median survival time (p=0.0002) compared with standard therapy.
TABLE 2
Efficacy in the Phase 3 First-Line Ovarian Carcinoma Study
TAXOL/Cisplatin
(n=196)
Cyclophosphamide/Cisplatin
(n=214)
$ Clinical Response*
---rate (percent)
---p-value
$ Pathological Response**
---rate (percent)
---p-value
•
Pathological Complete
Response:
---rate (percent)
---p-value
$ Time to Progression
---median (months)
---p-value
$ Survival
---median (months)
---p-value
(n=113)
62
34
21
16.6
35.5
0.04
0.001
0.20
0.0008
0.0002
(n=127)
48
20
16
13.0
24.2
* Among evaluable patients only.
** Includes patients with pathological complete response plus patients with microscopic residual disease.
The adverse event profile for patients receiving TAXOL in combination with cisplatin in this study was generally
consistent with that seen for the pooled analysis performed on data from 812 patients treated with single-agent
TAXOL in 10 clinical studies. These adverse events and adverse events from the phase 3 first-line ovarian
carcinoma study are described in the ADVERSE REACTIONS section of the label, in tabular (Table 8 & 9) and
narrative form.
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Second-Line Data: Data from five Phase 1 & 2 clinical studies (189 patients), a multicenter randomized Phase 3 study
(407 patients) as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral
center program were used in support of the use of TAXOL in patients who have failed initial or subsequent
chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose
of 135 to 170 mg/m2 in most patients (>90%) administered over 24 hours by continuous infusion. Response rates in
these two studies were 22% (95% Cl: 11% to 37%) and 30% (95% Cl: 18% to 46%) with a total of six complete and
18 partial responses in 92 patients. The median duration of overall response in these two studies measured from the
first day of treatment was 7.2 months (range: 3.5-15.8 months) and 7.5 months (range: 5.3-17.4 months),
respectively. The median survival was 8.1 months (range: 0.2-36.7 months) and 15.9 months (range: 1.8-34.5 +
months).
The Phase 3 study had a bifactorial design and compared the efficacy and safety of TAXOL, administered at
two different doses (135 or 175 mg/m2) and schedules (3- or 24-hour infusion). The overall response rate for the 407
patients was 16.2% (95% Cl: 12.8% to 20.2%), with 6 complete and 60 partial responses. Duration of response,
measured from the first day of treatment was 8.3 months (range: 3.2-21.6 months). Median time to progression was
3.7 months (range 0.1+ - 25.1+ months). Median survival was 11.5 months (range: 0.2-26.3 + months).
Response rates, median survival and median time to progression for the 4 arms are given in the following
table.
TABLE 3
Efficacy in the Phase 3 Second-Line Ovarian Carcinoma Study
175/3
(n=96)
175/24
(n=106)
135/3
(n=99)
135/24
(n=106)
$ Response
---rate (percent)
---95% Confidence Interval
14.6
(8.5-23.6)
21.7
(14.5-31.0)
15.2
(9.0-24.1)
13.2
(7.7-21.5)
$ Time to Progression
---median (months)
---95% Confidence Interval
4.4
(3.0-5.6)
4.2
(3.5-5.1)
3.4
(2.8-4.2)
2.8
(1.9-4.0)
$ Survival
---median (months)
---95% Confidence Interval
11.5
(8.4-14.4)
11.8
(8.9-14.6)
13.1
(9.1-14.6)
10.7
(8.1-13.6)
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Analyses were performed as planned by the bifactorial study design described in the protocol, by comparing
the two doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the two schedules irrespective of
dose. Patients receiving the 175 mg/m2 dose had a response rate similar to that for those receiving the 135 mg/m2
dose: 18% vs. 14% (p=0.28). No difference in response rate was detected when comparing the 3-hour with the 24-
hour infusion: 15% vs. 17% (p=0.50). Patients receiving the 175 mg/m2 dose of TAXOL had a longer time to
progression than those receiving the 135 mg/m2 dose: median 4.2 vs. 3.1 months (p=0.03). There was no statistically
significant difference in time to progression for patients receiving the 3-hour vs. the 24-hour infusion: 4.0 months vs.
3.7 months (p=0.08). Median survival was 11.6 months in patients receiving the 175 mg/m2 dose of TAXOL and 11.0
months in patients receiving the 135 mg/m2 dose (p=0.92). Median survival was 11.7 months for patients receiving
the 3-hour infusion of TAXOL and 11.2 months for patients receiving the 24-hour infusion (p=0.91). These statistical
analyses should be viewed with caution because of the multiple comparisons made.
TAXOL remained active in patients who had developed resistance to platinum-containing therapy (defined
as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum containing regimen)
with response rates of 14% in the Phase 3 study and 31% in the Phase 1 & 2 clinical studies.
The adverse event profile in this Phase 3 study was generally consistent with that seen for the pooled
analysis performed on data from 812 patients treated in ten clinical studies. These adverse events and adverse
events from the phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section of
the label, in tabular (Table 8 & 10) and narrative form.
The results of this randomized study support the use of TAXOL at doses of 135 to 175 mg/m2 , administered
by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic. However, the
study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.
Breast Carcinoma: Data from 83 patients accrued in three phase 2 open label studies and from 471 patients
enrolled in a phase 3 randomized study were available to support the use of TAXOL in patients with metastatic breast
carcinoma.
Phase 2 open label studies: Two studies were conducted in 53 patients previously treated with a maximum of one
prior chemotherapeutic regimen. TAXOL was administered in these 2 trials as a 24-hour infusion at initial doses of
250 mg/m2 (with G-CSF support) or 200 mg/m2 . The response rates were 57% (95% Cl: 37% to 75%) and 52%
(95% Cl: 32% to 72%), respectively. The third phase 2 study was conducted in extensively pretreated patients who
had failed anthracycline therapy and who had received a minimum of 2 chemotherapy regimens for the treatment of
metastatic disease. The dose of TAXOL was 200 mg/m2 as a 24-hour infusion with G-CSF support. Nine of 30
patients achieved a partial response, for a response rate of 30% (95% Cl: 15% to 50%).
Phase 3 randomized study: This multicenter trial was conducted in patients previously treated with one or two
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regimens of chemotherapy. Patients were randomized to receive TAXOL (paclitaxel) at a dose of either 175 mg/m2 or
135 mg/m2 given as a 3-hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired
performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy
either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven per cent of the patients
had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of
agents.
The overall response rate for the 454 evaluable patients was 26% (95% Cl: 22% to 30%), with 17 complete
and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1
months (range: 3.4-18.1 + months). Overall for the 471 patients, the median time to progression was 3.5 months
(range: 0.03-17.1 months). Median survival was 11.7 months (range: 0-18.9 months).
Response rates, median survival and median time to progression for the 2 arms are given in the following
table.
TABLE 4
Efficacy in the Phase 3 Second-Line Breast Carcinoma Study
175/3
(n=235)
135/3
(n=236)
$ Response
---rate (percent)
---p-value
$ Time to Progression
---median (months)
--- p-value
$ Survival
---median (months)
--- p-value
28
4.2
11.7
0.135
0.027
0.321
22
3.0
10.5
The adverse event profile of the patients who received single-agent Taxol in this Phase 3 study was
generally consistent with that seen for the pooled analysis performed on data from 812 patients treated in 10 clinical
studies. These adverse events and adverse events for the phase 3 breast carcinoma study are described in the
ADVERSE REACTIONS section of the label, in tabular (Table 8 & 11) and narrative form.
Non-Small Cell Lung Carcinoma (NSCLC):
In a Phase 3 open-label randomized study conducted by the Eastern Cooperative Oncology Group (ECOG), 599
patients were randomized to either TAXOL (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75
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mg/m2, TAXOL (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or
cisplatin (c) 75 mg/m2 on day 1 followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control).
Response rates, median time to progression, median survival, and one-year survival rates are given in the
following table.
TABLE 5
Efficacy Parameters in the Phase 3 First-Line NSCLC Study
T135/24
c75
(n=198)
T250/24
c75
(n=201)
VP100
a
c75
(n=200)
AA Response Rate
---rate (percent)
---p-value
b
25
0.001
23
<0.001
12
AA Time to Progression
---median (months)
---p-value
b
4.3
0.05
c
4.9
0.004
2.7
AA Survival
---median (months)
---p-value
b
9.3
0.12
10.0
0.08
7.4
AA One-Year Survival
---percent of patients
36
40
32
a Etoposide (VP) 100 mg/m
2 was administered IV on days 1, 2, and 3.
b Compared to cisplatin/etoposide
c Statistical significance is questionable due to multiple comparisons.
Response rate in each of the TAXOL/cisplatin arms was significantly higher than in the control
arm: TAXOL 135 mg/m2/24 hours plus cisplatin 25% vs. cisplatin/etoposide 12% (p=0.001) and TAXOL
250 mg/m2/24 hours plus cisplatin and G-CSF 23% vs. cisplatin/etoposide 12% (p<0.001). There was a
trend towards longer time to progression for the TAXOL 135 mg/m2/24 hours plus cisplatin arm (median
4.3 months) vs. cisplatin/etoposide arm (median 2.7 months) (p=0.05), and a significantly longer time to
progression for the TAXOL 250 mg/m2/24 hour plus cisplatin and G-CSF arm (median 4.9 months) vs.
cisplatin/etoposide arm (median 2.7 months) (p=0.004).
The median survival times in the TAXOL 135 mg/m2/24 hours plus cisplatin arm (median 9.3
months) and in the TAXOL 250 mg/m2/24 hours plus cisplatin and G-CSF arm (median 10.0 months)
were numerically superior to the median survival time in the cisplatin/etoposide arm (median 7.4
months). However, these differences were not statistically significant (p=0.12 and p=0.08, respectively.)
In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire
had 7 subscales which measured subjective assessment of treatment. Of the seven, the Lung Cancer
Specific Symptoms subscale showed a lesser rate of deterioration for the treatment arm of Taxol 135
mg/m2/24 hours plus cisplatin arm compared to the cisplatin/etoposide arm.
The adverse event profile for patients who received TAXOL in combination with cisplatin in this
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study was generally consistent with that seen for the pooled analysis performed on data from 812
patients treated with single-agent TAXOL in 10 clinical studies These adverse events and adverse events
from the phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS section of the label, in tabular
(Table 8 & 12) and narrative form.
AIDS-Related Kaposi==s Sarcoma: Data from two Phase 2 open label studies support the use of TAXOL as second-
line therapy in patients with AIDS-related Kaposi=s sarcoma. Fifty-nine of the 85 patients enrolled in these studies had
previously received systemic therapy, including interferon alpha (32%), DaunoXome7 (31%), DOXIL7 (2%), and
doxorubicin containing chemotherapy (42%), with 64% having received prior anthracyclines. Eighty-five percent of
the pretreated patients had progressed on, or could not tolerate, prior systemic therapy.
In Study CA139-174 patients received TAXOL at 135 mg/m2 as a 3-hour infusion every 3 weeks (intended
dose intensity 45 mg/m2/week). If no dose-limiting toxicity was observed, patients were to receive 155 mg/m2 and 175
mg/m2 in subsequent courses. Hematopoietic growth factors were not to be used initially. In Study CA139-281
patients received TAXOL at 100 mg/m2 as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m2/week).
In this study patients could be receiving hematopoietic growth factors before the start of TAXOL therapy, or this
support was to be initiated as indicated; the dose of TAXOL was not increased. The dose intensity of TAXOL used in
this patient population was lower than the dose intensity recommended for other solid tumors.
All patients had widespread and poor risk disease. Applying the ACTG staging criteria to patients with prior
systemic therapy, 93% were poor risk for extent of disease (T1), 88% had a CD4 count <200 cells/mm3 (I1), and 97%
had poor risk considering their systemic illness (S1).
All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study
CA139-281, there were 26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.
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TABLE 6
Extent of Disease at Study Entry
Percent of Patients
Prior Systemic Therapy
(n=59)
Visceral + edema + oral + cutaneous
Edema or lymph nodes
oral + cutaneous
Oral + cutaneous
Cutaneous Only
42
41
10
7
Although the planned dose intensity in the two studies was slightly different (45 mg/m2/week in Study CA139-
174 and 50 mg/m2/week in Study CA139-281), delivered dose intensity was 38-39 mg/m2/week in both studies, with a
similar range (20-24 to 51-61).
_____________________________________
DaunoXome7 is a registered trademark of NeXstar Pharmaceuticals, Incorporated.
DOXIL7 is a registered trademark of Sequus Pharmaceuticals, Incorporated.
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Efficacy: The efficacy of TAXOL was evaluated by assessing cutaneous tumor response according to the amended
ACTG criteria and by seeking evidence of clinical benefit in patients in six domains of symptoms and/or conditions
that are commonly related to AIDS-related Kaposi=s sarcoma.
Cutaneous Tumor Response (Amended ACTG Criteria): The objective response rate was 59% (95% CI: 46% to
72%) (35 of 59 patients) in patients with prior systemic therapy. Cutaneous responses were primarily defined as
flattening of more than 50% of previously raised lesions.
TABLE 7
Overall Best Response (Amended ACTG Criteria)
Percent of Patients
Prior Systemic
Therapy
(n=59)
Complete response
Partial response
Stable disease
Progression
Early death/toxicity
3
56
29
8
3
The median time to response was 8.1 weeks and the median duration of response measured from the first
day of treatment was 10.4 months (95% CI: 7.0 to 11.0 months) for the patients who had previously received systemic
therapy. The median time to progression was 6.2 months (95% CI: 4.6 to 8.7 months).
Additional Clinical Benefit: Most data on patient benefit were assessed retrospectively (plans for such analyses were
not included in the study protocols). Nonetheless, clinical descriptions and photographs indicated clear benefit in
some patients, including instances of improved pulmonary function in patients with pulmonary involvement, improved
ambulation, resolution of ulcers, and decreased analgesic requirements in patients with KS involving the feet and
resolution of facial lesions and edema in patients with KS involving the face, extremities, and genitalia.
Safety: The adverse event profile of TAXOL administered to patients with advanced HIV disease and poor-risk AIDS-
related Kaposi=s sarcoma was generally consistent with that seen in the pooled analysis of data from 812 patients
with solid tumors. These adverse events and adverse events from the phase 2 second-line Kaposi’s sarcoma studies
are described in the ADVERSE REACTIONS section of the label, in tabular (Table 8 & 13) and narrative form. In this
immunosuppressed patient population, however, a lower dose intensity of TAXOL and supportive therapy including
hematopoietic growth factors in patients with severe neutropenia are recommended. Patients with AIDS-related
Kaposi= sarcoma may have more severe hematologic toxicities than patients with solid tumors.
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INDICATIONS
TAXOL is indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As
first-line therapy, Taxol is indicated in combination with cisplatin.
TAXOL is indicated for the treatment of breast cancer after failure of combination chemotherapy for
metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an
anthracycline unless clinically contraindicated.
TAXOL, in combination with cisplatin, is indicated for the first-line treatment of non-small cell
lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.
TAXOL is indicated for the second-line treatment of AIDS-related Kaposi=s sarcoma.
CONTRAINDICATIONS
TAXOL is contraindicated in patients who have a history of hypersensitivity reactions to TAXOL or other drugs
formulated in Cremophor7 EL (polyoxyethylated castor oil).
TAXOL should not be used in patients with solid tumors who have baseline neutrophil counts of <1500
cells/mm3 or in patients with AIDS-related Kaposi=s sarcoma with baseline neutrophil counts of <1000 cells/mm3.
WARNINGS
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment,
angioedema, and generalized urticaria have occurred in 2-4% of patients receiving TAXOL in clinical trials. Fatal
reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids,
diphenhydramine, and H2 antagonists. (See DOSAGE AND ADMINISTRATION section.) Patients who experience
severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug.
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity.
Neutrophil nadirs occurred at a median of 11 days. TAXOL should not be administered to patients with baseline
neutrophil counts of less than 1500 cells/mm3 (<1000 cells/mm3 for patients with KS). Frequent monitoring of blood
counts should be instituted during TAXOL treatment. Patients should not be re-treated with subsequent cycles of
TAXOL until neutrophils recover to a level >1500 cells/mm3 (>1000 cells/mm3 for patients with KS) and platelets
recover to a level >100,000 cells/mm3.
Severe conduction abnormalities have been documented in <1% of patients during TAXOL therapy and in
some cases required pacemaker placement. If patients develop significant conduction abnormalities during TAXOL
infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during
subsequent therapy with TAXOL.
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Pregnancy
TAXOL can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period
of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the daily maximum recommended human dose on a
mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions and
increased fetal deaths. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1.0
mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m2 basis); teratogenic potential could
not be assessed at higher doses due to extensive fetal mortality.
There are no adequate and well-controlled studies in pregnant women. If TAXOL is used during pregnancy,
or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to
the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
PRECAUTIONS
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare
solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-
ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted TAXOL solutions should
preferably be stored in bottles (glass, polypropylene) or plastic bags, (polypropylene, polyolefin) and administered
through polyethylene-lined administration sets.
TAXOL should be administered through an in-line filter with a microporous membrane not greater than 0.22
microns. Use of filter devices such as IVEX-27 filters which incorporate short inlet and outlet PVC-coated tubing has
not resulted in significant leaching of DEHP.
Drug Interactions: In a Phase 1 trial using escalating doses of TAXOL (110-200 mg/m2) and cisplatin (50 or 75
mg/m2) given as sequential infusions, myelosuppression was more profound when TAXOL was given after cisplatin
than with the alternate sequence (i.e. TAXOL before cisplatin). Pharmacokinetic data from these patients
demonstrated a decrease in paclitaxel clearance of approximately 33% when TAXOL was administered following
cisplatin.
The metabolism of TAXOL is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the
absence of formal clinical drug interaction studies, caution should be exercised when administering TAXOL
concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. (See
CLINICAL PHARMACOLOGY section.)
Potential interactions between paclitaxel, a substrate of CYP3A4 and protease inhibitors (ritonavir,
saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4 have not been evaluated in
clinical trials.
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Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol)
may be increased when paclitaxel and doxorubicin are used in combination.
Hematology: TAXOL therapy should not be administered to patients with baseline neutrophil counts of less than
1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral
blood cell counts be performed on all patients receiving TAXOL. Patients should not be re-treated with subsequent
cycles of TAXOL until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000
cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of TAXOL
therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.
For patients with advanced HIV disease and poor-risk AIDS-related Kaposi=s sarcoma TAXOL, at the
recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1000 cells/mm3.
Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing
Cremophor7 EL (e.g. cyclosporin for injection concentrate and teniposide for injection concentrate) should not be
treated with TAXOL. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with
TAXOL should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H2
antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea,
hypotension or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension
requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria require immediate
discontinuation of TAXOL and aggressive symptomatic therapy. Patients who have developed severe
hypersensitivity reactions should not be rechallenged with TAXOL.
Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during administration of TAXOL,
but generally do not require treatment. Occasionally TAXOL infusions must be interrupted or discontinued because
of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of TAXOL infusion,
is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction
abnormalities. (See WARNINGS section.)
Nervous System: Although the occurrence of peripheral neuropathy is frequent, the development of severe
symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of TAXOL.
TAXOL contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and
other effects of alcohol. (See PRECAUTIONS: Pediatric Use section.)
Hepatic: There is evidence that the toxicity of TAXOL is enhanced in patients with elevated liver enzymes. Caution
should be exercised when administering TAXOL to patients with moderate to severe hepatic impairment and dose
adjustments should be considered.
Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild
and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have
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15
been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions
at a site of previous extravasation following administration of TAXOL at a different site, i.e., Arecall@, has been
reported rarely.
Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis and
fibrosis have been received as part of the continuing surveillance of TAXOL safety. In some cases the onset of the
injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of
extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of TAXOL (paclitaxel) has not
been studied.
Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and
in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation
assay.
Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats
at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m2
basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and
fetotoxicity. (See WARNINGS SECTION.)
Pregnancy: Pregnancy ACategory D.@ (See WARNINGS section.)
Nursing Mothers: It is not known whether the drug is excreted in human milk. Following intravenous administration
of carbon-14 labeled TAXOL to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher
than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human
milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be
discontinued when receiving TAXOL therapy.
Pediatric Use: The safety and effectiveness of TAXOL in pediatric patients have not been established.
There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical
trial in pediatric patients in which TAXOL was infused intravenously over 3 hours at doses ranging from 350 mg/m2 to
420 mg/m2. The toxicity is most likely attributable to the high dose of the ethanol component of the TAXOL vehicle
given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct
effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended
adult dosage) must be considered in assessing the safety of TAXOL for use in this population.
ADVERSE REACTIONS
Single-Agent
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16
Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with
breast carcinoma) enrolled in 10 studies who received single-agent TAXOL. Two hundred and seventy-five patients
were treated in 8 Phase 2 studies with TAXOL doses ranging from 135 to 300 mg/m2 administered over 24 hours (in 4
of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated
in the randomized Phase 3 ovarian carcinoma study which compared two doses (135 or 175 mg/m2) and two
schedules (3 or 24 hours) of TAXOL. Two hundred and thirty-six patients with breast carcinoma received TAXOL
(135 or 175 mg/m2) administered over 3 hours in a controlled study.
TABLE 8
Summary* of Adverse Events in 812 Patients With Solid Tumors Receiving Single-Agent TAXOL
$ Bone Marrow
---Neutropenia <2000/mm3
< 500/mm3
---Leukopenia <4000/mm3
<1000/mm3
---Thrombocytopenia <100,000/mm3
< 50,000/mm3
---Anemia <11 g/dL
< 8 g/dL
---Infections
---Bleeding
---Red Cell Transfusions
---Platelet Transfusions
$ Hypersensitivity Reaction**
---All
---Severe
$ Cardiovascular
---Vital Sign Changes***
---Bradycardia (N=537)
---Hypotension (N=532)
---Significant Cardiovascular Events
$$ Abnormal ECG
---All Pts
---Pts with normal baseline (N=559)
$ Peripheral Neuropathy
---Any symptoms
---Severe symptoms
$ Myalgia/Arthralgia
---Any symptoms
---Severe symptoms
$ Gastrointestinal
---Nausea and vomiting
---Diarrhea
---Mucositis
$ Alopecia
$ Hepatic (Pts with normal baseline and on study data)
---Bilirubin elevations (N=765)
---Alkaline phosphatase elevations (N=575)
---AST (SGOT) elevations (N=591)
$ Injection Site Reaction
% of Patients (n=812)
90
52
90
17
20
7
78
16
30
14
25
2
41
2
3
12
1
23
14
60
3
60
8
52
38
31
87
7
22
19
13
*Based on worst course analysis
**All patients received premedication
***During the first 3 hours of infusion
None of the observed toxicities were clearly influenced by age.
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17
Disease-Specific Tables of Adverse Events
First-Line Ovary in Combination
For the 409 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy study,
the following table shows the incidence of important adverse events.
TABLE 9
Frequency* of Important Adverse Events in the Phase 3 First-Line Ovarian Carcinoma Study
Percent of Patients
TAXOL (135/24)****/Cisplatin (75)
(n=196)
Cyclophosphamide (750)/Cisplatin (75)
(n=213)
$ Bone Marrow
---Neutropenia
---Thrombocytopenia
---Anemia
---Infections
---Febrile Neutropenia
<2,000/mm3
<500/mm3
<100,000/mm3
<50,000/mm3
<11 g/dL
<8 g/dL
96
81***
26
10
88
13
21
15***
92
58***
30
9
86
9
15
4***
$ Hypersensitivity Reaction**
---All
---Severe
8***
3***
1***
---***
$ Peripheral Neuropathy
---Any symptoms
---Severe symptoms
25
3***
20
---***
$ Nausea and Vomiting
---Any symptoms
---Severe symptoms
65
10
69
11
$ Myalgia/Arthralgia
---Any symptoms
---Severe symptoms
9***
1
2***
---
$ Diarrhea
---Any symptoms
---Severe symptoms
16***
4
8***
1
$ Asthenia
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18
---Any symptoms
---Severe symptoms
17***
1
10***
1
$ Alopecia
---Any symptoms
---Severe symptoms
55***
6
37***
8
*Based on worst course analysis
**All patients received premedication
*** py0.05 by Fisher Exact Test
****Taxol dose in mg/m2/infusion duration in hours
Second-Line Ovary
For the 403 patients who received single-agent TAXOL in the Phase 3 second-line ovarian carcinoma study,
the following table shows the incidence of important adverse events.
TABLE 10
Frequency* of Important Adverse Events in the Phase 3 Second-Line Ovarian Carcinoma Study
Percent of Patients
175/3***
(n=95)
175/24***
(n=105)
135/3***
(n=98)
135/24***
(n=105)
$ Bone Marrow
---Neutropenia
---Thrombocytopenia
---Anemia
---Infections
<2,000/mm3
<500/mm3
<100,000/mm3
<50,000/mm3
<11 g/dL
<8 g/dL
78
27
4
1
84
11
26
98
75
18
7
90
12
29
78
14
8
2
68
6
20
98
67
6
1
88
10
18
$ Hypersensitivity Reaction**
---All
---Severe
41
2
45
0
38
2
45
1
$ Peripheral Neuropathy
---Any symptoms
---Severe symptoms
63
1
60
2
55
0
42
0
$ Mucositis
---Any symptoms
---Severe symptoms
17
0
35
3
21
0
25
2
*Based on worst course analysis
**All patients received premedication
***Taxol dose in mg/m2/infusion duration in hours
Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development
of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was
no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose-related, but
schedule did not appear to affect the incidence.
Second-Line Breast
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For the 458 patients who received single-agent TAXOL in the Phase 3 second-line breast carcinoma study,
the following table shows the incidence of important adverse events by treatment arm (each arm was administered by
a 3-hour infusion).
TABLE 11
Frequency* of Important Adverse Events in the Phase 3
Second-Line Breast Carcinoma Study
Percent of Patients
175/3***
(n=229)
135/3***
(n=229)
$ Bone Marrow
---Neutropenia
---Thrombocytopenia
---Anemia
---Infections
---Febrile Neutropenia
$ Hypersensitivity Reaction**
---All
---Severe
$ Peripheral Neuropathy
---Any symptoms
---Severe symptoms
$ Mucositis
---Any symptoms
---Severe symptoms
<2,000/mm3
<500/mm3
<100,000/mm3
<50,000/mm3
<11 g/dL
<8 g/dL
90
28
11
3
55
4
23
2
36
0
70
7
23
3
81
19
7
2
47
2
15
2
31
<1
46
3
17
<1
*Based on worst course analysis
**All patients received premedication
***Taxol dose in mg/m2/infusion duration in hours
Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensivity reaction
(HSR) observed at the dose of 135 mg/m2.
First-Line NSCLC in Combination
In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to
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20
either TAXOL (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, TAXOL (T) 250 mg/m2
as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day
1 followed by etoposide (VP) 100 mg/m2 on days 1, 2 and 3 (control).
The following table shows the incidence of important adverse events, with severe events defined as at least
Grade III toxicity.
TABLE 12
Frequency* of Important Adverse Events in the Phase 3 Study for First-line NSCLC
Percent of Patients
T135/24
a
c75
(n=195)
T250/24
a
c75
(n=197)
VP100
b
c75
(n=196)
$ Bone Marrow
---Neutropenia <2,000/mm
3
< 500/mm
3
---Thrombocytopenia < normal
< 50,000/mm
3
---Anemia
< normal
< 8 g/dL
---Infections
$$ Hypersensitivity Reaction**
---All
---Severe
$$ Arthralgia/Myalgia
---Any symptoms
---Severe symptoms
$$ Nausea/Vomiting
---Any symptoms
---Severe symptoms
$$ Mucositis
---Any symptoms
---Severe symptoms
$$ Peripheral Neuropathy
---Any symptoms
---Severe symptoms
$$ Neuromotor Toxicity
---Any symptoms
---Severe symptoms
$$ Neurosensory Toxicity
---Any symptoms
---Severe symptoms
$$ Cardiovascular Events
---Any symptoms
---Severe symptoms
89
74***
48
6
94
22
38
16
1
21***
3
85
27
18
1
N/A
N/A
37
6
48
13
33
13
86
65
68
12
96
19
31
27
4***
42***
11
87
29
28
4
N/A
N/A
47
23
61
28***
39
12
84
55
62
16
95
28
35
13
1
9
1
81
22
16
2
N/A
N/A
44
7
25
8
24
8
*
Based on worst course analysis
**
All patients received premedication
***
p<0.05
a
Taxol dose in mg/m2 / infusion duration in hours
b
Etoposide (VP) 100 mg/m2 was administered IV on days 1, 2, and 3.
N/A
Not Available
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21
Toxicity was generally more severe in the high dose Taxol treatment arm (T250/c75) than in the low dose Taxol arm
(T135/c75). Compared to the cisplatin/etoposide arm, patients in the low dose Taxol arm experienced more severe
neutropenia and arthralgia/myalgia. The incidence of febrile neutropenia was not reported in this study.
Kaposi’s Sarcoma
The following table shows the frequency of important adverse events in the 85 patients with KS treated with
two different single-agent TAXOL regimens.
TABLE 13
Frequency* of Important Adverse Events in the
AIDS-Related Kaposi=s Sarcoma Studies
Percent of Patients
Study CA139-174
Taxol 135/3 q 3 wk***
(n=29)
Study CA139-281
Taxol 100/3 q 2 wk***
(n=56)
$ Bone Marrow
---Neutropenia
<2000/mm3
< 500/mm3
---Thrombocytopenia
<100,000/mm3
< 50,000/mm3
---Anemia
<11 g/dL
< 8 g/dL
---Febrile Neutropenia
$$ Opportunistic Infection
---Any
---Cytomegalovirus
---Herpes Simplex
---Pneumocystis carinii
---M. Avium intracellulare
---Candidiasis, esophageal
---Cryptosporidiosis
---Cryptococcal meningitis
---Leukoencephalopathy
$$ Hypersensitivity Reaction**
---All
$ Cardiovascular
---Hypotension
---Bradycardia
$ Peripheral Neuropathy
---Any
---Severe
$ Myalgia/Arthralgia
---Any
---Severe
$ Gastrointestinal
---Nausea and vomiting
---Diarrhea
---Mucositis
$ Renal (creatinine elevation)
---Any
---Severe (grade III/IV)
$ Discontinuation for drug toxicity
100
76
52
17
86
34
55
76
45
38
14
24
7
7
3
--
14
17
3
79
10
93
14
69
90
45
34
7
7
95
35
27
5
73
25
9
54
27
11
21
4
9
7
2
2
9
9
--
46
2
48
16
70
73
20
18
5
16
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22
*Based on worst course analysis
**All patients received premedication
***Taxol dose in mg/m2 / infusion duration in hours
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23
As demonstrated in this table, toxicity was more pronounced in the study utilizing TAXOL at a dose of 135
mg/m2 every 3 weeks than in the study utilizing TAXOL at a dose of 100 mg/m2 every 2 weeks. Notably, severe
neutropenia (76% versus 35%), febrile neutropenia (55% versus 9%) and opportunistic infections (76% versus 54%)
were more common with the former dose and schedule. The differences between the two studies with respect to
dose escalation and use of hematopoietic growth factors, as described above, should be taken into account. (See
CLINICAL STUDIES: AIDS-Related Kaposi==s Sarcoma section.) Note also that only 26% of the 85 patients in
these studies received concomitant treatment with protease inhibitors, whose effect on paclitaxel metabolism has not
yet been studied.
Narrative Discussion of Adverse Events
Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with
solid tumors treated with single-agent TAXOL in clinical studies. Toxicities that occurred with greater severity or
frequency in previously untreated patients with ovarian carcinoma or NSCLC who received TAXOL in combination
with cisplatin and that occurred with a difference that was clinically significant in this population are also described.
The frequency and severity of important adverse events for the Phase 3 first- and second-line ovarian, breast
carcinoma and NSCLC studies are presented above in tabular form by treatment arm. In addition, rare events have
been reported from the postmarketing experience or from other clinical studies. The frequency and severity of
adverse events have been generally similar for patients receiving TAXOL for the treatment of ovarian, breast, or lung
carcinoma or Kaposi=s sarcoma, but patients with AIDS-related Kaposi=s sarcoma may have more frequent and
severe hematologic toxicity, infections, and febrile neutropenia. These patients require a lower dose intensity and
supportive care. (See CLINICAL STUDIES: AIDS-Related Kaposi==s Sarcoma section.) Toxicities that were
observed only in or were noted to have occurred with greater severity in the population with Kaposi=s sarcoma and
that occurred with a difference that was clinically significant in this population are described.
Hematologic: Bone marrow suppression was the major dose-limiting toxicity of TAXOL. Neutropenia, the most
important hematologic toxicity, was dose and schedule dependent and was generally rapidly reversible. Among
patients treated in the Phase 3 second-line ovarian study with a 3-hour infusion, neutrophil counts declined below 500
cells/mm3 in 13% of the patients treated with a dose of 135 mg/m2 compared to 27% at a dose of 175 mg/m2 (p=0.05).
In the same study, severe neutropenia (<500 cells/mm3) was more frequent with the 24-hour than with the 3-hour
infusion; infusion duration had a greater impact on myelosuppression than dose. Neutropenia did not appear to
increase with cumulative exposure and did not appear to be more frequent nor more severe for patients previously
treated with radiation therapy.
In the study where TAXOL was administered to patients with ovarian carcinoma at a dose of 135 mg/m2/24
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24
hours in combination with cisplatin versus the control arm of cyclophosphamide plus cisplatin, the incidences of grade
IV neutropenia and of febrile neutropenia were significantly greater in the Taxol plus cisplatin arm than in the control
arm. Grade IV neutropenia occurred in 81% on the Taxol plus cisplatin arm versus 58% on the cyclophosphamide
plus cisplatin arm and febrile neutropenia occurred in 15% and 4% respectively. On the Taxol/cisplatin arm, there
were 35/1074 (3%) courses with fever in which Grade IV neutropenia was reported at some time during the course.
When TAXOL followed by cisplatin was administered to patients with advanced NSCLC in the ECOG
study, the incidences of Grade IV neutropenia were 74% (TAXOL 135 mg/m2/24 hours followed by
cisplatin) and 65% (TAXOL 250 mg/m2/24 hours followed by cisplatin and G-CSF) compared with 55% in
patients who received cisplatin/etoposide.
Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all patients and
9% of all courses; these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. In
the Phase 3 second-line ovarian study, infectious episodes were reported in 19% of the patients given either the 135
or 175 mg/m2 dose by a 3-hour infusion. Urinary tract infections and upper respiratory tract infections were the most
frequently reported infectious complications. In the immunosuppressed patient population with advanced HIV
disease and poor-risk AIDS-related Kaposi=s sarcoma, 61% of the patients reported at least one opportunistic
infection. (See CLINICAL STUDIES: AIDS-Related Kaposi==s Sarcoma section.) The use of supportive therapy,
including G-CSF, is recommended for patients who have experienced severe neutropenia. (See DOSAGE AND
ADMINISTRATION section.)
Thrombocytopenia was uncommon, and almost never severe (<50,000 cells/mm3). Twenty percent of the
patients experienced a drop in their platelet count below 100,000 cells/mm3 at least once while on treatment; 7% had
a platelet count <50,000 cells/mm3 at the time of their worst nadir. Bleeding episodes were reported in 4% of all
courses and by 14% of all patients but most of the hemorrhagic episodes were localized and the frequency of these
events was unrelated to the TAXOL dose and schedule. In the Phase 3 second-line ovarian study, bleeding episodes
were reported in 10% of the patients; no patients treated with the 3-hour infusion received platelet transfusions. In the
Phase 3 NSCLC study of TAXOL 135 mg/m2/24 hours followed by cisplatin, severe thrombocytopenia
(<50,000/mm3) was experienced by 6% of the patients.
Anemia (Hb <11 g/dL) was observed in 78% of all patients and was severe (Hb <8 g/dL) in 16% of the
cases. No consistent relationship between dose or schedule and the frequency of anemia was observed. Among all
patients with normal baseline hemoglobin, 69% became anemic on study but only 7% had severe anemia. Red cell
transfusions were required in 25% of all patients and in 12% of those with normal baseline hemoglobin levels.
Hypersensitivity Reactions (HSRs): All patients received premedication prior to TAXOL (See WARNINGS and
PRECAUTIONS: Hypersensitivity Reactions sections). The frequency and severity of HSRs were not affected by
the dose or schedule of TAXOL administration. In the Phase 3 second-line ovarian study, the 3-hour infusion was not
associated with a greater increase in HSRs when compared to the 24-hour infusion. Hypersensitivity reactions were
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25
observed in 20% of all courses and in 41% of all patients. These reactions were severe in less than 2% of the
patients and 1% of the courses. No severe reactions were observed after course 3 and severe symptoms occurred
generally within the first hour of TAXOL infusion. The most frequent symptoms observed during these severe
reactions were dyspnea, flushing, chest pain and tachycardia.
The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%),
dyspnea (2%), tachycardia (2%) and hypertension (1%). The frequency of hypersensitivity reactions remained
relatively stable during the entire treatment period.
Rare reports of chills and reports of back pain in association with hypersensitivity reactions have been
received as part of the continuing surveillance of TAXOL safety.
Cardiovascular: Hypotension, during the first 3 hours of infusion, occurred in 12% of all patients and 3% of all
courses administered. Bradycardia, during the first 3 hours of infusion, occurred in 3% of all patients and 1% of all
courses. In the Phase 3 second-line ovarian study, neither dose nor schedule had an effect on the frequency of
hypotension and bradycardia. These vital sign changes most often caused no symptoms and required neither
specific therapy nor treatment discontinuation. The frequency of hypotension and bradycardia were not influenced by
prior anthracycline therapy.
Significant cardiovascular events possibly related to single-agent TAXOL occurred in approximately 1% of
all patients. These events included syncope, rhythm abnormalities, hypertension and venous thrombosis. One of the
patients with syncope treated with TAXOL at 175 mg/m2 over 24 hours had progressive hypotension and died. The
arrhythmias included asymptomatic ventricular tachycardia, bigeminy and complete AV block requiring pacemaker
placement. Among patients with NSCLC treated with Taxol in combination with cisplatin in the Phase 3 study,
significant cardiovascular events occurred in 12-13%. The apparent increase in these cardiovascular events is
possibly due to the difference in cardiovascular risk factors in most patients with NSCLC who were treated with Taxol
and cisplatin.
Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on
study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities
were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients
developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific
repolarization abnormalities, sinus bradycardia, sinus tachycardia and premature beats. Among patients with normal
ECGs at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities.
Cases of myocardial infarction have been reported rarely. Congestive heart failure has been reported
typically in patients who have received other chemotherapy, notably anthracyclines. (See PRECAUTIONS: Drug
Interactions section.)
Rare reports of atrial fibrillation and supraventricular tachycardia have been received as part of the
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26
continuing surveillance of TAXOL safety.
Respiratory: Rare reports of interstitial pneumonia, lung fibrosis and pulmonary embolism, have been received as
part of the continuing surveillance of TAXOL safety. Rare reports of radiation pneumonitis have been received in
patients receiving concurrent radiotherapy.
Neurologic: The frequency and severity of neurologic manifestations were dose-dependent, but were not influenced
by infusion duration. Peripheral neuropathy was observed in 60% of all patients (3% severe) and in 52% (2%
severe) of the patients without pre-existing neuropathy.
The frequency of peripheral neuropathy increased with cumulative dose. Neurologic symptoms were
observed in 27% of the patients after the first course of treatment and in 34-51% from course 2 to 10.
Peripheral neuropathy was the cause of TAXOL discontinuation in 1% of all patients. Sensory symptoms
have usually improved or resolved within several months of TAXOL discontinuation. The incidence of neurologic
symptoms did not increase in the subset of patients previously treated with cisplatin. Pre-existing neuropathies
resulting from prior therapies are not a contraindication for TAXOL therapy. In patients with NSCLC, administration of
Taxol followed by cisplatin resulted in a greater incidence of neurotoxicity compared with single-agent Taxol;
neurosensory symptoms were noted in 48% of patients receiving Taxol 135 mg/m2 by 24 hour infusion followed by
cisplatin 75 mg/m2.
Other than peripheral neuropathy, serious neurologic events following TAXOL administration have been rare
(<1%) and have included grand mal seizures, syncope, ataxia and neuroencephalopathy.
Rare reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the
continuing surveillance of TAXOL safety. Optic nerve and/or visual disturbances (scintillating scotomata) have also
been reported, particularly in patients who have received higher doses than those recommended. These effects
generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in
patients have suggested persistent optic nerve damage.
Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of TAXOL and the frequency or
severity of arthralgia/myalgia. Sixty percent of all patients treated experienced arthralgia/myalgia; 8% experienced
severe symptoms. The symptoms were usually transient, occurred two or three days after TAXOL administration,
and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged
throughout the treatment period.
Hepatic: No relationship was observed between liver function abnormalities and either dose or schedule of TAXOL
administration. Among patients with normal baseline liver function 7%, 22% and 19% had elevations in bilirubin,
alkaline phosphatase and AST (SGOT), respectively. Prolonged exposure to TAXOL was not associated with
cumulative hepatic toxicity.
Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of
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27
the continuing surveillance of TAXOL safety.
Renal: Among the patients treated for Kaposi=s sarcoma with TAXOL, five patients had renal toxicity of grade III or IV
severity. One patient with suspected HIV nephropathy of grade IV severity had to discontinue therapy. The other
four patients had renal insufficiency with reversible elevations of serum creatinine.
Gastrointestinal (GI): Nausea/vomiting, diarrhea and mucositis were reported by 52%, 38% and 31% of all patients,
respectively. These manifestations were usually mild to moderate. Mucositis was schedule dependent and occurred
more frequently with the 24-hour than with the 3-hour infusion.
In patients with poor-risk AIDS-related Kaposi=s sarcoma, nausea/vomiting, diarrhea and mucositis were
reported by 69%, 79% and 28% of patients, respectively. One-third of patients with Kaposi=s sarcoma complained of
diarrhea prior to study start. (See CLINICAL STUDIES: AIDS-Related Kaposi==s Sarcoma section.)
In the first-line, phase 3 ovarian carcinoma study, the incidence of nausea and vomiting when TAXOL was
administered in combination with cisplatin appeared to be greater compared with the database for single-agent
TAXOL in ovarian and breast carcinoma. In the same study, diarrhea of any grade was reported more frequently
(16%) compared to the control arm (8%) (p=0.008), but there was no difference for severe diarrhea.
Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, and dehydration
have been received as part of the continuing surveillance of TAXOL safety. Rare reports of neutropenic enterocolitis
(typhlitis), despite the coadministration of G-CSF, were observed in patients treated with TAXOL alone and in
combination with other chemotherapeutic agents.
Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild
and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have
been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions
at a site of previous extravasation following administration of TAXOL at a different site, i.e., Arecall@, has been
reported rarely.
Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis and
fibrosis have been received as part of the continuing surveillance of TAXOL safety. In some cases the onset of the
injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of
extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. Transient skin changes due to
TAXOL related hypersensitivity reactions have been observed, but no other skin toxicities were significantly
associated with TAXOL administration. Nail changes (changes in pigmentation or discoloration of nail bed) were
uncommon (2%). Edema was reported in 21% of all patients (17% of those without baseline edema); only 1% had
severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and
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28
disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase
with time on study.
Rare reports of skin abnormalities related to radiation recall as well as reports of maculopapular rash and
pruritus have been received as part of the continuing surveillance of TAXOL safety.
Reports of asthenia and malaise have been received as part of the continuing surveillance of TAXOL safety.
In the phase 3 trial of Taxol 135 mg/m2 over 24 hours in combination with cisplatin as first-line therapy of ovarian
cancer, asthenia was reported in 17% of patients, significantly greater than the 10% incidence observed in the
control arm of cyclophosphamide/cisplatin.
Accidental Exposure: Upon inhalation, dyspnea, chest pain, burning eyes, sore throat and nausea have been
reported. Following topical exposure, events have included tingling, burning and redness.
OVERDOSAGE
There is no known antidote to TAXOL overdosage. The primary anticipated complications of overdosage would
consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Overdoses in pediatric patients may be
associated with acute ethanol toxicity (see PRECAUTIONS: Pediatric Use section).
DOSAGE AND ADMINISTRATION
Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for
infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-
ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted TAXOL solutions should be
stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through
polyethylene-lined administration sets.
All patients should be premedicated prior to TAXOL administration in order to prevent severe
hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered
approximately 12 and 6 hours before TAXOL, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to
TAXOL, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before TAXOL.
For patients with carcinoma of the ovary, the following regimens are recommended:
(1)
For previously untreated patients with carcinoma of the ovary, the recommended regimen, given
every 3 weeks, is TAXOL administered intravenously over 24 hours at a dose of 135 mg/m2
followed by cisplatin at a dose of 75 mg/m2.
(2)
In patients previously treated with chemotherapy for carcinoma of the ovary, TAXOL has been used
at several doses and schedules; however, the optimal regimen is not yet clear (see CLINICAL
STUDIES: Ovarian Carcinoma section). The recommended regimen is TAXOL 135 mg/m2 or 175
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29
mg/m2 administered intravenously over 3 hours every 3 weeks.
For patients with carcinoma of the breast, TAXOL at a dose of 175 mg/m2 administered intravenously over
3 hours every 3 weeks has been shown to be effective after failure of chemotherapy for metastatic disease or relapse
within 6 months of adjuvant chemotherapy. (See CLINICAL STUDIES: Breast Carcinoma section.)
For patients with non-small cell lung carcinoma, the recommended regimen, given every 3
weeks, is TAXOL administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin,
75 mg/m2.
For patients with AIDS-related Kaposi==s sarcoma, TAXOL administered at a dose of 135 mg/m2 given
intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks
is recommended (dose intensity 45-50 mg/m2/week). In the two clinical trials evaluating these schedules (see
CLINICAL STUDIES: AIDS-related Kaposi==s Sarcoma section), the former schedule (135 mg/m2 every 3 weeks)
was more toxic than the latter. In addition, all patients with low performance status were treated with the latter
schedule (100 mg/m2 every 2 weeks).
Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are
recommended in these patients:
1) Reduce the dose of dexamethasone as one of the three premedication drugs to 10 mg PO (instead of 20
mg PO);
2) Initiate or repeat treatment with TAXOL only if the neutrophil count is at least 1000 cells/mm3;
3) Reduce the dose of subsequent courses of TAXOL by 20% for patients who experience severe
neutropenia (neutrophil <500 cells/mm3 for a week or longer); and
4) Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.
For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of TAXOL should not be
repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3.
TAXOL should not be given to patients with AIDS-related Kaposi=s sarcoma if the baseline or subsequent neutrophil
count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a
week or longer) or severe peripheral neuropathy during TAXOL therapy should have dosage reduced by 20% for
subsequent courses of TAXOL. The incidence of neurotoxicity and the severity of neutropenia increase with dose.
Preparation and Administration Precautions: TAXOL is a cytotoxic anticancer drug and, as with other potentially
toxic compounds, caution should be exercised in handling TAXOL. The use of gloves is recommended. If TAXOL
solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical
exposure, events have included tingling, burning and redness. If TAXOL contacts mucous membranes, the
membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat
and nausea have been reported.
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30
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration
during drug administration (see PRECAUTIONS: Injection Site Reaction section).
Preparation for Intravenous Administration: TAXOL (paclitaxel) Injection must be diluted prior to infusion. TAXOL
should be diluted in 0.9% Sodium Chloride Injection, USP, 5% Dextrose injection, USP, 5% Dextrose and 0.9%
Sodium Chloride Injection, USP or 5% Dextrose in Ringer=s Injection to a final concentration of 0.3 to 1.2 mg/mL. The
solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25E C) and
room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant
losses in potency have been noted following simulated delivery of the solution through I.V. tubing containing an in-line
(0.22 micron) filter.
Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that
levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of
plasticized PVC containers and administration sets is not recommended. TAXOL solutions should be prepared and
stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those
which are polyethylene-lined, should be used.
TAXOL should be administered through an in-line filter with a microporous membrane not greater than 0.22
microns. Use of filter devices such as IVEX-27 filters which incorporate short inlet and outlet PVC-coated tubing has
not resulted in significant leaching of DEHP.
The Chemo Dispensing PinJ device or similar devices with spikes should not be used with vials of TAXOL
since they can cause the stopper to collapse resulting in loss of sterile integrity of the TAXOL solution.
Stability: Unopened vials of TAXOL (paclitaxel) Injection are stable until the date indicated on the package when
stored between 20E-25EC (68E-77EF), in the original package. Neither freezing nor refrigeration adversely affects
the stability of the product. Upon refrigeration components in the TAXOL vial may precipitate, but will redissolve upon
reaching room temperature with little or no agitation. There is no impact on product quality under these
circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded.
Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25EC) and
lighting conditions for up to 27 hours.
HOW SUPPLIED
NDC 0015-3475-30
30 mg/5 mL multidose vial individually packaged in a carton.
NDC 0015-3476-30
100 mg/16.7 mL multidose vial individually packaged in a carton.
NDC 0015-3479-11
300 mg/50 mL multidose vial individually package in a carton.
Storage: Store the vials in original cartons between 20E-25EC (68E-77EF). Retain in the original package to protect
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
from light.
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered.
Several guidelines on this subject have been published1-7. There is no general agreement that all of the procedures
recommended in the guidelines are necessary or appropriate.
IVEX-27 is the registered trademark of the Millipore Corporation.
Chemo Dispensing PinJ is a trademark of B. Braun Medical Incorporated.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
32
References:
1
Recommendations for the safe handling of parenteral antineoplastic drugs. NIH Publication No. 83-2621.
For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.
2
AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA 1985; 253 (11): 1590-1592.
3
National Study Commission on Cytotoxic Exposure--Recommendations for handling cytotoxic agents.
Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure.
Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston,
Massachusetts, 02115.
4
Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of
antineoplastic agents. Med J Australia 1983; 1:426-428.
5
Jones RB, et al: Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center.
CA-A Cancer Journal for Clinicians 1983; Sept./Oct. 258-263.
6
American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and
Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
7
Controlling occupational exposure to hazardous drugs (OSHA WORK-PRACTICE GUIDELINES). Am J
Health-Syst Pharm 1996; 53:1669-1685.
Mead Johnson
ONCOLOGY PRODUCTS
A Bristol-Myers Squibb Co.
Princeton, New Jersey 08543
U.S.A.
Issued
347630DIM-03
51-006186-02
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:15.679505
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20262s24lbl.pdf', 'application_number': 20262, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
12,384
|
Lescol
®
(fluvastatin sodium)
Capsules
Lescol
® XL
(fluvastatin sodium)
Extended-Release Tablets
Rx only
Prescribing Information
DESCRIPTION
Lescol® (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through
the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
Fluvastatin sodium is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-
indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of
fluvastatin sodium is C24H25FNO4•Na, its molecular weight is 433.46 and its structural
formula is:
This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and
is in part structurally distinct from the fungal derivatives of this therapeutic class.
Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water,
ethanol and methanol. Lescol is supplied as capsules containing fluvastatin sodium, equivalent
to 20 mg or 40 mg of fluvastatin, for oral administration. Lescol® XL (fluvastatin sodium) is
supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of
fluvastatin, for oral administration.
Active Ingredient: fluvastatin sodium
Inactive Ingredients in capsules: gelatin, magnesium stearate, microcrystalline cellulose,
pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide,
yellow iron oxide, and other ingredients.
Capsules may also include: benzyl alcohol, black iron oxide, butylparaben,
carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben,
silicon dioxide and sodium propionate.
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Page 2
Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium
stearate, yellow iron oxide, titanium dioxide and polyethylene glycol 8000.
CLINICAL PHARMACOLOGY
A variety of clinical studies have demonstrated that elevated levels of total cholesterol
(Total-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and apolipoprotein
B (a membrane transport complex for LDL-C) promote human atherosclerosis. Similarly,
decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A,
are associated with the development of atherosclerosis. Epidemiologic investigations have
established that cardiovascular morbidity and mortality vary directly with the level of Total-C
and LDL-C and inversely with the level of HDL-C.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL
and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently
found in a triad with low HDL-C levels and small LDL particles, as well as in association with
non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not
consistently been shown to be an independent risk factor for CHD. Furthermore, the
independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular
morbidity and mortality has not been determined.
In patients with hypercholesterolemia and mixed dyslipidemia, treatment with Lescol®
(fluvastatin sodium) or Lescol® XL (fluvastatin sodium) reduced Total-C, LDL-C,
apolipoprotein B, and triglycerides while producing an increase in HDL-C. Increases in
HDL-C are greater in patients with low HDL-C (<35 mg/dL). Neither agent had a consistent
effect on either Lp(a) or fibrinogen. The effect of Lescol or Lescol XL induced changes in
lipoprotein levels, including reduction of serum cholesterol, on cardiovascular mortality has
not been determined.
Mechanism of Action
Lescol is a competitive inhibitor of HMG-CoA reductase, which is responsible for the
conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a
precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces
the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby
increases the uptake of LDL particles. The end result of these biochemical processes is a
reduction of the plasma cholesterol concentration.
Pharmacokinetics/Metabolism
Oral Absorption
Fluvastatin is absorbed rapidly and completely following oral administration of the capsule,
with peak concentrations reached in less than 1 hour. Following administration of a 10 mg
dose, the absolute bioavailability is 24% (range 9%-50%). Administration with food reduces
the rate but not the extent of absorption. At steady state, administration of fluvastatin with the
evening meal results in a two-fold decrease in Cmax and more than two-fold increase in tmax as
compared to administration 4 hours after the evening meal. No significant differences in
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Page 3
extent of absorption or in the lipid-lowering effects were observed between the two
administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable
first-pass metabolism resulting in higher than expected plasma fluvastatin concentrations.
Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form.
In vivo studies showed that stereo-selective hepatic binding of the active form occurs during
the first pass resulting in a difference in the peak levels of the two enantiomers, with the active
to inactive peak concentration ratio being about 0.7. The approximate ratio of the active to
inactive approaches unity after the peak is seen and thereafter the two enantiomers decline
with the same half-life. After an intravenous administration, bypassing the first-pass,
metabolism, the ratios of the enantiomers in plasma were similar throughout the
concentration-time profiles.
Fluvastatin administered as Lescol XL 80 mg tablets reaches peak concentration in
approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a
low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range:
9%-66%) compared to that of the Lescol immediate-release capsule administered under
fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6H) and
increased the bioavailability of the XL tablet by approximately 50%. Once Lescol XL begins
to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after
a high-fat meal is much less than the peak concentration following a single dose or twice daily
dose of the 40 mg Lescol capsule. Overall variability in the pharmacokinetics of Lescol XL is
large (42%-64% CV for Cmax and AUC), and especially so after a high-fat meal (63%-89% for
Cmax and AUC). Intrasubject variability in the pharmacokinetics of Lescol XL under fasting
conditions (about 25% for Cmax and AUC) tends to be much smaller as compared to the
overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed
after Lescol XL administration.
Distribution
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is
estimated at 0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are
present systemically. At therapeutic concentrations, the protein binding of fluvastatin is not
affected by warfarin, salicylic acid and glyburide.
Metabolism
Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the
5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The
hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Both
enantiomers of fluvastatin are metabolized in a similar manner.
In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism,
predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin
metabolism are 2C8 (~5%) and 3A4 (~20%). (See PRECAUTIONS: Drug Interactions
Section).
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Page 4
Elimination
Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2%
present as unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of
fluvastatin, the clearance was 0.8 L/h/kg. Following multiple oral doses of radiolabeled
compound, there was no accumulation of fluvastatin; however, there was a 2.3- fold
accumulation of total radioactivity.
Steady-state plasma concentrations show no evidence of accumulation of fluvastatin
following immediate release capsule administration of up to 80 mg daily, as evidenced by a
beta-elimination half-life of less than 3 hours. However, under conditions of maximum rate of
absorption (i.e., fasting) systemic exposure to fluvastatin is increased 33% to 53% compared
to a single 20 mg or 40 mg dose of the immediate- release capsule. Following once daily
administration of the 80 mg Lescol XL tablet for 7 days, systemic exposure to fluvastatin is
increased (20%-30%) compared to a single dose of the 80 mg Lescol XL tablet. Terminal half-
life of Lescol XL was about 9 hours as a result of the slow-release formulation.
Single-dose and steady-state pharmacokinetic parameters in 33 subjects with
hypercholesterolemia for the capsules and in 35 healthy subjects for the extended-release
tablets are summarized below:
Table 1
Single-Dose and Steady-State Pharmacokinetic Parameters
Cmax
(ng/mL)
mean±SD
(range)
AUC
(ng·h/mL)
mean±SD
(range)
tmax
(hr)
mean±SD
(range)
CL/F
(L/hr)
mean±SD
(range)
t1/2
(hr)
mean±SD
(range)
Capsules
166±106
207±65
0.9±0.4
107±38.1
2.5±1.7
20 mg single
dose (n=17)
(48.9-517)
(111-288)
(0.5-2.0)
(69.5-181)
(0.5-6.6)
200±86
275±111
1.2±0.9
87.8±45
2.8±1.7
20 mg twice daily
(n=17)
(71.8-366)
(91.6-467)
(0.5-4.0)
(42.8-218)
(0.9-6.0)
273±189
456±259
1.2±0.7
108±44.7
2.7±1.3
40 mg single
dose (n=16)
(72.8-812)
(207-1221)
(0.75-3.0)
(32.8-193)
(0.8-5.9)
432±236
697±275
1.2±0.6
64.2±21.1
2.7±1.3
40 mg twice daily
(n=16)
(119-990)
(359-1559)
(0.5-2.5)
(25.7-111)
(0.7-5.0)
Extended-Release Tablets 80 mg single dose (n=24)
126±53
579±341
3.2± 2.6
-
-
80 mg single dose,
fasting (n=24)
(37-242)
(144-1760)
(1-12)
183±163
861±632
6
-
-
80 mg single dose,
fed state high- fat
meal (n=-24)
(21-733)
(199-3132)
(2-24)
Extended-Release Tablets 80 mg following 7 days dosing (steady-state) (n=11)
102±42
630±326
2.6±0.91
-
-
80 mg once daily,
fasting (n=11)
(43.9-181)
(247-1406)
(1.5-4)
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Page 5
Special Populations
Renal Insufficiency:
No significant (<6%) renal excretion of fluvastatin occurs in humans.
Hepatic Insufficiency:
Fluvastatin is subject to saturable first-pass metabolism/sequestration by the liver and is
eliminated primarily via the biliary route. Therefore, the potential exists for drug accumulation
in patients with hepatic insufficiency. Caution should therefore be exercised when fluvastatin
sodium is administered to patients with a history of liver disease or heavy alcohol ingestion
(see WARNINGS).
Fluvastatin AUC and Cmax values increased by about 2.5- fold in hepatic insufficiency
patients. This result was attributed to the decreased presystemic metabolism due to hepatic
dysfunction. The enantiomer ratios of the two isomers of fluvastatin in hepatic insufficiency
patients were comparable to those observed in healthy subjects.
Age:
Plasma levels of fluvastatin are not affected by age.
Gender:
Women tend to have slightly higher (but statistically insignificant) fluvastatin concentrations
than men for the immediate- release capsule. This is most likely due to body weight
differences, as adjusting for body weight decreases the magnitude of the differences seen. For
Lescol XL, there are 67% and 77% increases in systemic availability for women over men
under fasted and high- fat meal conditions.
Pediatric:
Pharmacokinetic data in the pediatric population are not available.
CLINICAL STUDIES
Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed
Dyslipidemia
In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinemia, Lescol®
(fluvastatin sodium) alone was administered to 1621 patients in daily dose regimens of 20 mg,
40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration. After 24 weeks of
treatment, daily doses of 20 mg, 40 mg, and 80 mg (40 mg twice daily) resulted in median
LDL-C reductions of 22% (n=747), 25% (n=748) and 36% (n=257), respectively. Lescol
treatment produced dose-related reductions in Apo B and in triglycerides and increases in
HDL-C. The median (25th, 75th percentile) percent changes from baseline in HDL-C after
12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice
daily) were +2 (-4,+10), +5 (-2,+12), and +4 (-3,+12), respectively. In a subgroup of patients
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Page 6
with primary mixed dyslipidemia, defined as baseline TG levels ≥200 mg/dL, treatment with
Lescol also produced significant decreases in Total-C, LDL-C, TG and Apo B and variable
increases in HDL-C. The median (25th, 75th percentile) percent changes from baseline in
HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg
(40 mg twice daily) in this population were +4 (-2,+12), +8 (+1,+15), and +4 (-3,+13),
respectively.
In a long-term open-label free titration study, after 96 weeks LDL-C decreases of 25%
(20 mg, n=68), 31% (40 mg, n=298) and 34% (80 mg, n=209) were seen. No consistent effect
on Lp(a) was observed.
Lescol® XL (fluvastatin sodium) Extended-Release Tablets have been studied in five
controlled studies of patients with Type IIa or IIb hyperlipoproteinemia. Lescol XL was
administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest
of these studies, Lescol XL given as a single daily dose of 80 mg significantly reduced
Total-C, LDL-C, TG and Apo B. Therapeutic response is well established within two weeks,
and a maximum response is achieved within four weeks. After four weeks of therapy, the
median decrease in LDL-C was 38% and at Week 24 endpoint the median LDL-C decrease
was 35%. Significant increases in HDL-C were also observed. The median (25th and 75th
percentile) percent changes from baseline in HDL-C for Lescol XL were +7(+0,+15) after 24
weeks of treatment.
Table 2
Median Percent Change in Lipid Parameters from Baseline to Week 24
Endpoint
All Placebo-Controlled Studies (Lescol®) and Active Controlled Trials (Lescol®
XL)
Total Chol.
TG
LDL
Apo B
HDL
Dose
N
% ∆
N
% ∆
N
% ∆
N
% ∆
N
% ∆
All Patients
Lescol 20 mg1
747
-17
747
-12
747
-22
114
-19
747
+3
Lescol 40 mg1
748
-19
748
-14
748
-25
125
-18
748
+4
Lescol 40 mg twice daily1
257
-27
257
-18
257
-36
232
-28
257
+6
Lescol XL 80 mg2
750
-25
750
-19
748
-35
745
-27
750
+7
Baseline TG ≥200 mg/dL
Lescol 20 mg1
148
-16
148
-17
148
-22
23
-19
148
+6
Lescol 40 mg1
179
-18
179
-20
179
-24
47
-18
179
+7
Lescol 40 mg twice daily1
76
-27
76
-23
76
-35
69
-28
76
+9
Lescol XL 80 mg2
239
-25
239
-25
237
-33
235
-27
239
+11
1 Data for Lescol from 12 placebo- controlled trials
2 Data for Lescol XL 80 mg tablet from three 24- week controlled trials
In patients with primary mixed dyslipidemia (Fredrickson Type IIb) as defined by
baseline plasma triglycerides levels ≥200 mg/dL, Lescol XL 80 mg produced a median
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reduction in triglycerides of 25%. In these patients, Lescol XL 80 mg produced median
(25th and 75th percentile) percent change from baseline in HDL-C of +11(+3,+20). Significant
decreases in Total-C, LDL-C, and Apo B were also achieved. In these studies, patients with
triglycerides >400 mg/dL were excluded.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
Fluvastatin sodium was studied in two open-label, uncontrolled, dose-titration studies which
enrolled pediatric patients with heterozygous familial hypercholesterolemia. The first study
enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level > 90th percentile
for age and one parent with primary hypercholesterolemia and either a family history of
premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226
mg/dL (range: 137-354 mg/dL). All patients were started on Lescol capsules 20 mg daily with
dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg bid) to achieve an
LDL-C goal of 96.7 to 123.7 mg/dL. Endpoint analyses were performed at Year 2. The
second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C
> 190 mg/dL or LDL-C > 160 mg/dL and one or more risk factors for coronary heart disease,
or LDL-C > 160 mg/dL and a proven LDL-receptor defect. The mean baseline LDL-C was
225 mg/dL (range: 148-343 mg/dL). All patients were started on Lescol capsules 20 mg daily
with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (Lescol 80 mg XL
tablet) to achieve an LDL-C goal of < 130 mg/dL. Endpoint analyses were performed at Week
114.
In the first study, Lescol 20 mg to 80 mg daily doses decreased plasma levels of Total-
C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL
(range: 74-336 mg/dL). In the second study, Lescol 20 mg to 80 mg daily doses decreased
plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved
LDL-C was 159 mg/dL (range: 90-295 mg/dL).
The majority of patients in both studies (83% in the first study and 89% in the second
study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26 % to 30% of
patients in both studies achieved a targeted LDL-C goal of < 130 mg/dL. The long-term
efficacy of Lescol or Lescol XL therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
Reduction in the Risk of Recurrent Cardiac Events
In the Lescol Intervention Prevention Study, the effect of Lescol 40 mg administered twice
daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal
myocardial infarction, or revascularization) was assessed in 1677 patients with coronary heart
disease who had undergone a percutaneous coronary intervention (PCI) procedure (mean time
from PCI to randomization=3 days). In this multicenter, randomized, double-blind, placebo-
controlled study, patients were treated with dietary/lifestyle counseling and either Lescol
40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. The study
population was 84% male, 98% Caucasian, with 37% >65 years of age. At baseline patients
had total cholesterol between 100 and 367 mg/dL (mean 201 mg/dL), LDL-C between 42 and
243 mg/dL (mean 132 mg/dL), triglycerides between 15 and 270 mg/dL (mean 70 mg/dL) and
HDL-C between 8 and 174 mg/dL (mean 39 mg/dL).
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Lescol significantly reduced the risk of recurrent cardiac events (Figure 1) by 22%
(p=0.013, 181 patients in the Lescol group vs. 222 patients in the placebo group).
Revascularization procedures comprised the majority of the initial recurrent cardiac events
(143 revascularization procedures in the Lescol group and 171 in the placebo group).
Consistent trends in risk reduction were observed in patients >65 years of age.
Figure 1.
Primary Endpoint – Recurrent Cardiac Events (Cardiac Death,
Nonfatal
MI or Revascularization Procedure) (ITT Population)
Outcome data for the Lescol Intervention Prevention Study are shown in Figure 2. After
exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6
months of the initial procedure involving the originally instrumental site, treatment with
Lescol was associated with a 32% (p=0.002) reduction in risk of late revascularization
procedures (CABG or PCI occurring at the original site >6 months after the initial procedure,
or at another site).
Figure 2.
Lescol® Intervention Prevention Study - Primary and Secondary
Endpoints
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Atherosclerosis
In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of Lescol therapy
on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in
patients with coronary artery disease and mild to moderate hypercholesterolemia (baseline
LDL-C range 115-190 mg/dL). In this randomized double-blind, placebo- controlled trial,
429 patients were treated with conventional measures (Step 1 AHA Diet) and either Lescol
40 mg/day or placebo. In order to provide treatment to patients receiving placebo with LDL-C
levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after
Week 12 to all patients in the study with baseline LDL-C values of ≥160 mg/dL. These
baseline levels were present in 25% of the study population. Quantitative coronary angiograms
were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients.
Lescol significantly slowed the progression of coronary atherosclerosis. Compared to
placebo, Lescol significantly slowed the progression of lesions as measured by within-patient
per-lesion change in minimum lumen diameter (MLD), the primary endpoint (see Figure 3
below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all
fluvastatin patients versus 22% of all placebo patients). Additionally, a significant difference
in favor of Lescol was found between all fluvastatin and all placebo patients in the distribution
among the three categories of definite progression, definite regression, and mixed or no
change. Beneficial angiographic results (change in MLD) were independent of patients’
gender and consistent across a range of baseline LDL-C levels.
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INDICATIONS AND USAGE
Therapy with lipid-altering agents should be used in addition to a diet restricted in saturated
fat and cholesterol (see National Cholesterol Education Program [NCEP] Treatment
Guidelines, below).
Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed
Dyslipidemia
Lescol® (fluvastatin sodium) and Lescol® XL (fluvastatin sodium) are indicated to reduce
elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase HDL-C in
patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and
IIb) whose response to dietary restriction of saturated fat and cholesterol and other
nonpharmacological measures has not been adequate.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
Lescol and Lescol XL are indicated as an adjunct to diet to reduce Total-C, LDL-C, and Apo
B levels in adolescent boys and girls who are at least one year post-menarche, 10-16 years of
age, with heterozygous familial hypercholesterolemia whose response to dietary restriction has
not been adequate and the following findings are present:
1. LDL-C remains ≥ 190 mg/dL or
2. LDL-C remains ≥ 160 mg/dL and:
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• there is a positive family history of premature cardiovascular disease or
• two or more other cardiovascular disease risk factors are present.
Therapy with lipid-altering agents should be considered only after secondary causes for
hyperlipidemia such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic
syndrome, dysproteinemias, obstructive liver disease, other medication, or alcoholism, have
been excluded. Prior to initiation of fluvastatin sodium, a lipid profile should be performed to
measure Total-C, HDL-C and TG. For patients with TG <400 mg/dL (<4.5 mmol/L), LDL-C
can be estimated using the following equation:
LDL-C = Total-C - HDL-C - 1/5 TG
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 many hypertriglyceridemic
patients LDL-C may be low or normal despite elevated Total-C. In such cases, Lescol is not
indicated.
Lipid determinations should be performed at intervals of no less than 4 weeks and
dosage adjusted according to the patient’s response to therapy.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are
summarized below:
Table 3
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%)
<100
≥100
≥130
(100-129: drug optional)††
2+ Risk factors
(10-year risk ≤20%)
<130
≥130
10-year risk 10%-20%: ≥130
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 <100mg/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 judgement also may call for deferring drug
therapy in this subcategory.
††† Almost all people with 0-1 risk factor have 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.
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At the time of hospitalization for an acute coronary event, consideration can be given
to initiating drug therapy at discharge if the LDL-C level is ≥130 mg/dL (NCEP-ATP II).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that the 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.
Table 4
Classification of Hyperlipoproteinemias
Lipid Elevations
Type
Lipoproteins
Elevated
Major
Minor
I (rare)
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
C = cholesterol, TG = triglycerides, LDL = low density lipoprotein, VLDL = very low density lipoprotein,
IDL = intermediate density lipoprotein
Neither Lescol nor Lescol XL have 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 fluvastatin in adolescence should be re-evaluated in adulthood
and appropriate changes made to their cholesterol-lowering regimen to achieve adult treatment
goals.
Secondary Prevention of Coronary Events
In patients with coronary heart disease, Lescol and Lescol XL are indicated to reduce the risk
of undergoing coronary revascularization procedures.
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Atherosclerosis
Lescol and Lescol XL are also indicated to slow the progression of coronary atherosclerosis in
patients with coronary heart disease as part of a treatment strategy to lower total and LDL
cholesterol to target levels.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication. Lescol® (fluvastatin sodium) and
Lescol® XL (fluvastatin sodium) are contraindicated in patients with active liver disease or
unexplained, persistent elevations in serum transaminases (see WARNINGS).
Pregnancy and Lactation
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during
pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential
components for fetal development (including synthesis of steroids and cell membranes). Since
HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of
other biologically active substances derived from cholesterol, they may cause fetal harm when
administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are
contraindicated during pregnancy and in nursing mothers. Fluvastatin sodium should be
administered to women of childbearing age only when such patients are highly unlikely
to conceive and have been informed of the potential hazards. If the patient becomes
pregnant while taking this class of drug, therapy should be discontinued and the patient
apprised of the potential hazard to the fetus.
WARNINGS
Liver Enzymes
Biochemical abnormalities of liver function have been associated with HMG-CoA reductase
inhibitors and other lipid-lowering agents. Approximately 1.1% of patients treated with
Lescol® (fluvastatin sodium) capsules in worldwide trials developed dose-related, persistent
elevations of transaminase levels to more than 3 times the upper limit of normal. Fourteen of
these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969
patients (1.1%) had persistent transaminase elevations with an average fluvastatin exposure of
approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of
patients with these abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which Lescol capsules were
used, persistent transaminase elevations (>3 times the upper limit of normal [ULN] on two
consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with
20, 40, and 80 mg (titrated to 40 mg twice daily) Lescol capsules, respectively. Ninety-one
percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred
within 12 weeks of therapy and in all patients with persistent liver function test abnormalities
there was an abnormal liver function test present at baseline or by Week 8.
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In the pooled analysis of the 24-week controlled trials, persistent transaminase
elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with Lescol® XL (fluvastatin
sodium) 80 mg, Lescol 40 mg and Lescol 40 mg twice daily, respectively. In 13 of 16 patients
treated with Lescol XL the abnormality occurred within 12 weeks of initiation of treatment
with Lescol XL 80 mg.
It is recommended that liver function tests be performed before the initiation of
therapy and at 12 weeks following initiation of treatment or elevation in dose. Patients
who develop transaminase elevations or signs and symptoms of liver disease should be
monitored to confirm the finding and should be followed thereafter with frequent liver
function tests until the levels return to normal. Should an increase in AST or ALT of three
times the upper limit of normal or greater persist (found on two consecutive occasions)
withdrawal of fluvastatin sodium therapy is recommended.
Active liver disease or unexplained transaminase elevations are contraindications to
the use of Lescol and Lescol XL (see CONTRAINDICATIONS). Caution should be exercised
when fluvastatin sodium is administered to patients with a history of liver disease or heavy
alcohol ingestion (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism). Such
patients should be closely monitored.
Skeletal Muscle
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported
with fluvastatin and with other drugs in this class. Myopathy, defined as muscle aching or
muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to
greater than 10 times the upper limit of normal, has been reported.
Myopathy should be considered in any patients with diffuse myalgias, muscle
tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to
report promptly unexplained muscle pain, tenderness or weakness, particularly if
accompanied by malaise or fever. Fluvastatin sodium therapy should be discontinued if
markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin
sodium 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 and/or rhabdomyolysis during treatment with HMG-CoA
reductase inhibitors has been reported to be increased if therapy with either cyclosporine,
gemfibrozil, erythromycin, or niacin is administered concurrently. Isolated cases of myopathy
have been reported during post-marketing experience with concomitant administration of
fluvastatin and colchicine. No information is available on the pharmacokinetic interaction
between fluvastatin and colchicine. However, myotoxicity, including muscle pain and
weakness and rhabdomyloysis, have been reported anecdotally with concomitant
administration of colchicine.
Myopathy was not observed in a clinical trial in 74 patients involving patients who
were treated with fluvastatin sodium together with niacin.
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Uncomplicated myalgia has been observed infrequently in patients treated with Lescol
at rates indistinguishable from placebo.
The use of fibrates alone may occasionally be associated with myopathy. The
combined use of HMG-CoA reductase inhibitors and fibrates should generally be avoided.
PRECAUTIONS
General
Before instituting therapy with Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin
sodium), an attempt should be made to control hypercholesterolemia with appropriate diet,
exercise, and weight reduction in obese patients, and to treat other underlying medical
problems (see INDICATIONS AND USAGE).
The HMG-CoA reductase inhibitors may cause elevation of 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 fluvastatin
sodium.
Homozygous Familial Hypercholesterolemia
HMG-CoA reductase inhibitors are reported to be less effective in patients with rare
homozygous familial hypercholesterolemia, possibly because these patients have few
functional LDL receptors.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever.
Women should be informed that if they become pregnant while receiving Lescol or
Lescol XL the drug should be discontinued immediately to avoid possible harmful effects on a
developing fetus from a relative deficit of cholesterol and biological products derived from
cholesterol. In addition, Lescol or Lescol XL should not be taken during nursing. (See
CONTRAINDICATIONS.)
Drug Interactions
The below listed drug interaction information is derived from studies using immediate- release
fluvastatin. Similar studies have not been conducted using the Lescol XL tablet.
Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin
(See WARNINGS: Skeletal Muscle).
In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450
(CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin
(~75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e.,
~5% and ~20%, respectively. If one pathway is inhibited in the elimination process of
fluvastatin other pathways may compensate.
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In vivo drug interaction studies with CYP3A4 inhibitors/substrates such as
cyclosporine, erythromycin, and itraconazole result in minimal changes in the
pharmacokinetics of fluvastatin, confirming less involvement of CYP3A4 isozyme.
Concomitant administration of fluvastatin and phenytoin increased the levels of phenytoin and
fluvastatin, suggesting predominant involvement of CYP2C9 in fluvastatin metabolism.
Niacin/Propranolol:
Concomitant administration of immediate- release fluvastatin sodium with niacin or
propranolol has no effect on the bioavailability of fluvastatin sodium.
Cholestyramine:
Administration of immediate- release fluvastatin sodium concomitantly with, or up to 4 hours
after cholestyramine, results in fluvastatin decreases of more than 50% for AUC and 50%-
80% for Cmax. However, administration of immediate- release fluvastatin sodium 4 hours after
cholestyramine resulted in a clinically significant additive effect compared with that achieved
with either component drug.
Cyclosporine:
Plasma cyclosporine levels remain unchanged when fluvastatin (20 mg daily) was
administered concurrently in renal transplant recipients on stable cyclosporine regimens.
Fluvastatin AUC increased 1.9- fold, and Cmax increased 1.3- fold compared to historical
controls.
Digoxin:
In a crossover study involving 18 patients chronically receiving digoxin, a single 40 mg dose
of immediate- release fluvastatin had no effect on digoxin AUC, but had an 11% increase in
digoxin Cmax and small increase in digoxin urinary clearance.
Erythromycin:
Erythromycin (500 mg, single dose) did not affect steady-state plasma levels of fluvastatin (40
mg daily).
Fluconazole:
Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with
fluconazole for 4 days results in an increase of fluvastatin Cmax (44%) and AUC (84%). Based
on this data, caution should be exercised when fluvastatin is co-administered with fluconazole.
Itraconazole:
Concomitant administration of fluvastatin (40 mg) and itraconazole (100 mg daily x 4 days)
does not affect plasma itraconazole or fluvastatin levels.
Gemfibrozil:
There is no change in either fluvastatin (20 mg twice daily) or gemfibrozil (600 mg twice
daily) plasma levels when these drugs are co-administered.
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Phenytoin:
Single morning dose administration of phenytoin (300 mg extended release) increased mean
steady-state fluvastatin (40 mg) Cmax by 27% and AUC by 40% whereas fluvastatin increased
the mean phenytoin Cmax by 5% and AUC by 20%. Patients on phenytoin should continue to
be monitored appropriately when fluvastatin therapy is initiated or when the fluvastatin dosage
is changed.
Diclofenac:
Concurrent administration of fluvastatin (40 mg) increased the mean Cmax and AUC of
diclofenac by 60% and 25% respectively.
Tolbutamide:
In healthy volunteers, concurrent administration of either single or multiple daily doses of
fluvastatin sodium (40 mg) with tolbutamide (1 g) did not affect the plasma levels of either
drug to a clinically significant extent.
Glibenclamide (Glyburide):
In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice
daily for 14 days) increased the mean Cmax, AUC, and t1/2 of glibenclamide approximately
50%, 69% and 121%, respectively. Glibenclamide (5-20 mg daily) increased the mean Cmax
and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in
glucose, insulin and C-peptide levels. However, patients on concomitant therapy with
glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when
their fluvastatin dose is increased to 40 mg twice daily.
Losartan:
Concomitant administration of fluvastatin with losartan has no effect on the bioavailability of
either losartan or its active metabolite.
Cimetidine/Ranitidine/Omeprazole:
Concomitant administration of immediate- release fluvastatin sodium with cimetidine,
ranitidine and omeprazole results in a significant increase in the fluvastatin Cmax (43%, 70%
and 50%, respectively) and AUC (24%-33%), with an 18%-23% decrease in plasma clearance.
Rifampicin:
Administration of immediate- release fluvastatin sodium to subjects pretreated with rifampicin
results in significant reduction in Cmax (59%) and AUC (51%), with a large increase (95%) in
plasma clearance.
Warfarin:
In vitro protein binding studies demonstrated no interaction at therapeutic concentrations.
Concomitant administration of a single dose of warfarin (30 mg) in young healthy males
receiving immediate- release fluvastatin sodium (40 mg/day x 8 days) resulted in no elevation
of racemic warfarin concentration. There was also no effect on prothrombin complex activity
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when compared to concomitant administration of placebo and warfarin. However, bleeding
and/or increased prothrombin times have been reported in patients taking coumarin
anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients
receiving warfarin-type anticoagulants should have their prothrombin times closely monitored
when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating
cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone
production.
Fluvastatin exhibited no effect upon non-stimulated cortisol levels and demonstrated
no effect upon thyroid metabolism as assessed by TSH. Small declines in total testosterone
have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting
that the observation was not due to a direct effect upon testosterone production. No effect
upon FSH in males was noted. Due to the limited number of premenopausal females studied
to date, no conclusions regarding the effect of fluvastatin upon female sex hormones may be
made.
Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for
periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to
ACTH stimulation. A clinical study evaluated the effect of fluvastatin at doses up to 80 mg
daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total
testosterone response was significantly reduced (p<0.05) relative to baseline in the 80 mg
group, it was not significant in comparison to the changes noted in groups receiving either
40 mg of fluvastatin or placebo.
Patients treated with fluvastatin sodium who develop clinical evidence of endocrine
dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA
reductase inhibitor or other agent used to lower cholesterol levels is administered to patients
receiving other drugs (e.g., ketoconazole, spironolactone, or cimetidine) that may decrease the
levels of endogenous steroid hormones.
CNS Toxicity
CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were
seen in the following animal studies: the 18-month mouse carcinogenicity study at
50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at
40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits
(300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was
characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal
cord at a dose of 5000 mg/kg and (in rat) by edema with separation of myelinated fibers of the
ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by
periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for
5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the
dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular
hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been
observed in dogs treated with other members of this class. No CNS lesions have been
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observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to
350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).
Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after
treatment with 1, 8, and 16 mg/kg/day for 2 years.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year)
mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and
26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low
incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the
24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct
contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition,
an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for
males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell
neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from
other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no
hepatic adenomas or carcinomas were observed.
The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and
30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous
cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These
treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the
mean human plasma drug concentration after a 40 mg oral dose.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic
activation, in the following studies: microbial mutagen tests using mutant strains of
Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3
cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in
V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no
evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.
In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels
for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility
or reproductive performance.
Seminal vesicles and testes were small in hamsters treated for 3 months at
20 mg/kg/day (approximately three times the 40 milligram human daily dose based on surface
area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as well as
vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were
also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax
achieved with a 40 milligram daily dose).
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 20
Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day
and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at
36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at
12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface
area. A study in which female rats were dosed during the third trimester at 12 and
24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal
and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day.
A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study
with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at
dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation
with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol
biosynthesis. The concurrent administration of mevalonic acid completely prevented the
maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on
Days 0 and 7 postpartum. Therefore, the maternal and neonatal lethality observed with
fluvastatin sodium reflect its exaggerated pharmacologic effect during pregnancy. There are
no data with fluvastatin sodium in pregnant women. However, rare reports of congenital
anomalies have been received following intrauterine exposure to other HMG-CoA reductase
inhibitors. There has been one report of severe congenital bony deformity, tracheo-esophageal
fistula, and anal atresia (VATER association) in a baby born to a woman who took another
HMG-CoA reductase inhibitor with dextroamphetamine sulfate during the first trimester of
pregnancy. Lescol or Lescol XL 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. If a woman becomes pregnant while taking Lescol or
Lescol XL, the drug should be discontinued and the patient advised again as to the potential
hazards to the fetus.
Nursing Mothers
Based on preclinical data, drug is present in breast milk in a 2:1 ratio (milk:plasma). Because
of the potential for serious adverse reactions in nursing infants, nursing women should not
take Lescol or Lescol XL (see CONTRAINDICATIONS).
Pediatric Use
The safety and efficacy of Lescol and Lescol XL in children and adolescent patients 9-16 years
of age with heterozygous familial hypercholesterolemia have been evaluated in open-label,
uncontrolled clinical trials of 2 years' duration. The most common adverse events observed
were influenza and infections. In these limited uncontrolled studies, there was no detectable
effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in
girls. See CLINICAL STUDIES: Heterozygous Familial Hypercholesterolemia in Pediatric
Patients; ADVERSE REACTIONS: Pediatric Patients (9-16 years of age); and DOSAGE
AND ADMINISTRATION: Heterozygous Familial Hypercholesterolemia in Pediatric
Patients. Adolescent females should be counseled on appropriate contraceptive methods while
on fluvastatin therapy (see CONTRAINDICATIONS: Pregnancy and Lactation).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 21
Geriatric Use
The effect of age on the pharmacokinetics of immediate- release fluvastatin sodium was
evaluated. Results indicate that for the general patient population plasma concentrations of
fluvastatin sodium do not vary as a function of age. (See also CLINICAL
PHARMACOLOGY: Pharmacokinetics/Metabolism.) Elderly patients (≥65 years of age)
demonstrated a greater treatment response in respect to LDL-C, Total-C and LDL/HDL ratio
than patients <65 years of age.
ADVERSE REACTIONS
In all clinical studies of Lescol® (fluvastatin sodium), 1.0% (32/2969) of fluvastatin-treated
patients were discontinued due to adverse experiences attributed to study drug (mean exposure
approximately 16 months ranging in duration from 1 to >36 months). This results in an
exposure adjusted rate of 0.8% (32/4051) per patient year in fluvastatin patients in controlled
studies compared to an incidence of 1.1% (4/355) in placebo patients. Adverse reactions have
usually been of mild to moderate severity.
In controlled clinical studies, 3.9% (36/912) of patients treated with Lescol® XL
(fluvastatin sodium) 80 mg discontinued due to adverse events (causality not determined).
Clinically relevant adverse experiences occurring in the Lescol and Lescol XL
controlled studies with a frequency >2%, regardless of causality, include the following:
Table 5
Clinically Relevant Adverse Experiences Occurring in >2% Patients
in Lescol® and Lescol XL® Controlled Studies
Lescol®1
(%)
Placebo1
(%)
Lescol® XL2
(%)
Adverse Event
(N=2326)
(N=960)
(N = 912)
Musculoskeletal
Myalgia
5.0
4.5
3.8
Arthritis
2.1
2.0
1.3
Arthropathy
NA
NA
3.2
Respiratory
Sinusitis
2.6
1.9
3.5
Bronchitis
1.8
1.0
2.6
Gastrointestinal
Dyspepsia
7.9
3.2
3.5
Diarrhea
4.9
4.2
3.3
Abdominal Pain
4.9
3.8
3.7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 22
Nausea
3.2
2.0
2.5
Flatulence
2.6
2.5
1.4
Psychiatric Disorders
Insomnia
2.7
1.4
0.8
Genitourinary
Urinary Tract Infection
1.6
1.1
2.7
Miscellaneous
Headache
8.9
7.8
4.7
Influenza-Like Symptoms
5.1
5.7
7.1
Accidental Trauma
5.1
4.8
4.2
Fatigue
2.7
2.3
1.6
Allergy
2.3
2.2
1.0
1 Controlled trials with Lescol Capsules (20 and 40 mg daily and 40 mg twice daily)
2 Controlled trials with Lescol XL 80 mg Tablets
The following effects have been reported with drugs in this class. Not all the effects
listed below have necessarily been associated with fluvastatin sodium 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
erythematosus-like syndrome, polymyalgia rheumatica, 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 23
Pediatric Patients
In two open-label, uncontrolled studies, 114 patients (66 boys and 48 girls) with heterozygous
familial hypercholesterolemia, 9-16 years of age, were treated for 2 years with fluvastatin
sodium administered as Lescol capsules 20 mg- 40 mg bid or Lescol XL 80 mg extended-
release tablets. The most common adverse events observed were influenza and infections.
(See CLINICAL STUDIES: Heterozygous Familial Hyercholesterolemia in Pediatric Patients
and PRECAUTIONS: Pediatric Use).
Concomitant Therapy
Fluvastatin sodium has been administered concurrently with cholestyramine and nicotinic
acid. No adverse reactions unique to the combination or in addition to those previously
reported for this class of drugs alone have been reported. Myopathy and rhabdomyolysis (with
or without acute renal failure) have been reported when another HMG-CoA reductase
inhibitor was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin,
or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA reductase
inhibitors and these agents is generally not recommended. (See WARNINGS: Skeletal
Muscle.)
OVERDOSAGE
The approximate oral LD50 is greater than 2 g/kg in mice and greater than 0.7 g/kg in rats.
The maximum single oral dose of Lescol® (fluvastatin sodium) capsules received by
healthy volunteers was 80 mg. No clinically significant adverse experiences were seen at this
dose. The maximum dose administered with an extended-release formulation was 640 mg for
two weeks. This dose was not well tolerated and produced a variety of GI complaints and an
increase in transaminase values (i.e., SGOT and SGPT).
There has been a single report of 2 children, one 2 years old and the other 3 years of
age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of
fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting
was induced by ipecac in both children and no capsules were noted in their emesis. Neither
child experienced any adverse symptoms and both recovered from the incident without
problems.
Should an accidental overdose occur, treat symptomatically and institute supportive
measures as required. The dialyzability of fluvastatin sodium and of its metabolites in humans
is not known at present.
Information about the treatment of overdose can often be obtained from a certified
Regional Poison Control Center. Telephone numbers of certified Regional Poison Control
Centers are listed in the Physicians’ Desk Reference®.*
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving Lescol®
(fluvastatin sodium) or Lescol® XL (fluvastatin sodium) and should continue on this diet
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 24
during treatment with Lescol or Lescol XL. (See NCEP Treatment Guidelines for details on
dietary therapy.)
For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting
dose is 40 mg as one capsule in the evening, 80 mg as one Lescol XL tablet administered as a
single dose at any time of the day or 80 mg in divided doses of the 40 mg capsule given twice
daily. For patients requiring LDL-C reduction to a goal of <25% a starting dose of 20 mg may
be used. The recommended dosing range is 20-80 mg/day. Lescol or Lescol XL may be taken
without regard to meals, since there are no apparent differences in the lipid-lowering effects of
fluvastatin sodium administered with the evening meal or 4 hours after the evening meal. Do
not break, crush or chew Lescol XL tablets or open Lescol capsules prior to administration.
Since the maximal reductions in LDL-C of a given dose are seen within 4 weeks,
periodic lipid determinations should be performed and dosage adjustment made according to
the patient’s response to therapy and established treatment guidelines. The therapeutic effect
of Lescol or Lescol XL is maintained with prolonged administration.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
The recommended starting dose is one 20 mg Lescol capsule. Dose adjustments, up to a
maximum daily dose administered either as Lescol capsules 40 mg twice daily or one Lescol
XL 80 mg tablet once daily, should be made at 6 week intervals. Doses should be
individualized according to the goal of therapy (see NCEP Pediatric Panel Guidelines and
INDICATIONS AND USAGE.)1.
Concomitant Therapy
Lipid-lowering effects on total cholesterol and LDL cholesterol are additive when immediate
release Lescol is combined with a bile-acid binding resin or niacin. When administering a
bile-acid resin (e.g., cholestyramine) and fluvastatin sodium, Lescol should be administered at
bedtime, at least 2 hours following the resin to avoid a significant interaction due to drug
binding to resin. (See also ADVERSE REACTIONS: Concomitant Therapy.)
Dosage in Patients with Renal Insufficiency
Since fluvastatin sodium is cleared hepatically with less than 6% of the administered dose
excreted into the urine, dose adjustments for mild to moderate renal impairment are not
necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe
renal impairment; therefore caution should be exercised when treating such patients at higher
doses.
HOW SUPPLIED
Lescol® (fluvastatin sodium) Capsules
20 mg
Brown and light brown imprinted twice with “
” and “20” on one half and “LESCOL” and
the Lescol® (fluvastatin sodium) logo twice on the other half of the capsule.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 25
Bottles of 30 capsules………………………………………………. NDC 0078-0176-15
Bottles of 100 capsules……………………………………………... NDC 0078-0176-05
40 mg
Brown and gold imprinted twice with “
” and “40” on one half and “LESCOL” and the
Lescol® (fluvastatin sodium) logo twice on the other half of the capsule.
Bottles of 30 capsules………………………………………………. NDC 0078-0234-15
Bottles of 100 capsules………………………………..……………. NDC 0078-0234-05
Lescol® XL (fluvastatin sodium) Extended-Release Tablets
80 mg
Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with
“Lescol XL” on one side and “80” on the other.
Bottles of 30 tablets………………………………………………… NDC 0078-0354-15
Bottle of 100 tablets………………………………………………… NDC 0078-0354-05
Store and Dispense
Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF) [see USP Controlled Room
Temperature]. Dispense in a tight container. Protect from light.
REFERENCES
1.
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.
*Trademark Thomas Healthcare,, Inc.
REV: OCTOBER 2006
T2006-97
PATIENT INFORMATION
LESCOL® [ lĕs-cŏl]
(fluvastatin sodium)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 26
Capsules
and
LESCOL® [ lĕs-cŏl] XL
(fluvastatin sodium)
Extended-Release Tablets
Rx only
Read the Patient Information that comes with LESCOL or LESCOL XL before you start
taking it, and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your doctor about your condition or treatment.
If you have any questions about LESCOL or LESCOL XL, ask your doctor or pharmacist.
What are LESCOL and LESCOL XL?
LESCOL and LESCOL XL are prescription medicines called "statins" that lower cholesterol
in your blood. They lower the "bad" cholesterol and triglycerides in your blood. They can
raise your "good" cholesterol as well.
LESCOL and LESCOL XL are for people whose cholesterol does not come down enough
with exercise and a low-fat diet alone.
LESCOL and LESCOL XL may be used in patients with heart disease (coronary artery
disease) to:
• lower the chances of heart problems which would require procedures to help restore blood
flow to the heart.
• slow the buildup of too much cholesterol in the arteries of the heart.
Treatment with LESCOL or LESCOL XL has not been shown to prevent heart attacks or
stroke.
LESCOL and LESCOL XL have the same active ingredient, fluvastatin. However, LESCOL
is a capsule that is taken one or two times a day and LESCOL XL is an extended-release tablet
that is only taken one time a day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 27
Who should not take LESCOL or LESCOL XL?
Do not take LESCOL or LESCOL XL if you:
• are pregnant or think you may be pregnant, or are planning to become pregnant.
LESCOL and LESCOL XL may harm your unborn baby. If you get pregnant, stop taking
LESCOL or LESCOL XL and call your doctor right away.
• are breast-feeding. LESCOL and LESCOL XL can pass into your breast milk and may
harm your baby
• have liver problems
• are allergic to LESCOL or LESCOL XL or any of its ingredients. The active
ingredient in LESCOL and LESCOL XL is fluvastatin. See the end of this leaflet for a
complete list of ingredients in LESCOL and LESCOL XL.
LESCOL and LESCOL XL have not been studied in children under 9 years of age.
Before taking LESCOL or LESCOL XL, tell your doctor if you:
• have muscle aches or weakness
• drink more than 2 glasses of alcohol daily
• have diabetes
• have a thyroid problem
• have kidney problems
Some medicines should not be taken with LESCOL or LESCOL XL. Tell your doctor about
all the medicines you take, including prescription and non-prescription medicines, vitamins
and herbal supplements. LESCOL and LESCOL XL and certain other medicines can interact
causing serious side effects. Especially tell your doctor if you take medicines for:
• your immune system
• cholesterol
• infections
• heart failure
• seizures
• diabetes
• heartburn or stomach ulcers
Know all the medicines you take. Keep a list of all the medicines you take with you to show
your doctor and pharmacist.
How should I take LESCOL or LESCOL XL?
• Take LESCOL or LESCOL XL exactly as prescribed. Your doctor will prescribe the one
that is right for you. Do not change your dose or stop LESCOL or LESCOL XL without
talking to your doctor. Your doctor may do blood tests to check your cholesterol levels
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 28
during treatment with LESCOL and LESCOL XL. Your dose of LESCOL or LESCOL
XL may be changed based on these blood test results.
• LESCOL XL tablets may be taken at any time of the day. Take LESCOL capsules at the
same time every evening. When LESCOL capsules are taken twice daily, the capsules
may be taken once in the morning and once in the evening. LESCOL and LESCOL XL
can be taken with or without food.
• LESCOL XL tablets must be swallowed whole with a liquid. Do not break, crush or
chew LESCOL XL tablets or open Lescol capsules. Tell your doctor if you cannot
swallow tablets whole. You may need LESCOL capsules or a different medicine instead
of LESCOL XL tablets.
• Your doctor should start you on a low-fat and low-cholesterol diet before giving you
LESCOL or LESCOL XL. Stay on this low-fat and low-cholesterol diet while taking
LESCOL or LESCOL XL.
• If you miss a dose of LESCOL or LESCOL XL, take it as soon as you remember. Do not
take Lescol or Lescol XL if it has been more than 12 hours since your last dose. Wait and
take the next dose at your regular time. Do not take 2 doses of Lescol or Lescol XL at
the same time.
• If you take too much LESCOL or LESCOL XL or overdose, call your doctor or Poison
Control Center right away. Or, go to the nearest emergency room.
What should I avoid while taking LESCOL or LESCOL XL?
• Talk to your doctor before you start any new medicines. This includes prescription and
nonprescription medicines, vitamins and herbal supplements. LESCOL and LESCOL XL
and certain other medicines can interact causing serious side effects.
• Do not get pregnant. If you get pregnant, stop taking LESCOL or LESCOL XL right away
and call your doctor.
What are the possible side effects of LESCOL and LESCOL XL?
When taking LESCOL and LESCOL XL, some patients may develop serious side effects,
including:
• muscle problems. These serious muscle problems can sometimes lead to kidney
problems, including kidney failure. You have a higher chance for muscle problems if
you are taking certain other medicines with LESCOL or LESCOL XL.
• liver problems. Your doctor may do blood tests to check your liver before you start
taking LESCOL or LESCOL XL, and while you are taking one of them.
Call your doctor right away if you have:
• muscle problems like weakness, tenderness, or pain that happen without a good
reason, especially if you also have a fever or feel more tired than usual
• nausea and vomiting
• passing brown or dark-colored urine
• you feel more tired than usual
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 29
• your skin and whites of your eyes get yellow
• stomach pain
The most common side effects of LESCOL or LESCOL XL are headache, upset stomach and
stomach pain, diarrhea, flu-like symptoms, muscle pain, sinus infection, tiredness, or trouble
sleeping. These side effects are usually mild and may go away.
Talk to your doctor or pharmacist if you have side effects that bother you or that will not go
away.
These are not all the side effects of LESCOL and LESCOL XL. Ask your doctor or pharmacist
for a complete list.
How should I store LESCOL and LESCOL XL?
• Store LESCOL and LESCOL XL at room temperature, 59° to 86° F (15° to 30° C). Protect
from light.
• Do not keep medicine that is out of date or that you no longer need.
• Keep LESCOL and LESCOL XL out of the reach of children. Be sure that if you
throw medicines away, it is out of the reach of children.
General information about LESCOL and LESCOL XL
Medicines are sometimes prescribed for conditions that are not mentioned in patient
information leaflets. Do not use LESCOL or LESCOL XL for a condition for which it was
not prescribed. Do not give LESCOL or LESCOL XL to other people, even if they have the
same problem you have. It may harm them.
This leaflet summarizes the most important information about LESCOL and LESCOL XL. If
you would like more information, talk with your doctor.
For information that is written for health professionals, ask your doctor or pharmacist or call
1-888-669-6682.
What are the ingredients in LESCOL and LESCOL XL?
Active Ingredient: fluvastatin sodium
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 30
Inactive Ingredients:
LESCOL Capsules: gelatin, magnesium stearate, microcrystalline cellulose,
pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide,
yellow iron oxide, and other ingredients. The capsules may also contain benzyl alcohol, black
iron oxide, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium,
methylparaben, propylparaben, silicon dioxide, and sodium propionate.
LESCOL XL Tablets: microcrystalline cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, potassium bicarbonate, povidone, magnesium stearate, yellow
iron oxide, titanium dioxide and polyethylene glycol 8000.
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Rev: April 2006 T2006-50
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: OCTOBER 2006
PRINTED IN THE U.S.A.
T2006-97/T2006-50
5001004
5001006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:15.700246
|
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|
12,385
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Lescol®/
Lescol® XL safely and effectively. See full prescribing information for
Lescol®/ Lescol® XL.
Lescol® (fluvastatin sodium) capsules/ Lescol® XL (fluvastatin sodium)
extended-release tablets for oral use
Initial U.S. Approval: 1993/ 2000
--------------INDICATIONS AND USAGE---------------------
LESCOL/LESCOL XL is an HMG-CoA reductase inhibitor (statin) indicated as
an adjunctive therapy to diet to:
Reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-C in adult
patients with primary hypercholesterolemia and mixed dyslipidemia (1.1)
Reduce elevated TC, LDL-C, and Apo B levels in boys and post-menarchal
girls, 10 to 16 years of age, with heterozygous familial hypercholesterolemia
after failing an adequate trial of diet therapy (1.1)
Reduce the risk of undergoing revascularization procedures in patients with
clinically evident CHD (1.2)
Slow the progression of atherosclerosis in patients with CHD (1.2)
Limitations of Use:
Neither LESCOL nor LESCOL XL have been studied in conditions where
the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e.,
hyperlipoproteinemia Types I, III, IV, or V) (1.3)
------------DOSAGE AND ADMINISTRATION-------------
Dose range: 20 mg to 80 mg/ day (2.1)
LESCOL/LESCOL XL can be taken with or without food. Only LESCOL
XL may be taken at any time of the day (2.1)
Do not break, crush or chew LESCOL XL tablets or open LESCOL capsules
prior to administration (2.1)
Adults: the recommended starting dose is 40 mg to 80 mg (administered as
one LESCOL 40 mg capsule twice daily, or one 80 mg LESCOL XL once
daily) (2.2)
Do not take two LESCOL 40 mg capsules at one time
Children with heterozygous familial hypercholesterolemia (ages 10 to 16,
inclusive): the recommended starting dose is LESCOL capsule 20 mg once
daily (2.3)
-----------DOSAGE FORMS AND STRENGTHS------------
LESCOL Capsules: 20 mg, 40 mg;
LESCOL XL Tablets: 80 mg (3)
---------------------CONTRAINDICATIONS-------------------
Hypersensitivity to any component of this medication (4)Active liver disease
or unexplained, persistent elevations in serum transaminases (4, 5.2)
Women who are pregnant or may become pregnant (4, 8.1)
Nursing mothers (4, 8.3)
---------------WARNINGS AND PRECAUTIONS------------
Skeletal muscle effects (e.g. myopathy and rhabdomyolysis): Risks
increase with advanced age (> 65), uncontrolled hypothyroidism, renal
impairment, and combination use with cyclosporine,or gemfibrozil (5.1, 8.5,
8.7)
Patients should be advised to report promptly any symptoms of myopathy.
LESCOL/LESCOL XL therapy should be discontinued if myopathy is
diagnosed or suspected (5.1)
Liver enzyme abnormalities: Persistent elevations in hepatic transaminases
can occur. Check liver enzyme tests before initiating therapy and as
clinically indicated thereafter (5.2)
-------------------ADVERSE REACTIONS----------------------
Most frequent adverse reactions (rate ≥2% and > placebo) are: headache,
dyspepsia, myalgia, abdominal pain and nausea (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
-------------------DRUG INTERACTIONS----------------------
Cyclosporine: Combination increases fluvastatin exposure. Limit LESCOL
dose to 20 mg (2.4, 7.1)
Fluconazole: Combination increases fluvastatin exposure. Limit LESCOL
dose to 20 mg (2.5, 7.2)
Concomitant lipid-lowering therapies: Use with fibrates or lipid-
modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal
muscle effects. Caution should be used when prescribing with
LESCOL/LESCOL XL (5.1,7.3,7.4)
Glyburide: Monitor blood glucose levels when fluvastatin dose is changed
(7)
Phenytoin: Monitor plasma phenytoin levels when fluvastatin treatment is
initiated or when the dosage is changed (7)
Warfarin and coumarin derivates: Monitor prothrombin times when
fluvastatin co-administration is initiated, discontinued, or the dosage
changed (7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
patient labeling
Revised: 02/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and
Mixed Dyslipidemia
1.2 Secondary Prevention of Cardiovascular Disease
1.3 Limitations of Use
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
2.2 Adult Patients with Hypercholesterolemia (Heterozygous Familial
and Nonfamilial) and Mixed Dyslipidemia
2.3 Pediatric Patients (10-16 years of age) with Heterozygous Familial
Hypercholesterolemia
2.4 Use with Cyclosporine
2.5 Use with Fluconazole
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Hypersensitivity to any Component of this Medication
4.2 Active Liver Disease
4.3 Pregnancy
4.4 Nursing Mothers
5 WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle
5.2 Liver Enzymes
5.3 Endocrine Effects
5.4 CNS Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Studies Experience in Adult Patients
6.2 Clinical Studies Experience in Pediatric Patients
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Cyclosporine
7.2 Fluconazole
7.3 Gemfibrozil
7.4 Other Fibrates
7.5 Niacin
7.6 Glyburide
7.7 Phenytoin
7.8 Warfarin
7.9 Colchicine
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
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and
Mixed Dyslipidemia
14.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients
14.3 Secondary Prevention of Cardiovascular Disease
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Muscle Pain
17.2 Liver Enzymes
17.3 Pregnancy
17.4 Breastfeeding
* Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 3093083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at
significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as
an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other non-pharmacologic
measures alone has been inadequate.
1.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia
LESCOL and LESCOL XL are indicated
●
as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C),
triglyceride (TG) and apolipoprotein B (Apo B) levels, and to increase high-density lipoprotein cholesterol (HDL-C)
in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb).
●
as an adjunct to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and adolescent girls who are at
least one year post-menarche, 10-16 years of age, with heterozygous familial hypercholesterolemia and the following
findings are present:
•
LDL-C remains ≥ 190 mg/dL or
•
LDL-C remains ≥ 160 mg/dL and:
there is a positive family history of premature cardiovascular disease or
two or more other cardiovascular disease risk factors are present
The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or
premature CVD is summarized below.
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
<170
<110
Borderline
170-199
110-129
High
≥200
≥130
Children treated with fluvastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to
their cholesterol-lowering regimen to achieve adult treatment goals.
1.2 Secondary Prevention of Cardiovascular Disease
In patients with clinically evident CHD, LESCOL and LESCOL XL are indicated to:
reduce the risk of undergoing coronary revascularization procedures
slow the progression of coronary atherosclerosis
1.3 Limitations of Use
Neither LESCOL nor LESCOL XL have 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 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
Dose range: 20 mg to 80 mg/ day.
LESCOL/LESCOL XL can be administered orally as a single dose, with or without food.
Do not break, crush or chew LESCOL XL tablets or open LESCOL capsules prior to administration.
Do not take two LESCOL 40 mg capsules at one time.
Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this
time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.
Reference ID: 3093083
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For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting dose is 40 mg as one capsule in the
evening, 80 mg as one LESCOL XL tablet administered as a single dose at any time of the day or 80 mg in divided doses
of the 40 mg capsule given twice daily. For patients requiring LDL-C reduction to a goal of <25% a starting dose of 20
mg may be used.
2.2 Adult Patients with Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia
Adult patients can be started on either LESCOL or LESCOL XL. The recommended starting dose for LESCOL is one 40
mg capsule in the evening, or one LESCOL 40 mg capsule twice daily. Do not take two LESCOL 40 mg capsules at one
time.
The recommended starting dose for LESCOL XL is one 80 mg tablet administered as a single dose at any time of the day.
2.3 Pediatric Patients (10-16 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended starting dose is one 20 mg LESCOL capsule. Dose adjustments, up to a maximum daily dose
administered either as LESCOL capsules 40 mg twice daily or one LESCOL XL 80 mg tablet once daily should be made
at 6 week intervals. Doses should be individualized according to the goal of therapy [see NCEP Pediatric Panel
Guidelines and CLINICAL STUDIES (14)]1.
1National 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.
2.4 Use with Cyclosporine
Do not exceed a dose of 20 mg b.i.d. LESCOL in patients taking cyclosporine [see Drug Interactions 7.1].
2.5 Use with Fluconazole
Do not exceed a dose of 20 mg b.i.d. LESCOL in patients taking fluconazole [see Drug Interactions 7.2].
3 DOSAGE FORMS AND STRENGTHS
LESCOL 20 mg capsules are brown and light brown imprinted twice with “ Triangle with S
” and “20” on one half and “LESCOL”
and the LESCOL® (fluvastatin sodium) logo twice on the other half of the capsule.
LESCOL 40 mg capsules are brown and gold imprinted twice with “ triangle with S
” and “40” on one half and “LESCOL” and
the LESCOL® (fluvastatin sodium) logo twice on the other half of the capsule.
LESCOL XL 80 mg tablets are yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with
“LESCOL XL” on one side and “80” on the other.
4 CONTRAINDICATIONS
4.1 Hypersensitivity to any Component of this Medication
LESCOL and LESCOL XL are contraindicated in patients with hypersensitivity to any component of this medication.
4.2 Active Liver Disease
LESCOL and LESCOL XL are contraindicated in patients with active liver disease or unexplained, persistent elevations
in serum transaminases [see Warnings and Precautions (5.2)].
4.3 Pregnancy
LESCOL and LESCOL XL are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol
and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal
development. LESCOL and LESCOL XL may cause fetal harm when administered to pregnant women. 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.
LESCOL and LESCOL XL should be administered to women of childbearing age only when such patients are highly
unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this
drug, LESCOL and LESCOL XL should be discontinued and the patient should be apprised of the potential hazard to the
fetus [see Use In Specific Populations (8.1)].
4.4 Nursing Mothers
Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to
cause serious adverse reactions in nursing infants, women who require treatment with LESCOL or LESCOL XL should
be advised not to breastfeed their infants [see Use In Specific Populations (8.3)].
Reference ID: 3093083
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5 WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle
Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with LESCOL/LESCOL
XL and other drugs in this class.
LESCOL/LESCOL XL should be prescribed with caution in patients with predisposing factors for myopathy. These
factors include advanced age (>65 years), renal impairment, and inadequately treated hypothyroidism.
The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine,
erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were
treated with LESCOL/LESCOL XL together with niacin. Isolated cases of myopathy have been reported during post-
marketing experience with concomitant administration of LESCOL/LESCOL XL and colchicine. No information is
available on the pharmacokinetic interaction between LESCOL/LESCOL XL and colchicine.
Uncomplicated myalgia has also been reported in LESCOL-treated patients [see Adverse Reactions (6)]. In clinical trials,
uncomplicated myalgia has been observed infrequently in patients treated with LESCOL at rates indistinguishable from
placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater
than 10 times the upper limit of normal, was <0.1% in fluvastatin clinical trials. Myopathy should be considered in any
patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be
advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or
fever.
LESCOL/LESCOL XL therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed
or suspected. LESCOL/LESCOL XL 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.
5.2 Liver Enzymes
Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine
aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors,
including LESCOL/LESCOL XL. In most cases, the elevations were transient and resolved or improved on continued
therapy or after a brief interruption in therapy.
Approximately 1.1% of patients treated with LESCOL capsules in worldwide trials developed dose-related, persistent
elevations of serum transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%)
were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase
elevations with an average LESCOL exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were
discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which LESCOL capsules were used, persistent transaminase
elevations (>3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%,
and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) LESCOL capsules,
respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred
within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver
function test present at baseline or by Week 8.
In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8% and 4.9%
of patients treated with LESCOL XL 80 mg, LESCOL 40 mg and LESCOL 40 mg twice daily, respectively. In 13 of 16
patients treated with LESCOL XL the abnormality occurred within 12 weeks of initiation of treatment with LESCOL XL
80 mg.
It is recommended that liver enzyme tests be performed prior to the initiation of LESCOL/LESCOL XL, and if signs or
symptoms of liver injury occur.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including
fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment
with LESCOL/LESCOL XL, promptly interrupt therapy. If an alternate etiology is not found do not restart
LESCOL/LESCOL XL.
Reference ID: 3093083
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In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.1 Active
liver disease or unexplained serum transaminase elevations are contraindications to the use of LESCOL and LESCOL XL
[see Contraindications (4) and Warnings and Precautions (5.2)]. Caution should be exercised when LESCOL is
administered to patients with a history of liver disease or heavy alcohol ingestion [see Clinical Pharmacology (12.4)].
Such patients should be closely monitored.
5.3 Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including
LESCOL/LESCOL XL.
Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt
adrenal or gonadal steroid hormone production.
LESCOL/LESCOL XL exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid
metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone
have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was
not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited
number of premenopausal females studied to date, no conclusions regarding the effect of LESCOL/LESCOL XL upon
female sex hormones may be made.
Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks
demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect
of LESCOL at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean
total testosterone response was significantly reduced (p<0.05) relative to baseline in the 80 mg group, it was not
significant in comparison to the changes noted in groups receiving either 40 mg of LESCOL or placebo.
Patients treated with LESCOL/LESCOL XL who develop clinical evidence of endocrine dysfunction should be evaluated
appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to
patients receiving other drugs (e.g. ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous
steroid hormones.
5.4 CNS Toxicity
CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following
animal studies: the 18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the
6-month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits
(300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by
conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema
with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity,
characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with
48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of
perivascular spaces, have been observed in dogs treated with other members of this drug class. No CNS lesions have been
observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat (up to
24 mg/kg/day), or dog (up to 16 mg/kg/day).
Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16
mg/kg/day for 2 years.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see Warnings and
Precautions (5.1)].
Liver Enzyme Abnormalities [see Warnings and Precautions (5.2)].
6.1 Clinical Studies Experience in Adult Patients
Because clinical studies on LESCOL/LESCOL XL are conducted in varying study populations and study designs, the
frequency of adverse reactions observed in the clinical studies of LESCOL/LESCOL XL cannot be directly compared
with that in the clinical studies of other statins and may not reflect the frequency of adverse reactions observed in clinical
practice.
Reference ID: 3093083
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In the LESCOL placebo-controlled clinical trials database of 2326 patients treated with LESCOL1 (age range 18-75 years,
44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of
patients on LESCOL and 2.3% patients on placebo discontinued due to adverse reactions regardless of causality. The most
common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were:
transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%) and diarrhea (0.2%).
In the LESCOL XL database of controlled clinical trials of 912 patients treated with LESCOL XL (age range 21-87 years,
52% women, 91% Caucasians, 4% Blacks, 5% other ethnicities) with a median treatment duration of 24 weeks, 3.9% of
patients on LESCOL XL discontinued due to adverse reactions regardless of causality. The most common adverse
reactions that led to treatment discontinuation were abdominal pain (0.7%), diarrhea (0.5%), nausea (0.4%), dyspepsia
(0.4%) and chest pain (0.3%).
Clinically relevant adverse experiences occurring in the LESCOL and LESCOL XL controlled studies with a frequency
>2%, regardless of causality, included the following:
Table 1 Clinical adverse events reported in >2% in patients treated with LESCOL/LESCOL XL and at an
incidence greater than placebo in placebo-controlled trials regardless of causality (% of patients) Pooled Dosages
1
1
2
LESCOL
Placebo
LESCOL XL
N=2326
N=960
N=912
(%)
(%)
(%)
Musculoskeletal
Myalgia
5.0
4.5
3.8
Arthritis
2.1
2.0
1.3
Arthropathy
NA
NA
3.2
Respiratory
Sinusitis
2.6
1.9
3.5
Bronchitis
1.8
1.0
2.6
Gastrointestinal
Dyspepsia
7.9
3.2
3.5
Diarrhea
4.9
4.2
3.3
Abdominal pain
4.9
3.8
3.7
Nausea
3.2
2.0
2.5
Flatulence
2.6
2.5
1.4
Tooth disorder
2.1
1.7
1.4
Psychiatric
Insomnia
2.7
1.4
0.8
Genitourinary
Urinary tract infection
1.6
1.1
2.7
Miscellaneous
Headache
8.9
7.8
4.7
Influenza-like symptoms
5.1
5.7
7.1
Accidental Trauma
5.1
4.8
4.2
Fatigue
2.7
2.3
1.6
Allergy
2.3
2.2
1.0
1 Controlled trials with LESCOL Capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo
2 Controlled trials with LESCOL XL 80 mg Tablets as compared to LESCOL Capsules
LESCOL Intervention Prevention Study
In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL 40 mg, administered twice daily on the risk
of recurrent cardiac events was assessed in 1677 patients with CHD who had undergone a percutaneous coronary
intervention (PCI) procedure. This was a multicenter, randomized, double-blind, placebo-controlled study, patients were
treated with dietary/lifestyle counseling and either LESCOL 40 mg (n=844) or placebo (n=833) given twice daily for a
median of 3.9 years [see Clinical Studies (14.3)].
Table 2 Clinical adverse events reported in ≥ 2% in patients treated with LESCOL/LESCOL XL and at an
incidence greater than placebo in the LIPS Trial regardless of causality (% of patients)
LESCOL
Placebo
40 mg b.i.d.
N=822
N=818
(%)
(%)
Reference ID: 3093083
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LESCOL
Placebo
40 mg b.i.d.
N=822
N=818
(%)
(%)
Cardiac disorders
Atrial fibrillation
2.4
2.0
Gastrointestinal disorders
Abdominal pain upper
6.3
4.5
Constipation
3.3
2.1
Dyspepsia
4.5
4.0
Gastric disorder
2.7
2.1
Nausea
2.7
2.3
General disorders
Fatigue
4.7
3.8
Edema peripheral
4.4
2.9
Infections and infestations
Bronchitis
2.3
2.0
Nasopharyngitis
2.8
2.1
Musculoskeletal and
Arthralgia
2.1
1.8
connective tissue disorders
Myalgia
2.2
1.6
Pain in extremity
4.1
2.7
Nervous system disorders
Dizziness
3.9
3.5
Syncope
2.4
2.2
Respiratory disorders
Dyspnea exertional
2.8
2.4
Vascular disorders
Hypertension
5.8
4.2
Intermittent claudication
2.3
2.1
6.2 Clinical Studies Experience in Pediatric Patients
In patients aged <18 years, efficacy and safety have not been studied for treatment periods longer than two years.
In two open-label, uncontrolled studies, 66 boys and 48 girls with heterozygous familial hypercholesterolemia ( 9-16
years of age, 80% Caucasian, 19% Other [ mixed ethnicity], 1% Asians) were treated with fluvastatin sodium
administered as LESCOL capsules 20 mg -40 mg twice daily, or LESCOL XL 80 mg extended-release tablet [see Clinical
Studies (14.2) and Use In Specific Populations (8.4)].
6.3 Postmarketing Experience
Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is
generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The
following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been
associated with fluvastatin sodium therapy.
Musculoskeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness,
myositis.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement,
facial paresis), tremor, dizziness, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve
palsy.
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).
Psychiatric: anxiety, insomnia, depression, psychic disturbances
Reference ID: 3093083
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Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or
more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica,
vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation
rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, 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,
cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, fatal and non-fatal hepatic failure.
Skin: rash, dermatitis, including bullous dermatitis, eczema, alopecia, pruritus, a variety of skin changes (e.g. nodules,
discoloration, dryness of skin/mucous membranes, changes to hair/nails).
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin;
thyroid function abnormalities.
7 DRUG INTERACTIONS
7.1 Cyclosporine
Cyclosporine coadministration increases fluvastatin exposure. Therefore, in patients taking cyclosporine, therapy should
be limited to LESCOL 20 mg twice daily [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.2 Fluconazole
Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an
increase of fluvastatin exposure. Therefore, in patients taking fluconazole, therapy should be limited to LESCOL 20 mg
twice daily [see Clinical Pharmacology (12.3)].
7.3 Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with
gemfibrozil, concomitant administration of LESCOL/LESCOL XL with gemfibrozil should be avoided.
7.4 Other Fibrates
Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with
concurrent administration of other fibrates, LESCOL/LESCOL XL should be administered with caution when used
concomitantly with other fibrates [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.5 Niacin
The risk of skeletal muscle effects may be enhanced when LESCOL is used in combination with lipid-modifying doses
(≥1 g/day) of niacin; a reduction in LESCOL dosage should be considered in this setting [see Warnings and Precautions
(5.1)].
7.6 Glyburide
Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy
of glyburide and fluvastatin should continue to be monitored appropriately [see Clinical Pharmacology (12.3)].
7.7 Phenytoin
Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be
monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed [see Clinical
Pharmacology (12.3)].
7.8 Warfarin
Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants
concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants
should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin
sodium is changed.
7.9 Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and
caution should be exercised when prescribing fluvastatin with colchicine.
Reference ID: 3093083
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category X
LESCOL/LESCOL XL is contraindicated in women who are or may become pregnant [see Contraindications (4)].
Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for
normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a
chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term
outcomes of primary hypercholesterolemia therapy
There are no adequate and well-controlled studies of use with LESCOL/LESCOL XL during pregnancy. Rare reports of
congenital anomalies have been received following intrauterine exposure to other statins. In a review2 of about 100
prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies,
spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number
of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of
prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in
the first trimester when pregnancy was identified.
Teratology studies with fluvastatin in rats and rabbits showed maternal toxicity at high dose levels, but there was no
evidence of embryotoxic or teratogenic potential [see Non-Clinical Toxicology (13)].
LESCOL or LESCOL XL 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. If a woman becomes pregnant while taking
LESCOL or LESCOL XL, the drug should be discontinued and the patient advised again as to the potential hazards to the
fetus.
8.3 Nursing Mothers
Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious
adverse reactions in nursing infants, nursing women should not take LESCOL or LESCOL XL [see Contraindications
(4)].
8.4 Pediatric Use
The safety and efficacy of LESCOL and LESCOL XL in children and adolescent patients 9-16 years of age with
heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration
of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled
studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length
in girls [see Clinical Studies (14.2), Adverse Reactions (6.3) and Dosage And Administration (2.2)]. Adolescent females
should be counseled on appropriate contraceptive methods while on LESCOL therapy [see Contraindications (4)].
8.5 Geriatric Use
Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age 65 years)
[see Clinical Pharmacology (12.3)]. Since advanced age (> 65 years) is a predisposing factor for myopathy,
LESCOL/LESCOL XL should be prescribed with caution in the elderly.
8.6 Hepatic Impairment
LESCOL and LESCOL XL are contraindicated in patients with active liver disease or unexplained, persistent elevations
in serum transaminases [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses
greater than 40 mg in patients with severe renal impairment; therefore caution should be exercised when treating such
patients at higher doses [see Clinical Pharmacology(12.3)].
10 OVERDOSAGE
To date, there has been limited experience with overdosage of fluvastatin. If an overdose occurs, it should be treated
symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of
fluvastatin sodium and of its metabolites in humans is not known at present [see Warnings and Precautions (5)].
Reference ID: 3093083
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In the pediatric population, there have been reports of overdosage with fluvastatin sodium in children including a 2 year-
old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of
fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in
both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both
recovered from the incident without problems.
In the postmarketing experience there have been reports of accidental ingestion of LESCOL tablets in infants up to 3 years
of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in
adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea. One
case of intentional overdose as suicide attempt in a 15 year-old female reported ingestion of 2,800 mg LESCOL XL with
hepatic enzyme elevation.
11 DESCRIPTION
LESCOL is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase.
Fluvastatin sodium is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic
acid, monosodium salt. The empirical formula of fluvastatin sodium is C24H25FNO4•Na, its molecular weight is 433.46
and its structural formula is: chemical structure
This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from
the fungal derivatives of this therapeutic class.
Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. LESCOL is
supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for oral administration.
LESCOL XL is supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for
oral administration.
Active Ingredient: fluvastatin sodium
Inactive Ingredients in capsules: calcium carbonate, gelatin, magnesium stearate, microcrystalline cellulose,
pregelatinized starch (corn), red iron oxide, sodium bicarbonate, talc, titanium dioxide, yellow iron oxide, and other
ingredients.
Capsules may also include: benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, edetate
calcium disodium, methylparaben, propylparaben, silicon dioxide, sodium lauryl sulfate, and sodium propionate.
Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, yellow iron oxide, titanium dioxide and
polyethylene glycol 8000.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
LESCOL is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of
cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and
thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma
cholesterol concentration.
12.3 Pharmacokinetics
Absorption:
Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute
bioavailability is 24% (range 9%-50%) after administration of a 10 mg dose.
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At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, a 11% decrease in
AUC, and a more than two-fold increase in tmax as compared to administration 4 hours after the evening meal. No
significant differences in the lipid-lowering effects were observed between the two administrations. After single or
multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional
plasma fluvastatin concentrations.
Fluvastatin administered as LESCOL XL 80 mg tablets reaches peak concentration in approximately 3 hours under fasting
conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the XL tablet is
approximately 29% (range: 9%-66%) compared to that of the LESCOL immediate-release capsule administered under
fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6h) and increased the bioavailability of
the XL tablet by approximately 50%. However, the maximum concentration of LESCOL XL seen after a high-fat meal is
less than the peak concentration following a single dose or twice daily dose of the 40 mg LESCOL capsule.
Distribution:
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At
therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.
Metabolism:
Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-
dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity,
but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a
similar manner.
In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9
isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4
isoenzymes are involved to a much less extent, i.e. approximately 5% and approximately 20%, respectively.
Excretion:
Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2%
present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-
life (t1/2) of fluvastatin is approximately 3 hours.
Specific Populations
Renal Impairment:
In patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-
fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers. In patients with end-stage
renal disease on hemodialysis, the AUC increased by approximately 1.5-fold. LESCOL XL was not evaluated in patients
with renal impairment. However, systemic exposures after administration of LESCOL XL are lower than after the 40 mg
immediate release capsule.
Hepatic Impairment:
In patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and Cmax increased approximately 2.5- fold
compared to healthy subjects after administration of a single 40 mg dose. The enantiomer ratios of the two isomers of
fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.
Geriatric:
Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49
years.
Gender:
In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there was no significant differences in
fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49
years), where there was an approximate 30% increase in AUC in females. Adjusting for body weight decreases the
magnitude of the differences seen. For LESCOL XL, the AUC increases 67% and 77% for women compared to men
under fasted and high- fat meal fed conditions, respectively.
Pediatric:
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Pharmacokinetic data in the pediatric population are not available.
Drug-Drug Interactions:
Data from drug-drug interactions studies involving coadministration of gemfibrozil, niacin, itraconazole, erythromycin,
tolbutamide or clopidogrel indicate that the PK disposition of fluvastatin is not significantly altered when fluvastatin is
coadministered with any of these drugs.
The below listed drug interaction information is derived from studies using LESCOL. Similar studies have not been
conducted using the LESCOL XL tablet.
Table 3 Effect of Co-administered Drugs on Fluvastatin Systemic Exposure
Co-administered drug and dosing
regimen
Cyclosporine – stable dose (b.i.d,)†
Fluvastatin
Dose (mg)*
20 mg QD for 14 weeks
Change in AUC **
↑ 90%
Change in Cmax **
↑ 30%
Fluconazole 400 mg QD day 1, 200 mg
b.i.d. day 2- 4†
40 mg QD
↑ 84%
↑ 44%
Cholestyramine 8 g QD
Rifampicin 600 mg QD for 6 days
20 mg QD administered 4
hrs after a meal plus
cholestyramine
20 mg QD
↓ 51%
↓ 53%
↓ 83%
↓ 42%
Cimetidine 400 mg b.i.d. for 5 days, QD
on Day 6
20 mg QD
↑ 30%
↑ 40%
Ranitidine 150 mg b.i.d. for 5 days, QD
on Day 6
20 mg QD
↑ 10%
↑ 50%
Omeprazole 40 mg QD for 6 days
20 mg QD
↑ 20%
↑ 37%
Phenytoin 300 mg QD
40 mg b.i.d. for 5 days
↑ 40 %
↑ 27%
Propranolol 40 mg b.i.d. for 3.5 days
Digoxin 0.1 – 0.5 mg QD for 3 weeks
40 mg QD
40 mg QD
↓ 5%
No change
No change
↑ 11%
Diclofenac 25 mg QD
40 mg QD for 8 days
↑50 %
↑ 80%
Glyburide 5 – 20 mg QD for 22 days
40 mg b.i.d for 14 days
↑ 51%
↑ 44%
Warfarin 30 mg QD
40 mg QD for 8 days
↑ 30%
↑ 67%
Clopidogrel 300 mg loading dose on day
80 mg XL QD for 19 days
2%
↑ 27%
10, 75 mg QD on days 11-19
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*Single dose unless otherwise noted
**Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%);
symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
† Considered clinically significant [see Dosage And Administration (2) and Drug Interactions (7)]
Data from drug-drug interaction studies involving fluvastatin and coadministration of either gemfibrozil, tolbutamide or
lorsartan indicate that the PK disposition of either gemfibrozil, tolbutamide or lorsartan is not significantly altered when
coadministered with fluvastatin.
Table 4 Effect of Fluvastatin Co-Administration on Systemic Exposure of Other Drugs
Fluvastatin dosage regimen
Co-administered drug
*
**
**
Name and Dose (mg)
Change in AUC
Change in Cmax
40 mg QD for 5 days
Phenytoin 300 mg QD†
↑ 20%
↑ 5%
40 mg b.i.d. for 21 days
Glyburide 5 – 20 mg QD for
↑ 70%
↑ 50%
22 days †
40 mg QD for 8 days
Diclofenac 25 mg QD
↑ 25%
↑ 60%
40 mg QD for 8 days
Warfarin 30 mg QD
S-warfarin: ↑7%
S-warfarin: ↑ 10%
R-warfarin: no
R-warfarin: ↑ 6%
change
*Single dose unless otherwise noted
**Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%);
symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
† Considered clinically significant [see Dosage And Administration (2) and Drug Interactions (7)]
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment
levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration
after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the
24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to
fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell
adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid
follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA
reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were
observed.
The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically
significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15
mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human
plasma drug concentration after a 40 mg oral dose.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following
studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant
transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal
aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of
mutagenicity in vivo in either a rat or mouse micronucleus test.
In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20
mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.
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Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the
40 mg human daily dose based on surface area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as
well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated
for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 mg daily dose).
Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10
mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These
doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2
surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in
maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on
the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in
the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels
of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of
HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid
completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on
days 0 and 7 postpartum.
14 CLINICAL STUDIES
14.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia
In 12 placebo-controlled studies in patients with primary hypercholesterolemia and mixed dyslipidemia, LESCOL was
administered to 1621 patients in daily dose regimens of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks
duration (Table 5). After 24 weeks of treatment, treatment with LESCOL resulted in significantly reduced plasma LDL-C,
TC, TG, and Apo B compared to placebo and was associated with variable increases in HDL-C across the dose range.
LESCOL XL has been studied in five controlled studies of patients with primary hypercholesterolemia and mixed
dyslipidemia. LESCOL XL was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three
largest of these studies, LESCOL XL given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG and
Apo B and resulted in increases in HDL-C (Table 5).
In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥200 mg/dL and <400 mg/dL,
treatment with LESCOL/LESCOL XL produced significant decreases in Total-C, LDL-C, TG and Apo B and variable
increases in HDL-C (Table 5).
Table 5 Median Percent Change in Lipid Parameters from Baseline to Week 24 Endpoint
All Placebo-Controlled Studies (LESCOL) and Active Controlled Trials (LESCOL XL)
Total Chol
TG
LDL
Apo B
HDL
Dose
N
% ∆
N
% ∆
N
% ∆
N
% ∆
N
% ∆
All Patients
LESCOL 20 mg1
747
-17
747
-12
747
-22
114
-19
747
+3
LESCOL 40 mg 1
748
-19
748
-14
748
-25
125
-18
748
+4
LESCOL 40 mg twice daily1
257
-27
257
-18
257
-36
232
-28
257
+6
LESCOL XL 80 mg2
750
-25
750
-19
748
-35
745
-27
750
+7
Baseline TG ≥200 mg/dL
LESCOL 20 mg1
148
-16
148
-17
148
-22
23
-19
148
+6
LESCOL 40 mg1
179
-18
179
-20
179
-24
47
-18
179
+7
LESCOL 40 mg twice daily1
76
-27
76
-23
76
-35
69
-28
76
+9
LESCOL XL 80 mg2
239
-25
239
-25
237
-33
235
-27
239
+11
1 Data for LESCOL from 12 placebo-controlled trials
2 Data for LESCOL XL 80 mg tablet from three 24- week controlled trials
14.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients
LESCOL was studied in two open-label, uncontrolled, dose-titration studies. The first study enrolled 29 pre-pubertal boys,
9-12 years of age, who had an LDL-C level >90th percentile for age and one parent with primary hypercholesterolemia
and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226
mg/dL (range: 137-354 mg/dL). All patients were started on LESCOL capsules 20 mg daily with dose adjustments every
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6 weeks to 40 mg daily then 80 mg daily (40 mg b.i.d.) to achieve an LDL-C goal between 96.7 – 123.7 mg/dL. Endpoint
analyses were performed at Year 2. LESCOL decreased plasma levels of Total-C and LDL-C by 21% and 27%,
respectively. The mean achieved LDL-C was 161 mg/dL (range: 74-336 mg/dL).
The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C >190 mg/dL or LDL-C
>160 mg/dL and one or more risk factors for coronary heart disease, or LDL-C >160 mg/dL and a proven LDL-receptor
defect. The mean baseline LDL-C was 225 mg/dL (range: 148-343 mg/dL). All patients were started on LESCOL
capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (LESCOL 80 mg XL tablet)
to achieve an LDL-C goal of <130 mg/dL. Endpoint analyses were performed at Week 114. LESCOL decreased plasma
levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range: 90-295
mg/dL).
The majority of patients in both studies (83% in the first study and 89% in the second study) were titrated to the maximum
daily dose of 80 mg. At study endpoint, 26% to 30% of patients in both studies achieved a targeted LDL-C goal of <130
mg/dL. The long-term efficacy of LESCOL or LESCOL XL therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
14.3 Secondary Prevention of Cardiovascular Disease
In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL 40 mg administered twice daily on the risk
of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal myocardial infarction, or revascularization)
was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure (mean
time from PCI to randomization=3 days). In this multicenter, randomized, double-blind, placebo-controlled study, patients
were treated with dietary/lifestyle counseling and either LESCOL 40 mg (n=844) or placebo (n=833) given twice daily for
a median of 3.9 years. The study population was 84% male, 98% Caucasian, with 37% >65 years of age. Mean baseline
lipid concentrations were: total cholesterol 201 mg/dL, LDL-C 132 mg/dL, triglycerides 70 mg/dL and HDL-C 39 mg/dL.
LESCOL significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p=0.013, 181 patients in the
LESCOL group vs. 222 patients in the placebo group). Revascularization procedures comprised the majority of the initial
recurrent cardiac events (143 revascularization procedures in the LESCOL group and 171 in the placebo group).
Consistent trends in risk reduction were observed in patients >65 years of age.
Figure 1 Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal
MI or Revascularization Procedure) (ITT Population) Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal
MI or Revascularization Procedure) (ITT Population)
Outcome data for the LESCOL Intervention Prevention Study are shown in Figure 2. After exclusion of revascularization
procedures (CABG and repeat PCI) occurring within the first 6 months of the initial procedure involving the originally
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instrumental site, treatment with LESCOL was associated with a 32% (p=0.002) reduction in risk of late revascularization
procedures (CABG or PCI occurring at the original site >6 months after the initial procedure, or at another site).
Figure 2 LESCOL® Intervention Prevention Study - Primary and Secondary Endpoints LESCOL® Intervention Prevention Study -Primary and Secondary Endpoints
In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of LESCOL therapy on coronary
atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with CAD and mild to moderate
hypercholesterolemia (baseline LDL-C range 115-190 mg/dL). In this randomized double-blind, placebo- controlled trial,
429 patients were treated with conventional measures (Step 1 AHA Diet) and either LESCOL 40 mg/day or placebo. In
order to provide treatment to patients receiving placebo with LDL-C levels ≥160 mg/dL at baseline, adjunctive therapy
with cholestyramine was added after Week 12 to all patients in the study with baseline LDL-C values of ≥160 mg/dL
which were present in 25% of the study population. Quantitative coronary angiograms were evaluated at baseline and 2.5
years in 340 (79%) angiographic evaluable patients.
Compared to placebo, LESCOL significantly slowed the progression of coronary atherosclerosis as measured by within-
patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (Figure 3 below), percent diameter
stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients).
A significant difference in favor of LESCOL was found between all fluvastatin and all placebo patients in the distribution
among the three categories of definite progression, definite regression, and mixed or no change. Beneficial angiographic
results (change in MLD) were independent of patients’ gender and consistent across a range of baseline LDL-C levels.
Figure 3 Change in Minimum Lumen Diameter (mm) Change in Minimum Lumen Diameter (mm)
Figure 4 Change in % Diameter Stenosis
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Change in % diameter stenosis
15 REFERENCES
1. 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.
2. 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 HOW SUPPLIED/STORAGE AND HANDLING
LESCOL ® (fluvastatin sodium) Capsules
20 mg
Brown and light brown imprinted twice with “ triangle with S
” and “20” on one half and “LESCOL” and the LESCOL® (fluvastatin
sodium) logo twice on the other half of the capsule.
Bottles of 30 capsules………………………………………………………………….……………...NDC 0078-0176-15
Bottles of 100 capsules………………………………………………………………………………..NDC 0078-0176-05
40 mg
Brown and gold imprinted twice with “ triangle with S
” and “40” on one half and “LESCOL” and the LESCOL® (fluvastatin
sodium) logo twice on the other half of the capsule.
Bottles of 30 capsules……………………………………………………………………….………...NDC 0078-0234-15
Bottles of 100 capsules………………………………………………………………………………..NDC 0078-0234-05
LESCOL® XL (fluvastatin sodium) Extended-Release Tablets
80 mg
Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “LESCOL XL” on one side and
“80” on the other.
Bottles of 30 tablets…………………………………………………………………………………...NDC 0078-0354-15
Bottle of 100 tablets…………………………………………………………………………………...NDC 0078-0354-05
Store and Dispense
Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF) [see USP Controlled Room Temperature]. Dispense in a
tight container. Protect from light.
17 PATIENT COUNSELING INFORMATION
Information for Patients
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Patients taking LESCOL/LESCOL XL should be advised that high cholesterol is a chronic condition and they should
adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular
exercise program, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with LESCOL/LESCOL XL [see
Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals
prescribing a new medication that they are taking LESCOL/LESCOL XL.
17.1 Muscle Pain
Patients starting therapy with LESCOL/LESCOL XL 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.
17.2 Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of LESCOL/LESCOL XL and if signs or
symptoms of liver injury occur. All patients treated with LESCOL/LESCOL XL should be advised to report promptly any
symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or
jaundice.
17.3 Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while
using LESCOL/LESCOL XL. Discuss future pregnancy plans with your patients, and discuss when to stop taking
LESCOL/LESCOL XL if they are trying to conceive. Patients should be advised that if they become pregnant they should
stop taking LESCOL/LESCOL XL and call their healthcare professional.
17.4 Breastfeeding
Women who are breastfeeding should not use LESCOL/LESCOL XL. Patients who have a lipid disorder and are
breastfeeding should be advised to discuss the options with their healthcare professional.
T2012-XX
Reference ID: 3093083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FDA-Approved Patient Labeling
LESCOL® (fluvastatin sodium) Capsules
20 mg, 40 mg
LESCOL ® XL (fluvastatin sodium) Extended-Release Tablets
80 mg
Rx Only
You must read and follow all instructions before using LESCOL or LESCOL XL.
Read the Patient Information every time you or a family member gets LESCOL or LESCOL XL. There may be new
information. This Patient Information does not take the place of talking with your doctor about your medical condition or
treatment. If you have any questions about LESCOL or LESCOL XL, ask your doctor or pharmacist.
What are LESCOL and LESCOL XL?
LESCOL and LESCOL XL are prescription medicines called "statins" that lower cholesterol in your blood. They lower
the "bad" cholesterol and triglycerides in your blood. They can raise your "good" cholesterol as well.
LESCOL and LESCOL XL are for people whose cholesterol does not come down enough with exercise and a low-fat diet
alone.
LESCOL and LESCOL XL may be used in patients with heart disease (coronary artery disease) to:
lower the chances of heart problems which would require procedures to help restore blood flow to the heart.
slow the buildup of too much cholesterol in the arteries of the heart.
Treatment with LESCOL or LESCOL XL has not been shown to prevent heart attacks or stroke.
LESCOL and LESCOL XL have the same active ingredient, fluvastatin. However, LESCOL is a capsule that is taken one
or two times a day and LESCOL XL is an extended-release tablet that is only taken one time a day.
Who should not take LESCOL or LESCOL XL?
Do not take LESCOL or LESCOL XL if you:
are pregnant or think you may be pregnant, or are planning to become pregnant. LESCOL and LESCOL XL may
harm your unborn baby. If you get pregnant, stop taking LESCOL or LESCOL XL and call your doctor right
away.
are breast-feeding. LESCOL and LESCOL XL can pass into your breast milk and may harm your baby
have liver problems
are allergic to LESCOL or LESCOL XL or any of its ingredients. The active ingredient in LESCOL and LESCOL
XL is fluvastatin. See the end of this leaflet for a complete list of ingredients in LESCOL and LESCOL XL.
LESCOL and LESCOL XL have not been studied in children under 9 years of age.
Before taking LESCOL or LESCOL XL, tell your doctor if you:
have muscle aches or weakness
drink more than 2 glasses of alcohol daily
have diabetes
have a thyroid problem
have kidney problems
Some medicines should not be taken with LESCOL or LESCOL XL. Tell your doctor about all the medicines you take,
including prescription and non-prescription medicines, vitamins and herbal supplements. LESCOL and LESCOL XL and
certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for:
Reference ID: 3093083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
your immune system
cholesterol
infections
heart failure
seizures
diabetes
heartburn or stomach ulcers
Know all the medicines you take. Keep a list of all the medicines you take with you to show your doctor and pharmacist.
How should I take LESCOL or LESCOL XL?
Your doctor will prescribe the medicine that is right for you. Take LESCOL or LESCOL XL exactly as
prescribed. Do not change your dose or stop LESCOL or LESCOL XL without talking to your doctor. Your
doctor may do blood tests to check your cholesterol levels during treatment with LESCOL and LESCOL XL.
Your dose of LESCOL or LESCOL XL may be changed based on these blood test results.
LESCOL XL tablets may be taken at any time of the day. Take LESCOL capsules at the same time every
evening. When LESCOL capsules are taken twice daily, the capsules may be taken once in the morning and once
in the evening. LESCOL and LESCOL XL can be taken with or without food.
LESCOL XL tablets must be swallowed whole with a liquid. Do not break, crush or chew LESCOL XL tablets or
open LESCOL capsules. Tell your doctor if you cannot swallow tablets whole. You may need LESCOL capsules
or a different medicine instead of LESCOL XL tablets.
Your doctor should start you on a low-fat and low-cholesterol diet before giving you LESCOL or LESCOL XL.
Stay on this low-fat and low-cholesterol diet while taking LESCOL or LESCOL XL.
If you miss a dose of LESCOL or LESCOL XL, take it as soon as you remember. Do not take LESCOL or
LESCOL XL if it has been more than 12 hours since your last dose. Wait and take the next dose at your regular
time. Do not take 2 doses of LESCOL or LESCOL XL at the same time.
If you take too much LESCOL or LESCOL XL or overdose, call your doctor or Poison Control Center right
away. Or, go to the nearest emergency room.
What should I avoid while taking LESCOL or LESCOL XL?
Talk to your doctor before you start any new medicines. This includes prescription and nonprescription
medicines, vitamins and herbal supplements. LESCOL and LESCOL XL and certain other medicines can interact
causing serious side effects.
Do not get pregnant. If you get pregnant, stop taking LESCOL or LESCOL XL right away and call your doctor.
What are the possible side effects of LESCOL and LESCOL XL?
When taking LESCOL and LESCOL XL, some patients may develop serious side effects, including:
muscle problems. These serious muscle problems can sometimes lead to kidney problems, including kidney failure. You
have a higher chance for muscle problems if you are taking certain other medicines with LESCOL or LESCOL XL. Call
your doctor right away if you have:
muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if you also have
a fever or feel more tired than usual
liver problems. Your doctor should do blood tests to check your liver before you start taking LESCOL or LESCOL XL,
and if you have symptoms of liver problems while you take LESCOL or LESCOL XL. Call your doctor right away if you
have the following symptoms of liver problems:
• feel tired or weak
• loss of appetite
• upper belly pain
Reference ID: 3093083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• dark amber colored urine
• yellowing of your skin or the whites of your eyes
The most common side effects of LESCOL or LESCOL XL are headache, upset stomach and stomach pain, diarrhea, flu-
like symptoms, muscle pain, sinus infection, tiredness, or trouble sleeping. These side effects are usually mild and may go
away. The following additional side effects have been reported with LESCOL/LESCOL XL: memory loss, and
confusion.
Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.
These are not all the side effects of LESCOL and LESCOL XL. Ask your doctor or pharmacist for a complete list.
How should I store LESCOL and LESCOL XL?
Store LESCOL and LESCOL XL at room temperature, 59° to 86° F (15° to 30° C). Protect from light.
Do not keep medicine that is out of date or that you no longer need.
Keep LESCOL and LESCOL XL out of the reach of children. Be sure that if you throw medicines away, it is out
of the reach of children.
General information about LESCOL and LESCOL XL
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use
LESCOL or LESCOL XL for a condition for which it was not prescribed. Do not give LESCOL or LESCOL XL to other
people, even if they have the same problem you have; it may harm them.
For more information, you can also visit the Novartis Internet site at www.LESCOLXL.com or call the Novartis help line
at 1-888-669-6682.
What are the ingredients in LESCOL and LESCOL XL?
Active Ingredient: fluvastatin sodium
Inactive Ingredients:
LESCOL Capsules: calcium carbonate, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch
(corn), red iron oxide, sodium bicarbonate, talc, titanium dioxide, yellow iron oxide, and other ingredients. The capsules
may also contain benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, edetate calcium
disodium, methylparaben, propylparaben, silicon dioxide, sodium lauryl sulfate, and sodium propionate.
LESCOL XL Tablets: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, potassium
bicarbonate, povidone, magnesium stearate, yellow iron oxide, titanium dioxide and polyethylene glycol 8000.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2012-XX/T2012-XX
February 2012/ February 2012
Reference ID: 3093083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020261s046lbl.pdf', 'application_number': 20261, 'submission_type': 'SUPPL ', 'submission_number': 46}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20262slbl.pdf', 'application_number': 20262, 'submission_type': 'SUPPL ', 'submission_number': 26}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20262slbl.pdf', 'application_number': 20262, 'submission_type': 'SUPPL ', 'submission_number': 28}
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Percent of Patients
(n 812)
• Bone Marrow
—Neutropenia <2,000/mm3
90
<500/mm3
52
—Leukopenia <4,000/mm3
90
<1,000/mm3
17
—Thrombocytopenia <100,000/mm3
20
<50,000/mm3
7
—Anemia
<11 g/dL
78
<8 g/dL
16
—Infections
30
—Bleeding
14
—Red Cell Transfusions
25
—Platelet Transfusions
2
• Hypersensitivity Reactionb
—All
41
—Severe†
2
• Cardiovascular
—Vital Sign Changesc
—Bradycardia (n 537)
3
—Hypotension (n 532)
12
—Significant Cardiovascular Events
1
Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m2) administered over 3 hours in
a controlled study.
TABLE 10. SUMMARYa OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT
PACLITAXEL
a Based on worst course analysis.
b All patients received premedication.
c During the first 3 hours of infusion.
† Severe events are defined as at least Grade III toxicity.
None of the observed toxicities were clearly influenced by age.
Disease-Specific Adverse Event Experiences
First-Line Ovary in Combination
For the 1,084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11
shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy
(6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).
TABLE 11. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA
STUDIES
a
Based on worst course analysis.
b
Paclitaxel (T) dose in mg/m2/infusion duration in hours.
c
Cyclophosphamide (C) or cisplatin (c) dose in mg/m2.
d
p<0.05 by Fisher exact test.
e
<130,000/mm3 in the Intergroup study.
f
<12 g/dL in the Intergroup study.
g
All patients received premedication.
h
In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was
collected as either neuromotor or neurosensory symptoms.
†
Severe events are defined as at least Grade III toxicity.
NC Not Collected
Second-Line Ovary
For the 403 patients who received single-agent paclitaxel injection in the Phase 3 second-line ovarian carcinoma study, the
following table shows the incidence of important adverse events.
TABLE 12. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA
STUDY
a Based on worst course analysis.
b Paclitaxel dose in mg/m2/infusion duration in hours.
c All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe
hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or
schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose related, but schedule did not appear to affect the
incidence.
Adjuvant Breast
For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events
for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population)
who, per the study protocol, were monitored more intensively than other patients.
TABLE 13. FREQUENCYa OF IMPORTANT SEVEREb ADVERSE EVENTS IN THE PHASE 3 ADJUVANT BREAST
CARCINOMA STUDY
a Based on worst course analysis.
b Severe events are defined as at least Grade III toxicity.
c Patients received 600 mg/m2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m2, 75 mg/m2, or 90 mg/m2
(with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4 courses.
d Paclitaxel (T) following 4 courses of AC at a dose of 175 mg/m2/3 hours every 3 weeks for 4 courses.
e The incidence of febrile neutropenia was not reported in this study.
f All patients were to receive premedication.
The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that
safety data were collected differently based on enrollment cohort. However, since safety data were collected consistently across
regimens, the safety of the sequential addition of paclitaxel following AC therapy may be compared with AC therapy alone.
Compared to patients who received AC alone, patients who received AC followed by paclitaxel experienced more Grade III/IV
neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-
like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional 4 courses of treatment with
paclitaxel, 2 deaths (0.1%) were attributed to treatment. During paclitaxel treatment, Grade IV neutropenia was reported for 15%
of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%.
The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events increased with higher doses of
doxorubicin.
Breast Cancer After Failure of Initial Chemotherapy
For the 458 patients who received single-agent paclitaxel in the Phase 3 breast carcinoma study, the following table shows the
incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion).
TABLE 14. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY OF BREAST CANCER AFTER
FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY
a Based on worst course analysis.
b Paclitaxel dose in mg/m2/infusion duration in hours.
c All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed
at the dose of 135 mg/m2.
First-Line NSCLC in Combination
In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either paclitaxel (T)
135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, paclitaxel (T) 250 mg/m2 as a 24-hour infusion in
combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100
mg/m2 on days 1, 2, and 3 (control).
The following table shows the incidence of important adverse events.
TABLE 15. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY FOR FIRST-LINE NSCLC
a Based on worst course analysis.
b Paclitaxel (T) dose in mg/m2/infusion duration in hours; cisplatin (c) dose in mg/m2.
c Paclitaxel dose in mg/m2/infusion duration in hours with G-CSF support; cisplatin dose in mg/m2.
d Etoposide (VP) dose in mg/m2 was administered IV on days 1, 2, and 3; cisplatin dose in mg/m2.
e p<0.05.
f All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
Toxicity was generally more severe in the high-dose paclitaxel treatment arm (T250/c75) than in the low-dose paclitaxel arm
(T135/c75). Compared to the cisplatin/etoposide arm, patients in the low-dose paclitaxel arm experienced more
arthralgia/myalgia of any grade and more severe neutropenia. The incidence of febrile neutropenia was not reported in this study.
Kaposi’s Sarcoma
The following table shows the frequency of important adverse events in the 85 patients with KS treated with 2 different single-
agent paclitaxel regimens.
TABLE 16. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSI’S SARCOMA STUDIES
a Based on worst course analysis.
b Paclitaxel dose in mg/m2/infusion duration in hours.
c All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
As demonstrated in this table, toxicity was more pronounced in the study utilizing paclitaxel at a dose of 135 mg/m2 every 3
weeks than in the study utilizing paclitaxel at a dose of 100 mg/m2 every 2 weeks. Notably, severe neutropenia (76% vs 35%),
febrile neutropenia (55% vs 9%), and opportunistic infections (76% vs 54%) were more common with the former dose and
schedule. The differences between the 2 studies with respect to dose escalation and use of hematopoietic growth factors, as
described above, should be taken into account (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma). Note also that
only 26% of the 85 patients in these studies received concomitant treatment with protease inhibitors, whose effect on paclitaxel
metabolism has not yet been studied.
Adverse Event Experiences by Body System
The following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent
paclitaxel in clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with
ovarian carcinoma or NSCLC who received paclitaxel in combination with cisplatin or in patients with breast cancer who received
paclitaxel after doxorubicin/cyclophosphamide in the adjuvant setting and that occurred with a difference that was clinically
significant in these populations are also described.
The frequency and severity of important adverse events for the Phase 3 ovarian carcinoma, breast carcinoma, NSCLC, and the
Phase 2 Kaposi’s sarcoma carcinoma studies are presented above in tabular form by treatment arm. In addition, rare events have
been reported from postmarketing experience or from other clinical studies. The frequency and severity of adverse events have
been generally similar for patients receiving paclitaxel for the treatment of ovarian, breast, or lung carcinoma or Kaposi’s
sarcoma, but patients with AIDS-related Kaposi’s sarcoma may have more frequent and severe hematologic toxicity, infections
(including opportunistic infections, see TABLE 16), and febrile neutropenia. These patients require a lower dose intensity and
supportive care (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma). Toxicities that were observed only in or were
noted to have occurred with greater severity in the population with Kaposi’s sarcoma and that occurred with a difference that
was clinically significant in this population are described. Elevated liver function tests and renal toxicity have a higher incidence
in KS patients as compared to patients with solid tumors.
Hematologic
Bone marrow suppression was the major dose-limiting toxicity of paclitaxel. Neutropenia, the most important hematologic
toxicity, was dose and schedule dependent and was generally rapidly reversible. Among patients treated in the Phase 3 second-
line ovarian study with a 3-hour infusion, neutrophil counts declined below 500 cells/mm3 in 14% of the patients treated with a
dose of 135 mg/m2 compared to 27% at a dose of 175 mg/m2 (p 0.05). In the same study, severe neutropenia (<500 cells/mm3)
was more frequent with the 24-hour than with the 3-hour infusion; infusion duration had a greater impact on myelosuppression
than dose. Neutropenia did not appear to increase with cumulative exposure and did not appear to be more frequent nor more
severe for patients previously treated with radiation therapy.
In the study where paclitaxel was administered to patients with ovarian carcinoma at a dose of 135 mg/m2/24 hours in
combination with cisplatin versus the control arm of cyclophosphamide plus cisplatin, the incidences of grade IV neutropenia
and of febrile neutropenia were significantly greater in the paclitaxel plus cisplatin arm than in the control arm. Grade IV
neutropenia occurred in 81% on the paclitaxel plus cisplatin arm versus 58% on the cyclophosphamide plus cisplatin arm, and
febrile neutropenia occurred in 15% and 4% respectively. On the paclitaxel/cisplatin arm, there were 35/1074 (3%) courses with
fever in which Grade IV neutropenia was reported at some time during the course. When paclitaxel followed by cisplatin was
administered to patients with advanced NSCLC in the ECOG study, the incidences of Grade IV neutropenia were 74%
(paclitaxel 135 mg/m2/24 hours followed by cisplatin) and 65% (paclitaxel 250 mg/m2/24 hours followed by cisplatin and G-CSF)
compared with 55% in patients who received cisplatin/etoposide.
Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all patients and 9% of all courses;
these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. In the Phase 3 second-line
ovarian study, infectious episodes were reported in 20% and 26% of the patients treated with a dose of 135 mg/m2 or 175 mg/m2
given as 3-hour infusions, respectively. Urinary tract infections and upper respiratory tract infections were the most frequently
reported infectious complications. In the immunosuppressed patient population with advanced HIV disease and poor-risk AIDS-
related Kaposi’s sarcoma, 61% of the patients reported at least one opportunistic infection (see CLINICAL STUDIES, AIDS-
Related Kaposi’s Sarcoma). The use of supportive therapy, including G-CSF, is recommended for patients who have
experienced severe neutropenia (see DOSAGE AND ADMINISTRATION).
Thrombocytopenia was reported. Twenty percent of the patients experienced a drop in their platelet count below 100,000
cells/mm3 at least once while on treatment; 7% had a platelet count <50,000 cells/mm3 at the time of their worst nadir. Bleeding
episodes were reported in 4% of all courses and by 14% of all patients, but most of the hemorrhagic episodes were localized
and the frequency of these events was unrelated to the paclitaxel dose and schedule. In the Phase 3 second-line ovarian study,
bleeding episodes were reported in 10% of the patients; no patients treated with the 3-hour infusion received platelet
transfusions. In the adjuvant breast carcinoma trial, the incidence of severe thrombocytopenia and platelet transfusions
increased with higher doses of doxorubicin.
Anemia (Hb <11 g/dL) was observed in 78% of all patients and was severe (Hb <8 g/dL) in 16% of the cases. No consistent
relationship between dose or schedule and the frequency of anemia was observed. Among all patients with normal baseline
hemoglobin, 69% became anemic on study but only 7% had severe anemia. Red cell transfusions were required in 25% of all
patients and in 12% of those with normal baseline hemoglobin levels.
The adverse event profile for the patients who received paclitaxel subsequent to AC was consistent with that seen in the pooled
analysis of data from 812 patients (TABLE 10) treated with single-agent paclitaxel in 10 clinical studies. These adverse events
are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 13) and narrative form.
After Failure of Initial Chemotherapy
Data from 83 patients accrued in 3, Phase 2 open-label studies and from 471 patients enrolled in a Phase 3 randomized study
were available to support the use of paclitaxel in patients with metastatic breast carcinoma.
Phase 2 Open-Label Studies
Two studies were conducted in 53 patients previously treated with a maximum of 1 prior chemotherapeutic regimen. Paclitaxel
was administered in these 2 trials as a 24-hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The
response rates were 57% (95% CI, 37 to 75%) and 52% (95% CI, 32 to 72%), respectively. The third Phase 2 study was
conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of 2
chemotherapy regimens for the treatment of metastatic disease. The dose of paclitaxel was 200 mg/m2 as a 24-hour infusion
with G-CSF support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% CI, 15 to 50%).
Phase 3 Randomized Study
This multicenter trial was conducted in patients previously treated with 1 or 2 regimens of chemotherapy. Patients were
randomized to receive paclitaxel at a dose of either 175 mg/m2 or 135 mg/m2 given as a 3-hour infusion. In the 471 patients
enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases.
These patients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%).
Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered
resistant to this class of agents.
The overall response rate for the 454 evaluable patients was 26% (95% CI, 22 to 30%), with 17 complete and 99 partial
responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range, 3.4 to 18.1+
months). Overall for the 471 patients, the median time to progression was 3.5 months (range, 0.03 to 17.1 months). Median
survival was 11.7 months (range, 0 to 18.9 months).
Response rates, median survival and median time to progression for the 2 arms are given in the following table.
TABLE 5. EFFICACY IN BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF
ADJUVANT CHEMOTHERAPY
The adverse event profile of the patients who received single-agent paclitaxel in the Phase 3 study was consistent with that seen
for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from
the Phase 3 breast carcinoma study are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 14) and
narrative form.
Non-Small Cell Lung Carcinoma (NSCLC)
In a Phase 3 open-label randomized study conducted by the ECOG, 599 patients were randomized to either paclitaxel (T) 135
mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, paclitaxel (T) 250 mg/m2 as a 24-hour infusion in
combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100
mg/m2 on days 1, 2, and 3 (control). Response rates, median time to progression, median survival, and 1-year survival rates are
given in the following table. The reported p-values have not been adjusted for multiple comparisons. There were statistically
significant differences favoring each of the paclitaxel plus cisplatin arms for response rate and time to tumor progression. There
was no statistically significant difference in survival between either paclitaxel plus cisplatin arm and the cisplatin plus etoposide
arm.
TABLE 6. EFFICACY PARAMETERS IN THE PHASE 3 FIRST-LINE NSCLC STUDY
a Etoposide (VP) 100 mg/m2 was administered IV on days 1, 2, and 3.
b Compared to cisplatin/etoposide.
In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had 7 subscales that measured
subjective assessment of treatment. Of the 7, the Lung Cancer Specific Symptoms subscale favored the paclitaxel 135
mg/m2/24 hour plus cisplatin arm compared to the cisplatin/etoposide arm. For all other factors, there was no difference in the
treatment groups.
The adverse event profile for patients who received paclitaxel in combination with cisplatin in this study was generally consistent
with that seen for the pooled analysis of data from 812 patients treated with single-agent paclitaxel in 10 clinical studies. These
adverse events and adverse events from the Phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS
section in tabular (TABLES 10 and 15) and narrative form.
AIDS-Related Kaposi’s Sarcoma
Data from 2, Phase 2 open-label studies support the use of paclitaxel as second-line therapy in patients with AIDS-related
Kaposi’s sarcoma. Fifty-nine of the 85 patients enrolled in these studies had previously received systemic therapy, including
interferon alpha (32%), DaunoXome® (31%), DOXIL® (2%), and doxorubicin containing chemotherapy (42%), with 64% having
received prior anthracyclines. Eighty five percent of the pretreated patients had progressed on, or could not tolerate, prior
systemic therapy1.
In Study CA139-174, patients received paclitaxel at 135 mg/m2 as a 3-hour infusion every 3 weeks (intended dose intensity 45
mg/m2/week). If no dose-limiting toxicity was observed, patients were to receive 155 mg/m2 and 175 mg/m2 in subsequent
courses. Hematopoietic growth factors were not to be used initially. In Study CA139-281, patients received paclitaxel at 100
mg/m2 as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m2/week). In this study patients could be receiving
hematopoietic growth factors before the start of paclitaxel therapy, or this support was to be initiated as indicated; the dose of
paclitaxel was not increased. The dose intensity of paclitaxel used in this patient population was lower than the dose intensity
recommended for other solid tumors.
All patients had widespread and poor-risk disease. Applying the ACTG staging criteria to patients with prior systemic therapy,
93% were poor risk for extent of disease (T1), 88% had a CD4 count <200 cells/mm3 (I1), and 97% had poor risk considering
their systemic illness (S1).
All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study CA139-281, there were
26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.
TABLE 7. EXTENT OF DISEASE AT STUDY ENTRY
PERCENT OF PATIENTS
Although the planned dose intensity in the 2 studies was slightly different (45 mg/m2/week in Study CA139-174 and 50
mg/m2/week in Study CA139-281), delivered dose intensity was 38 to 39 mg/m2/week in both studies, with a similar range (20
to 24 to 51 to 61).
Efficacy
The efficacy of paclitaxel was evaluated by assessing cutaneous tumor response according to the amended ACTG criteria and
by seeking evidence of clinical benefit in patients in 6 domains of symptoms and/or conditions that are commonly related to
AIDS-related Kaposi’s sarcoma.
Cutaneous Tumor Response (Amended ACTG Criteria)
The objective response rate was 59% (95% CI, 46 to 72%) (35 of 59 patients) in patients with prior systemic therapy. Cutaneous
responses were primarily defined as flattening of more than 50% of previously raised lesions.
TABLE 8. OVERALL BEST RESPONSE (AMENDED ACTG CRITERIA)
PERCENT OF PATIENTS
The median time to response was 8.1 weeks and the median duration of response measured from the first day of treatment was
10.4 months (95% CI, 7 to 11 months) for the patients who had previously received systemic therapy. The median time to
progression was 6.2 months (95% CI, 4.6 to 8.7 months).
Additional Clinical Benefit
Most data on patient benefit were assessed retrospectively (plans for such analyses were not included in the study protocols).
Nonetheless, clinical descriptions and photographs indicated clear benefit in some patients, including instances of improved
pulmonary function in patients with pulmonary involvement, improved ambulation, resolution of ulcers, and decreased analgesic
requirements in patients with Kaposi’s sarcoma (KS) involving the feet and resolution of facial lesions and edema in patients with
KS involving the face, extremities, and genitalia.
Safety
The adverse event profile of paclitaxel administered to patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s
sarcoma was generally similar to that seen in the pooled analysis of data from 812 patients with solid tumors. These adverse
events and adverse events from the Phase 2 second-line Kaposi’s sarcoma studies are described in the ADVERSE REACTIONS
section in tabular (TABLES 10 and 16) and narrative form. In this immunosuppressed patient population, however, a lower dose
intensity of paclitaxel and supportive therapy including hematopoietic growth factors in patients with severe neutropenia are
recommended. Patients with AIDS-related Kaposi’s sarcoma may have more severe hematologic toxicities than patients with
solid tumors.
INDICATIONS AND USAGE
Paclitaxel Injection, USP is indicated as subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line
therapy, Paclitaxel Injection, USP is indicated in combination with cisplatin.
Paclitaxel Injection, USP is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to
standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on
disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the
benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen
and progesterone receptor-negative tumors (see CLINICAL STUDIES, Breast Carcinoma).
Paclitaxel Injection, USP is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic
disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless
clinically contraindicated.
Paclitaxel Injection, USP, in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in
patients who are not candidates for potentially curative surgery and/or radiation therapy.
Paclitaxel Injection, USP is indicated for the second-line treatment of AIDS-related Kaposi’s sarcoma.
CONTRAINDICATIONS
Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated
in polyoxyl 35 castor oil.
Paclitaxel should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm3 or in
patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil counts of <1,000 cells/mm3.
WARNINGS
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema,
and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred
in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists
(see DOSAGE AND ADMINISTRATION). Patients who experience severe hypersensitivity reactions to paclitaxel should not be
rechallenged with the drug.
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred
at a median of 11 days. Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500
cells/mm3 (<1,000 cells/mm3 for patients with KS). Frequent monitoring of blood counts should be instituted during paclitaxel
treatment. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500
cells/mm3 (>1,000 cells/mm3 for patients with KS) and platelets recover to a level >100,000 cells/mm3.
Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases
requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate
therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with
paclitaxel.
Pregnancy
Paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of
organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m2 basis)
caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths.
Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1 mg/kg/day (about 1/15 the daily
maximum recommended human dose on a mg/m2 basis); teratogenic potential could not be assessed at higher doses due to
extensive fetal mortality.
There are no adequate and well-controlled studies in pregnant women. If paclitaxel is used during pregnancy, or if the patient
becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-
bearing potential should be advised to avoid becoming pregnant.
PRECAUTIONS
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions
for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate],
which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should preferably be stored in bottles (glass,
polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of
filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant
leaching of DEHP.
Drug Interactions
In a Phase 1 trial using escalating doses of paclitaxel (110 to 200 mg/m2) and cisplatin (50 or 75 mg/m2) given as sequential
infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e.,
paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of
approximately 33% when paclitaxel was administered following cisplatin.
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised
when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CTP2C8
and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g.,
midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir,
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and
inducers (e.g., rifampin and carbamazepine) of CYP3A4 (see CLINICAL PHARMACOLOGY).
Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and
rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8 (see CLINICAL PHARMACOLOGY).
Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and
nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.
Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased
when paclitaxel and doxorubicin are used in combination.
Hematology
Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order
to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all
patients receiving paclitaxel. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to
a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3
for 7 days or more) during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is
recommended.
For patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, paclitaxel, at the recommended dose for
this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm3.
Hypersensitivity Reactions
Patients with a history of severe hypersensitivity reactions to products containing polyoxyl 35 castor oil (e.g., cyclosporin for
injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the
occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids
(such as dexamethasone), diphenhydramine and H2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as
flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions,
such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require
immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe
hypersensitivity reactions should not be rechallenged with paclitaxel.
Cardiovascular
Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel, but generally do not
require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent
hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous
cardiac monitoring is not required except for patients with serious conduction abnormalities (see WARNINGS). When paclitaxel
is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is
recommended (see ADVERSE REACTIONS).
Nervous System
Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and
requires a dose reduction of 20% for all subsequent courses of paclitaxel.
Paclitaxel contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of
alcohol (see PRECAUTIONS, Pediatric Use).
Hepatic
There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with serum total bilirubin >2 times
ULN (see CLINICAL PHARMACOLOGY). Extreme caution should be exercised when administering paclitaxel to such patients,
with dose reduction as recommended in DOSAGE AND ADMINISTRATION, TABLE 17.
Injection Site Reaction
Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema,
tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the
24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following
administration of paclitaxel at a different site, i.e., “recall,” has been reported.
More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some
cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to
closely monitor the infusion site for possible infiltration during drug administration.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of paclitaxel has not been studied.
Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus
test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.
Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal
to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m2 basis). At this dose,
paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity (see WARNINGS).
Pregnancy
Pregnancy Category D (see WARNINGS).
Nursing Mothers
It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon 14-labeled paclitaxel
to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel
with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving paclitaxel therapy.
Pediatric Use
The safety and effectiveness of paclitaxel in pediatric patients have not been established.
There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric
patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m2 to 420 mg/m2. The toxicity
is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time.
The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be
discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the
safety of paclitaxel for use in this population.
Geriatric Use
Of 2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and effectiveness in the treatment of advanced
ovarian cancer, breast carcinoma, or NSCLC, and 1,570 patients who were randomized to receive paclitaxel in the adjuvant
breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies,
severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in
elderly patients. In 2 clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of
cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative
efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line
treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters
favored the younger group. TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies
according to age.
TABLE 9. SELECTED ADVERSE EVENTS IN GERIATRIC PATIENTS RECEIVING PACLITAXEL IN CLINICAL STUDIES
* p<0.05
a Paclitaxel dose in mg/m2/infusion duration in hours; cisplatin doses in mg/m2.
b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-Line Ovarian Cancer study (see
TABLE 11).
c Paclitaxel dose in mg/m2/infusion duration in hours.
d Paclitaxel (T) following 4 courses of doxorubicin and cyclophosphamide (AC) at a dose of 175 mg/m2/3 hours every 3 weeks
for 4 courses.
e Peripheral neuropathy reported as neurosensory toxicity in the Intergroup Adjuvant Breast Cancer study (see TABLE 13).
f Peripheral neuropathy reported as neurosensory toxicity in the ECOG NSCLC study (see TABLE 15).
Information for Patients
(See Patient Information Leaflet).
ADVERSE REACTIONS
Pooled Analysis of Adverse Event Experiences from Single-Agent Studies
Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast
carcinoma) enrolled in 10 studies who received single-agent paclitaxel injection. Two hundred and seventy-five patients were
treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m2 administered over 24 hours (in 4 of these
studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized
Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m2) and 2 schedules (3 or 24 hours) of paclitaxel.
Page 3
Page 2
T135/24
T250/24 VP100a
c75
c75
c75
(n 198)
(n 201)
(n 200)
• Response
—rate (percent)
25
23
12
—p-valueb
0.001
<0.001
• Time to Progression
—median (months)
4.3
4.9
2.7
—p-valueb
0.05
0.004
• Survival
—median (months)
9.3
10
7.4
—p-valueb
0.12
0.08
• 1-Year Survival
—percent of patients
36
40
32
Prior Systemic Therapy
(n 59)
Visceral ± edema ± oral ± cutaneous
42
Edema or lymph nodes ± oral ± cutaneous
41
Oral ± cutaneous
10
Cutaneous only
7
Prior Systemic Therapy
(n 59)
Complete response
3
Partial response
56
Stable disease
29
Progression
8
Early death/toxicity
3
Percent of Patients
(n 812)
• Abnormal ECG
—All Pts
23
—Pts with normal baseline (n 559)
14
• Peripheral Neuropathy
—Any symptoms
60
—Severe symptoms†
3
• Myalgia/Arthralgia
—Any symptoms
60
—Severe symptoms†
8
• Gastrointestinal
—Nausea and vomiting
52
—Diarrhea
38
—Mucositis
31
• Alopecia
87
• Hepatic (Pts with normal baseline
and on study data)
—Bilirubin elevations (n 765) 7
—Alkaline phosphatase
elevations (n 575)
22
—AST (SGOT) elevations (n 591)
19
• Injection Site Reaction
13
Percent of Patients
Intergroup
GOG-111
T175/3b C750c T135/24b C750c
c75c c75c c75c c75c
(n 339)
(n 336) (n 196) (n 213)
• Bone Marrow
—Neutropenia <2,000/mm3
91d
95d
96
92
<500/mm3
33d
43d
81d
58d
—Thrombocytopenia <100,000/mm3e
21d
33d
26
30
<50,000/mm3
3d
7d
10
9
—Anemia
<11 g/dLf
96
97
88
86
<8 g/dL
3d
8d
13
9
—Infections
25 27
21
15
—Febrile Neutropenia
4
7
15d
4d
• Hypersensitivity Reaction
—All
11d
6d
8d,g
1d,g
—Severe†
1
1
3d,g
—d,g
• Neurotoxicityh
—Any symptoms
87d
52d
25
20
—Severe symptoms†
21d
2d
3d
—d
• Nausea and Vomiting
—Any symptoms
88
93
65
69
—Severe symptoms†
18
24
10
11
• Myalgia/Arthralgia
—Any symptoms
60d
27d
9d
2d
—Severe symptoms†
6d
1d
1 —
• Diarrhea
—Any symptoms
37d
29d
16d
8d
—Severe symptoms†
2
3
4
1
• Asthenia
—Any symptoms
NC
NC 17d
10d
—Severe symptoms†
NC
NC
1
1
• Alopecia
—Any symptoms
96d
89d
55d
37d
—Severe symptoms†
51d
21d
6
8
Percent of Patients
175/3b
175/24b
135/3b
135/24b
(n 95)
(n 105) (n 98) (n 105)
• Bone Marrow
—Neutropenia <2,000/mm3
78
98
78
98
<500/mm3
27
75
14
67
—Thrombocytopenia <100,000/mm3
4 18
8 6
<50,000/mm3
1
7 2 1
—Anemia
<11 g/dL
84
90
68
88
<8 g/dL
11
12
6
10
—Infections
26
29
20
18
• Hypersensitivity Reactionc
—All
41 45 38 45
—Severe†
2 0 2 1
• Peripheral Neuropathy
—Any symptoms
63 60 55 42
—Severe symptoms†
1
2
0
0
• Mucositis
—Any symptoms
17
35
21
25
—Severe symptoms†
0
3
0
2
Percent of Patients
Early Population
Total Population
ACc
ACc followed by Td
ACc
ACc followed by Td
(n 166)
(n 159) (n 1551)
(n 1570)
• Bone Marrowe
—Neutropenia <500/mm3
79
76 48
50
—Thrombocytopenia <50,000/mm3
27
25
11
11
—Anemia
<8 g/dL
17
21
8
8
—Infections
6
14
5
6
—Fever Without Infection
—
3
<1
1
• Hypersensitivity Reactionf
1
4
1
2
• Cardiovascular Events
1
2
1
2
• Neuromotor Toxicity
1
1
<1
1
• Neurosensory Toxicity
—
3
<1
3
• Myalgia/Arthralgia
—
2
<1
2
• Nausea/Vomiting
13
18 8
9
• Mucositis
13
4
6
5
Percent of Patients
175/3b 135/3b
(n 229)
(n 229)
• Bone Marrow
—Neutropenia
<2,000/mm3
90
81
<500/mm3
28
19
—Thrombocytopenia
<100,000/mm3
11
7
<50,000/mm3
3
2
—Anemia
<11 g/dL
55
47
<8 g/dL
4
2
—Infections
23
15
—Febrile Neutropenia
2
2
• Hypersensitivity Reactionc
—All
36
31
—Severe†
0
<1
• Peripheral Neuropathy
—Any symptoms
70
46
—Severe symptoms†
7
3
• Mucositis
—Any symptoms
23
17
—Severe symptoms†
3
<1
Percent of Patients
T135/24b T250/24c VP100d
c75 c75 c75
(n 195)
(n 197) (n 196)
• Bone Marrow
—Neutropenia
<2,000/mm3
89
86
84
<500/mm3
74e
65
55
—Thrombocytopenia
< normal
48
68
62
<50,000/mm3
6
12
16
—Anemia
< normal
94
96
95
<8 g/dL
22
19
28
—Infections
38
31
35
• Hypersensitivity Reactionf
—All
16
27
13
—Severe†
1
4e
1
• Arthralgia/Myalgia
—Any symptoms
21e
42e
9
—Severe symptoms†
3
11
1
• Nausea/Vomiting
—Any symptoms
85
87
81
—Severe symptoms†
27
29 22
• Mucositis
—Any symptoms
18
28
16
—Severe symptoms†
1
4
2
• Neuromotor Toxicity
—Any symptoms
37
47
44
—Severe symptoms†
6
12
7
• Neurosensory Toxicity
—Any symptoms
48
61
25
—Severe symptoms†
13
28e
8
• Cardiovascular Events
—Any symptoms
33
39
24
—Severe symptoms†
13
12
8
Percent of Patients
Study CA139-174 Study CA139-281
Paclitaxel 135/3b
Paclitaxel 100/3b
q 3 wk q 2 wk
(n 29) (n 56)
• Bone Marrow
—Neutropenia
<2,000/mm3
100
95
<500/mm3
76
35
—Thrombocytopenia
<100,000/mm3
52
27
<50,000/mm3
17
5
—Anemia
<11 g/dL
86
73
<8 g/dL
34 25
—Febrile Neutropenia
55
9
• Opportunistic Infection
—Any
76
54
—Cytomegalovirus
45
27
—Herpes Simplex
38
11
—Pneumocystis carinii
14
21
—M. avium intracellulare
24
4
—Candidiasis, esophageal
7
9
—Cryptosporidiosis
7
7
—Cryptococcal meningitis
3
2
—Leukoencephalopathy
—
2
• Hypersensitivity Reactionc
—All
14
9
• Cardiovascular
—Hypotension
17
9
—Bradycardia
3
—
• Peripheral Neuropathy
—Any
79
46
—Severe†
10
2
• Myalgia/Arthralgia
—Any
93
48
—Severe†
14
16
• Gastrointestinal
—Nausea and Vomiting
69
70
—Diarrhea
90
73
—Mucositis
45
20
• Renal (creatinine elevation)
—Any
34
18
—Severe†
7
5
• Discontinuation for drug toxicity
7
16
N.B. - DUE TO TECHNICAL REASONS, IN ORDER TO
CARRY OUT THE MODIFICATIONS REQUESTED, THE WHOLE
ARTWORK HAS HAD TO BE REDONE. FOR SAFETY
REASONS, WE ADVISE YOU TO CHECK THE WHOLE DRAFT
CAREFULLY.
What should I tell my healthcare provider before receiving paclitaxel?
Before receiving paclitaxel, tell your healthcare provider about all your medical conditions, including if you:
• have liver problems
• have heart problems
• are pregnant or plan to become pregnant. Paclitaxel can harm your unborn baby. Talk to your healthcare
provider if you are pregnant or plan to become pregnant.
• are breast-feeding or plan to breast-feed. It is not known if paclitaxel passes into your breast milk. You and your healthcare
provider should decide if you will receive paclitaxel or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins,
and herbal supplements.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new
medicine.
How will I receive paclitaxel?
• Paclitaxel is injected into a vein (intravenous [IV] infusion) by your healthcare provider.
Your healthcare provider will do certain tests while you receive paclitaxel.
What are the possible side effects of paclitaxel?
Tell your healthcare provider right away if you have:
• severe stomach pain
• severe diarrhea
The most common side effects of Paclitaxel Injection, USP include:
• low red blood cell count (anemia) feeling weak or tired
• hair loss
• numbness, tingling, or burning in your hands or feet (neuropathy)
• joint and muscle pain
• nausea and vomiting
• hypersensitivity reaction - trouble breathing; sudden swelling of your face, lips, tongue, throat, or trouble swallowing; hives
(raised bumps) or rash
• diarrhea
• mouth or lip sores (mucositis)
• infections - if you have a fever (temperature above 100.4°F) or other sign of infection, tell your healthcare provider right away
• swelling of your hands, face, or feet
• bleeding events
• irritation at the injection site
• low blood pressure (hypotension)
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 paclitaxel. 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 paclitaxel.
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use paclitaxel
for a condition for which it was not prescribed. Do not give paclitaxel to other people, even if they have the same symptoms
that you have. It may harm them.
This patient information leaflet summarizes the most important information about paclitaxel. If you would like more information,
talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about paclitaxel that is
written for health professionals. For more information call 1-866-562-4708 or go to www.wgcriticalcare.com
What are the ingredients in paclitaxel?
Active ingredient: paclitaxel, USP.
Inactive ingredients include: purified polyoxl 35 castor oil and dehydrated alcohol, USP.
What is cancer?
Under normal conditions, the cells in your body divide and grow in an orderly, controlled way. Cell division and growth are
necessary for the human body to perform its functions and to repair itself, when necessary. Cancer cells are different from
Patients (n/total [%])
Neutropenia Peripheral Neuropathy
(Grade IV)
(Grades III/IV)
INDICATION
Age (y)
Age (y)
(Study/Regimen)
≥65
<65
≥65
<65
• OVARIAN Cancer
(Intergroup First-Line/T175/3 c75a)
34/83 (41)
78/252 (31)
24/84 (29)*b
46/255 (18)b
(GOG-111 First-Line/T135/24 c75a)
48/61 (79)
106/129 (82)
3/62 (5)
2/134 (1)
(Phase 3 Second-Line/T175/3c)
5/19 (26)
21/76 (28)
1/19 (5)
0/76 (0)
(Phase 3 Second-Line/T175/24c)
21/25 (84)
57/79 (72)
0/25 (0)
2/80 (3)
(Phase 3 Second-Line/T135/3c)
4/16 (25)
10/81 (12)
0/17 (0)
0/81 (0)
(Phase 3 Second-Line/T135/24c)
17/22 (77) 53/83 (64)
0/22 (0)
0/83 (0)
(Phase 3 Second-Line Pooled)
47/82 (57)* 141/319 (44)
1/83 (1)
2/320 (1)
• Adjuvant BREAST Cancer
(Intergroup/AC followed by Td)
56/102 (55) 734/1468 (50)
5/102 (5)e
46/1468 (3)e
• BREAST Cancer After Failure of Initial Therapy
(Phase 3/T175/3c)
7/24 (29)
56/200 (28)
3/25 (12)
12/204 (6)
(Phase 3/T135/3c)
7/20 (35)
37/207 (18)
0/20 (0)
6/209 (3)
• Non-Small Cell LUNG Cancer
(ECOG/T135/24 c75a)
58/71 (82)
86/124 (69)
9/71 (13)f
16/124 (13)f
(Phase 3/T175/3 c80a)
37/89 (42)*
56/267 (21)
11/91 (12)*
11/271 (4)
175/3
135/3
(n 235) (n 236)
• Response
—rate (percent)
28
22
—p-value
0.135
• Time to Progression
—median (months)
4.2
3
—p-value
0.027
• Survival
—median (months)
11.7
10.5
—p-value
0.321
(over)
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020262s051lbl.pdf', 'application_number': 20262, 'submission_type': 'SUPPL ', 'submission_number': 51}
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NDA 20-263/S-024
Page 3
(No. 3612)
TAPDN126-V2, Rev. March 2, 2004
1993-Year TAP Pharmaceutical Products Inc.
For Pediatric Use
LUPRON®
(leuprolide acetate) Injection
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing
hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The
chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-
arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:
LUPRON Injection is a sterile, aqueous solution intended for daily subcutaneous injection. It is
available in a 2.8 mL multiple dose vial containing leuprolide acetate (5 mg/mL), sodium chloride,
USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water
for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF.
CLINICAL PHARMACOLOGY
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given
continuously and in therapeutic doses. Animal and human studies indicate that following an initial
stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of
ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
Pharmacokinetics
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 4
A pharmacokinetic study of leuprolide acetate in children has not been performed.
Absorption:
In adults, bioavailability by subcutaneous administration is comparable to that by intravenous
administration.
Distribution:
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration
to healthy adult male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43%
to 49%.
Metabolism:
In healthy adult male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that
the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately
3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller
inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide
(Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached
maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug
concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of
mean leuprolide concentrations.
Excretion:
Following administration of LUPRON DEPOT 3.75 mg to three adult patients, less than 5% of the
dose was recovered as parent and M-I metabolite in the urine.
Special Populations:
The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 5
Drug Interactions:
No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate.
However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and the drug
is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.
CLINICAL STUDIES
In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to
prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females
respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and
development. Natural maturation occurs when gonadotropins return to pubertal levels following
discontinuation of leuprolide acetate.
The following physiologic effects have been noted with the chronic administration of leuprolide
acetate in this patient population.
1.
Skeletal Growth. A measurable increase in body length can be noted since the epiphyseal
plates will not close prematurely.
2.
Organ Growth. Reproductive organs will return to a prepubertal state.
3.
Menses. Menses, if present, will cease.
INDICATIONS AND USAGE
LUPRON Injection is indicated in the treatment of children with central precocious puberty. Children
should be selected using the following criteria:
1.
Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual
characteristics earlier than 8 years in females and 9 years in males.
2.
Clinical diagnosis should be confirmed prior to initiation of therapy:
•
Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The
sensitivity and methodology of this assay must be understood.
•
Bone age advanced 1 year beyond the chronological age.
3.
Baseline evaluation should also include:
•
Height and weight measurements.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 6
•
Sex steroid levels.
•
Adrenal steroid level to exclude congenital adrenal hyperplasia.
•
Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting
tumor.
•
Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor.
•
Computerized tomography of the head to rule out intracranial tumor.
CONTRAINDICATIONS
1.
Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON
Injection. Reports of anaphylactic reactions to synthetic GnRH (Factrel) or GnRH agonist
analogs have been reported in the medical literature1.
2.
LUPRON is contraindicated in women who are or may become pregnant while receiving the
drug. LUPRON may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate
throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits.
(See PRECAUTIONS Pregnancy, Teratogenic Effects section.) The effects on fetal mortality are
expected consequences of the alterations in hormonal levels brought about by this drug.
Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered
during pregnancy. If this drug is administered during pregnancy or if the patient becomes
pregnant while taking any formulation of LUPRON, the patient should be apprised of the
potential hazard to the fetus.
WARNINGS
During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the
natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be
observed (see CLINICAL PHARMACOLOGY section).
Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the
pubertal process. The consequences of poor control include the return of pubertal signs such as
menses, breast development, and testicular growth. The long-term consequences of inadequate control
of gonadal steroid secretion are unknown, but may include a further compromise of adult stature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 7
PRECAUTIONS
Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of LUPRON Injection,
may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the
injection site.
Information for Parents:
Prior to starting therapy with LUPRON Injection, the parent or guardian must be aware of the
importance of continuous therapy. Adherence to daily drug administration schedules must be accepted
if therapy is to be successful. Irregular dosing could restart the maturation process.
•
During the first 2 months of therapy, a female may experience menses or spotting. If bleeding
continues beyond the second month, notify the physician.
•
Any irritation at the injection site should be reported to the physician immediately. If the child
experiences an allergic reaction to other drugs like LUPRON, this drug should not be used.
•
Report any unusual signs or symptoms to the physician, like continued pubertal changes,
substantial mood swings or behavioral changes.
Laboratory Tests:
Response to leuprolide acetate should be monitored 1-2 months after the start of therapy with a GnRH
stimulation test and sex steroid levels. Measurement of bone age for advancement should be done
every 6-12 months.
Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see WARNINGS
section). Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline
to prepubertal levels.
Drug Interactions:
See CLINICAL PHARMACOLOGY, Pharmacokinetics section
Drug/Laboratory Test Interactions:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 8
Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal
system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of
benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was
administered subcutaneously at high daily doses of 0.6 to 4 mg/kg (>100 times the clinical doses of 7.5
to 15 mg/month based on body surface area). There was a significant but not dose-related increase of
pancreatic islet-cell adenomas in females and of testes interstitial cell adenomas in males (highest
incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary
abnormalities were observed at daily dose as high as 60 mg/kg (>5,000 times the clinical doses based
on body surface area). Adult patients have been treated with leuprolide acetate for up to three years
with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without
demonstrable pituitary abnormalities.
Although no clinical studies have been completed in children to assess the full reversibility of fertility
suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other
GnRH analogs have shown functional recovery. However, following a study with leuprolide acetate,
immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In
spite of the failure to recover histologically, the treated males proved to be as fertile as the controls.
Also, no histologic changes were observed in the female rats following the same protocol. In both
sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents
on the reproductive performance of the F1 generation was not tested. The clinical significance of these
findings is unknown.
Pregnancy, Teratogenic Effects: Pregnancy Category X- (see CONTRAINDICATIONS section).
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg
(1/1200 to 1/12 the human pediatric dose) to rabbits, LUPRON produced a dose-related increase in
major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal
malformations. There was increased fetal mortality and decreased fetal weights with the two higher
doses of LUPRON in rabbits and with the highest dose in rats.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 9
Nursing Mothers:
It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by
nursing mothers.
ADVERSE REACTIONS
Clinical Trials:
Potential exacerbation of signs and symptoms during the first few weeks of treatment (See
PRECAUTIONS section) is a concern in patients with rapidly advancing central precocious puberty.
In two studies of children with central precocious puberty, in 2% or more of the patients receiving the
drug, the following adverse reactions were reported to have a possible or probable relationship to drug
as ascribed by the treating physician. Reactions considered not drug related are excluded.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 10
Number of Patients
N = 395 (Percent)
Body as a Whole
General Pain
7 (2)
Integumentary System
Acne/Seborrhea
7 (2)
Injection Site Reactions
Including Abscess
21 (5)
Rash Including
Erythema Multiforme
8 (2)
Urogenital System
Vaginitis/Bleeding/Discharge
7 (2)
In those same studies, the following adverse reactions were reported in less than 2% of the patients.
Body as a Whole - Body Odor, Fever, Headache, Infection; Cardiovascular System - Syncope,
Vasodilation; Digestive System - Dysphagia, Gingivitis, Nausea/Vomiting; Endocrine
System - Accelerated Sexual Maturity; Metabolic and Nutritional Disorders-Peripheral Edema, Weight
Gain; Nervous System-Nervousness, Personality Disorder, Somnolence, Emotional Lability;
Respiratory System - Epistaxis; Integumentary System - Alopecia, Skin Striae; Urogenital
System - Cervix Disorder, Gynecomastia/Breast Disorders, Urinary Incontinence.
Postmarketing
During postmarketing surveillance, which includes other dosage forms and other patient populations,
the following adverse events were reported.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of
about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders,
gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Cardiovascular System – Hypotension, Pulmonary embolism; Gastrointestinal System – Hepatic
dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth;
Central/Peripheral Nervous System – Peripheral neuropathy, Spinal fracture/paralysis, Hearing
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 11
disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal
System – Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders; Urogenital
System – Prostate pain.
Changes in Bone Density: Decreased bone density has been reported in the medical literature in men
who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial,
25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at
least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had
lower bone density scores than the nontreated control group. The effects on bone density in children
are unknown.
See other LUPRON Injection and LUPRON DEPOT package inserts for adverse events reported in
other patient populations.
OVERDOSAGE
In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose,
expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the
injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In
early clinical trials using leuprolide acetate in adult patients, doses as high as 20 mg/day for up to two
years caused no adverse effects differing from those observed with the 1 mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON Injection can be administered by a patient/parent or health care professional.
The dose of LUPRON Injection must be individualized for each child. The dose is based on a mg/kg
ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio.
After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH
stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone
age for advancement should be monitored every 6-12 months. The dose should be titrated upward until
no progression of the condition is noted either clinically and/or by laboratory parameters.
The first dose found to result in adequate downregulation can probably be maintained for the duration
of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 12
move into higher weight categories after beginning therapy at very young ages and low dosages. It is
recommended that adequate downregulation be verified in such patients whose weight has increased
significantly while on therapy.
As with other drugs administered by injection, the injection site should be varied periodically.
Discontinuation of LUPRON Injection should be considered before age 11 for females and age 12 for
males.
The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If
total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose
will be considered the maintenance dose.
Follow the pictorial directions on the reverse side of this package insert for administration.
NOTE: As with other parenteral products, inspect the solution for discoloration and particulate matter
before each use.
HOW SUPPLIED
LUPRON (leuprolide acetate) Injection is a sterile solution supplied in a 2.8 mL multiple-dose vial.
The vial is packaged as follows:
•
14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC
0300-3612-28.
•
Six-vial carton, NDC 0300-3612-24.
•
Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use.
•
Use the syringes supplied with LUPRON Injection. Insulin syringes may be substituted for use
with LUPRON Injection.
RX ONLY
U.S. Patent Nos. 4,005,063; 4,005,194.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-263/S-024
Page 13
REFERENCE
1.
MacLeod TL, et al. Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone.
Fertil Steril 1987 Sept;48(3):500-502
Manufactured for
TAP Pharmaceuticals Inc.
Lake Forest, IL 60045
by Abbott Laboratories
North Chicago, IL 60064 U.S.A
® – Registered
(No. 3612)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20263slr024_lupron_lbl.pdf', 'application_number': 20263, 'submission_type': 'SUPPL ', 'submission_number': 24}
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035411
7
8
9
LUPRON DEPOT-PED
®
(leuprolide acetate for depot suspension)
7.5 mg, 11.25 mg and 15 mg
only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of
naturally occurring gonadotropin-releasing hormone
(GnRH or LH-RH). The analog possesses greater
potency than the natural hormone.The chemical name is
5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-
leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate
(salt) with the following structural formula:
LUPRON DEPOT-PED is available in a prefilled dual-
chamber
syringe
containing
sterile
lyophilized
microspheres which, when mixed with diluent, become a
suspension intended as a single intramuscular injection.
The front chamber of LUPRON DEPOT-PED 7.5 mg,
11.25 mg, and 15 mg prefilled dual-chamber syringe
contains leuprolide acetate (7.5/11.25/15 mg), purified
gelatin (1.3/1.95/2.6 mg), DL-lactic and glycolic acids
copolymer (66.2/99.3/132.4 mg), and D-mannitol
(13.2/19.8/26.4 mg). The second chamber of diluent
contains carboxymethylcellulose sodium (5 mg),
D-mannitol (50 mg), polysorbate 80 (1 mg), water for
injection, USP, and glacial acetic acid, USP to control
pH.
During the manufacture of LUPRON DEPOT-PED,
acetic acid is lost, leaving the peptide.
CLINICAL PHARMACOLOGY
Leuprolide acetate, a GnRH agonist, acts as a potent
inhibitor of gonadotropin secretion when given
continuously and in therapeutic doses. Human studies
indicate that following an initial stimulation of
gonadotropins, chronic stimulation with leuprolide
acetate results in suppression or “downregulation” of
these hormones and consequent suppression of ovarian
and testicular steroidogenesis. These effects are
reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
H
N
O
O
O
C
H
H
H
N
N
C
CH
2
CH
H
N
N
N
CH
CH2
C
O H
N CH
CH
OH
2
O
C
H
N CH
CH2
OH
O
C
H
N
CH3
CH2
CH3 CH
CH
O
C
H
N CH
CH3
CH2
O
C
H
N CH
CH2
CH2
CH2
N
H
C
NH
NH2
O
C N
O
C
H
N CH2CH3
CH3COOH
•
CH3 CH
1 2
In those same studies, the following adverse reactions
were reported in less than 2% of the patients.
Body as a Whole - Body Odor, Fever, Headache,
Infection;
Cardiovascular
System
-
Syncope,
Vasodilation; Digestive System - Dysphagia, Gingivitis,
Nausea/Vomiting; Endocrine System - Accelerated
Sexual Maturity; Metabolic and Nutritional Disorders -
Peripheral Edema, Weight Gain; Nervous System -
Emotional Lability, Nervousness, Personality Disorder,
Somnolence;
Respiratory
System
-
Epistaxis;
Integumentary System
- Alopecia, Skin Striae;
Urogenital System - Cervix Disorder, Gynecomastia/
Breast Disorders, Urinary Incontinence.
Postmarketing
During postmarketing surveillance, which includes other
dosage forms, the following adverse events were
reported.
Symptoms consistent with an anaphylactoid or
asthmatic process have been rarely reported. Rash,
urticaria, and photosensitivity reactions have also been
reported.
Localized reactions including induration and abscess
have been reported at the site of injection.
Cardiovascular System - Hypotension; Hemic and
Lymphatic System
- Decreased WBC;
Central/
Peripheral Nervous System - Peripheral neuropathy,
Spinal fracture/paralysis; Musculoskeletal System -
Tenosynovitis-like symptoms; Urogenital System -
Prostate pain.
See other LUPRON DEPOT and LUPRON Injection
package inserts for other events reported in different
patient populations.
OVERDOSAGE
In rats, subcutaneous administration of 125 to
250 times the recommended human pediatric dose,
expressed on a per body weight basis, resulted in
dyspnea, decreased activity, and local irritation at the
injection site. There is no evidence at present that there
is a clinical counterpart of this phenomenon. In early
clinical trials using leuprolide acetate in adult patients,
doses as high as 20 mg/day for up to two years caused
no adverse effects differing from those observed with
the 1 mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT-PED must be administered under the
supervision of a physician.
The dose of LUPRON DEPOT-PED must be
individualized for each child. The dose is based on a
mg/kg ratio of drug to body weight. Younger children
require higher doses on a mg/kg ratio.
For each dosage form, after 1-2 months of initiating
therapy or changing doses, the child must be monitored
with a GnRH stimulation test, sex steroids, and Tanner
staging to confirm downregulation. Measurements of
bone age for advancement should be monitored every
6-12 months. The dose should be titrated upward until
no progression of the condition is noted either clinically
and/or by laboratory parameters.
The first dose found to result in adequate
downregulation can probably be maintained for the
duration of therapy in most children. However, there are
insufficient data to guide dosage adjustment as patients
move into higher weight categories after beginning
therapy at very young ages and low dosages. It is
recommended that adequate downregulation be verified
in such patients whose weight has increased
significantly while on therapy.
Discontinuation of LUPRON DEPOT-PED should be
considered before age 11 for females and age 12 for
males.
The recommended starting dose is 0.3 mg/kg/4 weeks
(minimum 7.5 mg) administered as a single intramuscular
injection. The starting dose will be dictated by the child’s
weight.
≤25 kg
7.5 mg
> 25-37.5 kg
11.25 mg
> 37.5 kg
15 mg
If total downregulation is not achieved, the dose
should be titrated upward in increments of 3.75 mg
every 4 weeks. This dose will be considered the
maintenance dose.
The lyophilized microspheres are to be reconstituted
and administered as a single intramuscular injection. For
optimal performance of the prefilled dual chamber
syringe (PDS), read and follow the following instructions:
1. The LUPRON DEPOT powder should be visually
inspected and the syringe should NOT BE USED if
clumping or caking is evident. A thin layer of powder
on the wall of the syringe is considered normal. The
diluent should appear clear.
2. To prepare for injection, screw the white plunger into
the end stopper until the stopper begins to turn.
3. Hold the syringe UPRIGHT. Release the diluent by
SLOWLY PUSHING (6 to 8 seconds) the plunger until
the first stopper is at the blue line in the middle of the
barrel.
4. Keep the syringe UPRIGHT.
Gently mix the
microspheres (powder) thoroughly to form a uniform
suspension. The suspension will appear milky. If the
powder adheres to the stopper or caking/clumping is
present, tap the syringe with your finger to disperse.
DO NOT USE if any of the powder has not gone into
suspension.
5. Hold the syringe UPRIGHT. With the opposite hand
pull the needle cap upward without twisting.
6. Keep the syringe UPRIGHT. Advance the plunger to
expel the air from the syringe.
7. Inject
the
entire
contents
of
the
syringe
intramuscularly at the time of reconstitution. The
suspension
settles
very
quickly
following
reconstitution; therefore, LUPRON DEPOT should be
mixed and used immediately.
NOTE: Aspirated blood would be visible just below the
luer lock connection if a blood vessel is accidentally
penetrated. If present, blood can be seen through the
transparent LuproLoc™safety device.
AFTER INJECTION
8. Withdraw the needle. Immediately activate the
LuproLoc™safety device by pushing the arrow
forward with the thumb or finger until the device is
fully extended and a CLICK is heard or felt.
Since the product does not contain a preservative, the
suspension should be discarded if not used
immediately.
As with other drugs administered by injection, the
injection site should be varied periodically.
HOW SUPPLIED
LUPRON DEPOT-PED is packaged as follows:
Kit with prefilled
dual-chamber syringe
7.5 mg
NDC 0300-2108-01
Kit with prefilled
dual-chamber syringe
11.25 mg NDC 0300-2282-01
Kit with prefilled
dual-chamber syringe
15 mg
NDC 0300-2440-01
Each syringe contains sterile lyophilized microspheres
which is leuprolide incorporated in a biodegradable
copolymer of lactic and glycolic acids. When mixed with
diluent, LUPRON DEPOT-PED is administered as a
single IM injection.
An information pamphlet for parents is included with
the kit.
Store at 25°C (77°F); excursions permitted to 15-30°C
(59-86°F) [See USP Controlled Room Temperature]
REFERENCE
1. MacLeod TL, et al. Anaphylactic reaction to synthetic
luteinizing hormone-releasing hormone. Fertil Steril
1987 Sept; 48(3):500-502.
U.S. Patent Nos. 4,652,441; 4,677,191; 4,728,721;
4,849,228; 4,917,893; 5,330,767; 5,476,663; 5,823,997;
5,980,488; and 6,036,976. Other patents pending.
Manufactured for
TAP Pharmaceuticals Inc.
Lake Forest, IL 60045, U.S.A.
by Takeda Pharmaceutical Company Limited
Osaka, JAPAN 540-8645
™-Trademark
® — Registered Trademark
(Nos. 2108, 2282, 2440)
03-5411-R13; Revised: January, 2005
© 1993 - 2005, TAP Pharmaceutical Products Inc.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
3
4
5
6
Pharmacokinetics
Absorption Following a single LUPRON DEPOT
7.5 mg injection to adult patients, mean peak leuprolide
plasma concentration was almost 20 ng/mL at 4 hours
and then declined to 0.36 ng/mL at 4 weeks. However,
intact leuprolide and an inactive major metabolite could
not be distinguished by the assay which was employed
in the study.
Nondetectable leuprolide plasma
concentrations have been observed during chronic
LUPRON
DEPOT
7.5
mg
administration,
but
testosterone levels appear to be maintained at castrate
levels.
Distribution
The mean steady-state volume of
distribution of leuprolide following intravenous bolus
administration to healthy male volunteers was 27 L.
In vitro binding to human plasma proteins ranged from
43% to 49%.
Metabolism In healthy male volunteers, a 1 mg bolus of
leuprolide administered intravenously revealed that the
mean systemic clearance was 7.6 L/h, with a terminal
elimination half-life of approximately 3 hours based on a
two compartment model.
In rats and dogs, administration of 14C-labeled
leuprolide was shown to be metabolized to smaller
inactive peptides, a pentapeptide (Metabolite I),
tripeptides (Metabolites II and III) and a dipeptide
(Metabolite IV). These fragments may be further
catabolized.
The major metabolite (M-I) plasma concentrations
measured in 5 prostate cancer patients reached
maximum concentration 2 to 6 hours after dosing and
were approximately 6% of the peak parent drug
concentration. One week after dosing, mean plasma
M-I concentrations were approximately 20% of mean
leuprolide concentrations.
Excretion Following administration of LUPRON DEPOT
3.75 mg to 3 patients, less than 5% of the dose was
recovered as parent and M-I metabolite in the urine.
Special Populations The pharmacokinetics of the drug
in hepatically and renally impaired patients have not
been determined.
CLINICAL STUDIES
In children with central precocious puberty (CPP),
stimulated and basal gonadotropins are reduced to
prepubertal levels. Testosterone and estradiol are
reduced to prepubertal levels in males and females
respectively. Reduction of gonadotropins will allow for
normal physical and psychological growth and
development.
Natural
maturation
occurs
when
gonadotropins return to pubertal levels following
discontinuation of leuprolide acetate.
The following physiologic effects have been noted
with the chronic administration of leuprolide acetate in
this patient population.
1. Skeletal Growth. A measurable increase in body
length can be noted since the epiphyseal plates will
not close prematurely.
2. Organ Growth. Reproductive organs will return to a
prepubertal state.
3. Menses. Menses, if present, will cease.
In a study of 22 children with central precocious
puberty, doses of LUPRON DEPOT were given every
4 weeks and plasma levels were determined according
to weight categories as summarized below:
Trough Plasma
Leuprolide Level
Patient Weight
Group Weight
Mean ± SD
Range (kg)
Average (kg)
Dose (mg)
(ng/mL)*
20.2 - 27.0
22.7
7.5
0.77±0.033
28.4 - 36.8
32.5
11.25
1.25±1.06
39.3 - 57.5
44.2
15.0
1.59±0.65
*Group average values determined at Week 4 immediately
prior to leuprolide injection. Drug levels at 12 and 24 weeks
were similar to respective 4 week levels.
INDICATIONS AND USAGE
LUPRON DEPOT-PED is indicated in the treatment of
children with central precocious puberty. Children should
be selected using the following criteria:
1. Clinical diagnosis of CPP (idiopathic or neurogenic)
with onset of secondary sexual characteristics earlier
than 8 years in females and 9 years in males.
2. Clinical diagnosis should be confirmed prior to
initiation of therapy:
• Confirmation of diagnosis by a pubertal response to
a GnRH stimulation test. The sensitivity and
methodology of this assay must be understood.
• Bone age advanced one year beyond the
chronological age.
3. Baseline evaluation should also include:
• Height and weight measurements.
• Sex steroid levels.
• Adrenal steroid level to exclude congenital adrenal
hyperplasia.
• Beta human chorionic gonadotropin level to rule out
a chorionic gonadotropin-secreting tumor.
• Pelvic/adrenal/testicular ultrasound to rule out a
steroid secreting tumor.
• Computerized tomography of the head to rule out
intracranial tumor.
CONTRAINDICATIONS
LUPRON DEPOT-PED is contraindicated in women who
are or may become pregnant while receiving the drug.
When administered on day 6 of pregnancy at test
dosages of 0.00024, 0.0024, and 0.024 mg/kg
(1/1200 to 1/12 of the human pediatric dose) to rabbits,
LUPRON DEPOT produced a dose-related increase in
major fetal abnormalities. Similar studies in rats failed to
demonstrate an increase in fetal malformations. There
was increased fetal mortality and decreased fetal
weights with the two higher doses of LUPRON DEPOT
in rabbits and with the highest dose in rats. The effects
on fetal mortality are logical consequences of the
alterations in hormonal levels brought about by this
drug. Therefore, the possibility exists that spontaneous
abortion may occur if the drug is administered during
pregnancy.
Leuprolide acetate is contraindicated in children
demonstrating hypersensitivity to GnRH, GnRH agonist
analogs, or any of the excipients.
A report of an anaphylactic reaction to synthetic
GnRH (Factrel) has been reported in the medical
literature.1
WARNINGS
During the early phase of therapy, gonadotropins and
sex steroids rise above baseline because of the natural
stimulatory effect of the drug. Therefore, an increase in
clinical signs and symptoms may be observed. (See
CLINICAL PHARMACOLOGY section.)
Noncompliance with drug regimen or inadequate
dosing may result in inadequate control of the pubertal
process. The consequences of poor control include the
return of pubertal signs such as menses, breast
development, and testicular growth. The long-term
consequences of inadequate control of gonadal steroid
secretion are unknown, but may include a further
compromise of adult stature.
PRECAUTIONS
Laboratory Tests Response to LUPRON DEPOT-PED
should be monitored 1-2 months after the start of
therapy with a GnRH stimulation test and sex steroid
levels. Measurement of bone age for advancement
should be done every 6-12 months.
Sex steroids may increase or rise above prepubertal
levels if the dose is inadequate. (See WARNINGS
section.) Once a therapeutic dose has been established,
gonadotropin and sex steroid levels will decline to
prepubertal levels.
Drug Interactions No pharmacokinetic-based drug-
drug interaction studies have been conducted. However,
because leuprolide acetate is a peptide that is primarily
degraded by peptidase and not by cytochrome
P-450 enzymes as noted in specific studies, and the
drug is only about 46% bound to plasma proteins, drug
interactions would not be expected to occur.
Drug/Laboratory Test Interactions Administration of
LUPRON DEPOT 3.75 mg in women results in
suppression of the pituitary-gonadal system. Normal
function is usually restored within three months after
treatment is discontinued. Therefore, diagnostic tests of
pituitary gonadotropic and gonadal functions conducted
during treatment and for up to three months after
discontinuation of LUPRON DEPOT may be misleading.
Information for Parents Prior to starting therapy with
LUPRON DEPOT-PED, the parent or guardian must be
aware of the importance of continuous therapy.
Adherence to 4 week drug administration schedules
must be accepted if therapy is to be successful.
• During the first 2 months of therapy, a female may
experience menses or spotting. If bleeding continues
beyond the second month, notify the physician.
• Any irritation at the injection site should be reported to
the physician immediately.
• Report any unusual signs or symptoms to the
physician.
Carcinogenesis,
Mutagenesis,
Impairment
of
Fertility
A two-year carcinogenicity study was
conducted in rats and mice. In rats, a dose-related
increase of benign pituitary hyperplasia and benign
pituitary adenomas was noted at 24 months when the
drug was administered subcutaneously at high daily
doses (0.6 to 4 mg/kg). There was a significant but not
dose-related increase of pancreatic islet-cell adenomas
in females and of testicular interstitial cell adenomas in
males (highest incidence in the low dose group). In
mice, no leuprolide acetate-induced tumors or pituitary
abnormalities were observed at a dose as high as
60 mg/kg for two years. Adult patients have been treated
with leuprolide acetate for up to three years with doses
as high as 10 mg/day and for two years with doses as
high as 20 mg/day without demonstrable pituitary
abnormalities.
Although no clinical studies have been completed in
children to assess the full reversibility of fertility
suppression, animal studies (prepubertal and adult rats
and monkeys) with leuprolide acetate and other GnRH
analogs have shown functional recovery. However,
following a study with leuprolide acetate, immature male
rats demonstrated tubular degeneration in the testes
even after a recovery period. In spite of the failure to
recover histologically, the treated males proved to be as
fertile as the controls. Also, no histologic changes were
observed in the female rats following the same protocol.
In both sexes, the offspring of the treated animals
appeared normal. The effect of the treatment of the
parents on the reproductive performance of the
F1 generation was not tested.The clinical significance of
these findings is unknown.
Pregnancy, Teratogenic Effects Pregnancy Category
X. (See CONTRAINDICATIONS section.)
Nursing Mothers It is not known whether leuprolide
acetate is excreted in human milk. LUPRON should not
be used by nursing mothers.
Geriatric Use See also the labeling for LUPRON
DEPOT 7.5 mg which is indicated for the palliative
treatment of advanced prostate cancer. For LUPRON
DEPOT-PED 11.25 mg and LUPRON DEPOT-PED 15
mg, no clinical information has been established for
persons aged 65 and over.
ADVERSE REACTIONS
Clinical Trials
Potential exacerbation of signs and symptoms during
the first few weeks of treatment (See PRECAUTIONS
section.) is a concern in patients with rapidly advancing
central precocious puberty.
In two studies of children with central precocious
puberty, in 2% or more of the patients receiving the
drug, the following adverse reactions were reported to
have a possible or probable relationship to drug as
ascribed by the treating physician. Reactions which are
not considered drug-related are excluded.
Number of Patients
N = 395
(%)
Body as a Whole
General Pain
7
(2)
Integumentary System
Acne/Seborrhea
7
(2)
Injection Site Reactions
Including Abscess
21
(5)
Rash Including
Erythema Multiforme
8
(2)
Urogenital System
Vaginitis/Bleeding/
Discharge
7
(2)
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
035410
INSTRUCTIONS
ON HOW TO
MIX AND
ADMINISTER
NOTE: LUPRON DEPOT
® and
LUPRON DEPOT-PED
®
must be administered under the
supervision of a physician.
LUPRON DEPOT
®
LUPRON DEPOT-PED
®
PREFILLED DUAL-CHAMBER SYRINGE
LEUPROLIDE ACETATE FOR DEPOT SUSPENSION
ADDITIONAL INFORMATION
• None of the components is hazardous;
therefore, no special handling or disposal
procedures are needed.
• Dispose of the syringe according to local
regulations/procedures.
LuproLoc™
U.S. Patent Nos. 5,823,997 and 5,980,488.
Other patents pending.
TAP Pharmaceuticals Inc.
Lake Forest, IL 60045
(Nos. 2108, 2282, 2440, 3346, 3641, 3642, 3663, 3683)
03-5410-R7; Revised: January, 2005
TM-Trademark
®- Registered Trademark
©2002-2005 TAP Pharmaceutical Products Inc.
Printed in U.S.A.
If you have any questions regarding
the drug or the mixing/administration
procedure, please call
1-800-622-2011
for further assistance.
Attention Review Revised
Mixing Instructions
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
For optimal performance of the prefilled dual
chamber syringe (PDS), read and follow the
following instructions:
1.The LUPRON DEPOT powder should be visually
inspected and the syringe should NOT BE USED
if clumping or caking is evident. A thin layer of
powder on the wall of the syringe is considered
normal. The diluent should appear clear.
2.To prepare for injection,
screw the white plunger
into the end stopper until
the stopper begins to turn.
3.Hold the syringe UPRIGHT.
Release the diluent by
SLOWLY PUSHING (6 to 8
seconds) the plunger until
the first stopper is at the
blue line in the middle of
the barrel.
4. Keep the syringe
UPRIGHT. Gently mix the
microspheres (powder)
thoroughly to form a
uniform suspension.The
suspension will appear
milky. If the powder
adheres to the stopper or
caking/ clumping is
present, tap the syringe
with your finger to
disperse. DO NOT USE if
any of the powder has not
gone into suspension.
5. Hold the syringe UPRIGHT. With the opposite
hand pull the needle cap upward without
twisting.
6. Keep the syringe UPRIGHT. Advance the
plunger to expel the air from the syringe.
7. Inject the entire contents of the syringe
intramuscularly at the time of reconstitution.
The suspension settles very quickly following
reconstitution; therefore, LUPRON DEPOT
should be mixed and used immediately.
NOTE: Aspirated blood
would be visible just below
the luer lock connection if a
blood vessel is accidentally
penetrated. If present, blood
can be seen through the
transparent LuproLoc™ safety
device.
AFTER INJECTION
8. Withdraw the needle. Immediately activate
the LuproLoc™ safety device by pushing the
arrow forward with the thumb or finger,
as illustrated,until the device is fully extended
and a CLICK is heard or felt.
CLICK
blue line
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:16.499184
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020263s026lbl.pdf', 'application_number': 20263, 'submission_type': 'SUPPL ', 'submission_number': 26}
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12,390
|
NDA 020262/S-048
Page 4
TAXOL® (paclitaxel) INJECTION
(Patient Information Included)
WARNING
TAXOL® (paclitaxel) should be administered under the supervision of a physician experienced
in the use of cancer chemotherapeutic agents. Appropriate management of complications is
possible only when adequate diagnostic and treatment facilities are readily available.
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension
requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients
receiving TAXOL in clinical trials. Fatal reactions have occurred in patients despite
premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2
antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe
hypersensitivity reactions to TAXOL should not be rechallenged with the drug.
TAXOL therapy should not be given to patients with solid tumors who have baseline neutrophil
counts of less than 1500 cells/mm3 and should not be given to patients with AIDS-related
Kaposi’s sarcoma if the baseline neutrophil count is less than 1000 cells/mm3. In order to
monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe
and result in infection, it is recommended that frequent peripheral blood cell counts be performed
on all patients receiving TAXOL.
DESCRIPTION
TAXOL (paclitaxel) Injection is a clear, colorless to slightly yellow viscous solution. It is
supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to
intravenous infusion. TAXOL is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50
mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg
of purified Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol,
USP.
Paclitaxel is a natural product with antitumor activity. TAXOL (paclitaxel) is obtained via a
semi-synthetic process from Taxus baccata. The chemical name for paclitaxel is 5β,20-Epoxy
*Cremophor® EL is the registered trademark of BASF Aktiengesellschaft.
Cremophor® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
NDA 020262/S-048
Page 5
1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one
4,10-diacetate
2-benzoate
13-ester
with
(2R,3S)-N-benzoyl-3-phenylisoserine.
Paclitaxel has the following structural formula:
Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and
a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216–
217° C.
CLINICAL PHARMACOLOGY
Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from
tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results
in the inhibition of the normal dynamic reorganization of the microtubule network that is
essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces
abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of
microtubules during mitosis.
Following intravenous administration of TAXOL, paclitaxel plasma concentrations declined in a
biphasic manner. The initial rapid decline represents distribution to the peripheral compartment
and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of
paclitaxel from the peripheral compartment.
Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of TAXOL at dose
levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer
patients and are summarized in the following table.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 6
TABLE 1
SUMMARY OF PHARMACOKINETIC PARAMETERS—MEAN VALUES
Dose
(mg/m2)
Infusion
Duration (h)
N
(patients)
Cmax
(ng/mL)
AUC(0–∞)
(ng•h/mL)
T-HALF
(h)
CLT
(L/h/m2)
135
24
2
195
6300
52.7
21.7
175
24
4
365
7993
15.7
23.8
135
3
7
2170
7952
13.1
17.7
175
3
5
3650
15007
20.2
12.2
Cmax=Maximum plasma concentration
AUC(0–∞)=Area under the plasma concentration-time curve from time 0 to infinity
CLT=Total body clearance
It appeared that with the 24-hour infusion of TAXOL, a 30% increase in dose (135 mg/m2 vs 175
mg/m2) increased the Cmax by 87%, whereas the AUC(0-∞) remained proportional. However, with
a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC(0-∞) were increased by 68% and
89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour
infusion of TAXOL, ranged from 227 to 688 L/m2, indicating extensive extravascular
distribution and/or tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received
single doses of 15 to 135 mg/m2 given by 1-hour infusions (n=15), 30 to 275 mg/m2 given by 6
hour infusions (n=36), and 200 to 275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 and 2
studies. Values for CLT and volume of distribution were consistent with the findings in the Phase
3 study. The pharmacokinetics of TAXOL in patients with AIDS-related Kaposi’s sarcoma have
not been studied.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from
0.1 to 50 µg/mL, indicate that between 89 to 98% of drug is bound; the presence of cimetidine,
ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
After intravenous administration of 15 to 275 mg/m2 doses of TAXOL as 1-, 6-, or 24-hour
infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to
12.6% of the dose, indicating extensive non-renal clearance. In 5 patients administered a 225 or
250 mg/m2 dose of radiolabeled TAXOL as a 3-hour infusion, a mean of 71% of the
radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total
recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of
5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α
hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and
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tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the
cytochrome P450 isozyme CYP2C8; and to 2 minor metabolites, 3'-p-hydroxypaclitaxel and 6α,
3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α
hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam,
quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the
concentrations used exceeded those found in vivo following normal therapeutic doses.
Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8,
also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel
may also be altered in vivo as a result of interactions with compounds that are substrates,
inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See PRECAUTIONS: Drug
Interactions.)
The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with
varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel
exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN)
administered 175 mg/m2 was increased, but with no apparent increase in the frequency or
severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a
statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose
(110 mg/m2), but no observed increase in plasma exposure. (See PRECAUTIONS: Hepatic and
DOSAGE AND ADMINISTRATION.) The effect of renal dysfunction on the disposition of
paclitaxel has not been investigated.
Possible interactions of paclitaxel with concomitantly administered medications have not been
formally investigated.
CLINICAL STUDIES
Ovarian Carcinoma
First-Line Data: The safety and efficacy of TAXOL followed by cisplatin in patients with
advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter,
randomized, controlled trials. In an Intergroup study led by the European Organization for
Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National
Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage IIB–C, III, or IV
disease (optimally or non-optimally debulked) received either TAXOL 175 mg/m2 infused over
3 hours followed by cisplatin 75 mg/m2 (Tc) or cyclophosphamide 750 mg/m2 followed by
cisplatin 75 mg/m2 (Cc) for a median of 6 courses. Although the protocol allowed further
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therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the
Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease (>1 cm
residual disease after staging laparotomy or distant metastases) received either TAXOL 135
mg/m2 infused over 24 hours followed by cisplatin 75 mg/m2 or cyclophosphamide 750 mg/m2
followed by cisplatin 75 mg/m2 for 6 courses.
In both studies, patients treated with TAXOL (paclitaxel) in combination with cisplatin had
significantly higher response rate, longer time to progression, and longer survival time compared
with standard therapy. These differences were also significant for the subset of patients in the
Intergroup study with non-optimally debulked disease, although the study was not fully powered
for subset analyses (TABLES 2A and 2B). Kaplan-Meier survival curves for each study are
shown in FIGURES 1 and 2.
TABLE 2A
EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES
Intergroup
GOG-111
(non-optimally debulked subset)
T175/3a
C750a
T135/24a
C750a
c75
c75
c75
c75
(n=218)
(n=227)
(n=196)
(n=214)
•
Clinical Responseb
(n=153)
(n=153)
(n=113)
(n=127)
—rate (percent)
58
43
62
48
—p-valuec
0.016
0.04
•
Time to Progression
—median (months)
13.2
9.9
16.6
13.0
—p-valuec
0.0060
0.0008
—hazard ratio (HR)c
0.76
0.70
—95% CIc
0.62–0.92
0.56–0.86
•
Survival
—median (months)
29.5
21.9
35.5
24.2
—p-valuec
0.0057
0.0002
—hazard ratioc
0.73
0.64
—95% CIc
0.58–0.91
0.50–0.81
a TAXOL dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.
b Among patients with measurable disease only.
c Unstratified for the Intergroup Study, Stratified for Study GOG-111.
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TABLE 2B
EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA INTERGROUP
STUDY
T175/3a
C750a
c75
c75
•
Clinical Responseb
(n=342)
(n=162)
(n=338)
(n=161)
—rate (percent)
59
45
—p-valuec
0.014
•
Time to Progression
—median (months)
15.3
11.5
—p-valuec
0.0005
—hazard ratioc
0.74
—95% CIc
0.63–0.88
•
Survival
—median (months)
35.6
25.9
—p-valuec
0.0016
—hazard ratioc
0.73
—95% CIc
0.60–0.89
a TAXOL dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.
b Among patients with measurable disease only.
c Unstratified.
FIGURE 1
SURVIVAL: Cc VERSUS Tc (INTERGROUP) graph
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FIGURE 2
SURVIVAL: Cc VERSUS Tc (GOG-111) graph
The adverse event profile for patients receiving TAXOL in combination with cisplatin in these
studies was qualitatively consistent with that seen for the pooled analysis of data from 812
patients treated with single-agent TAXOL in 10 clinical studies. These adverse events and
adverse events from the Phase 3 first-line ovarian carcinoma studies are described in the
ADVERSE REACTIONS section in tabular (TABLES 10 and 11) and narrative form.
Second-Line Data: Data from 5, Phase 1 and 2 clinical studies (189 patients), a multicenter
randomized Phase 3 study (407 patients), as well as an interim analysis of data from more than
300 patients enrolled in a treatment referral center program were used in support of the use of
TAXOL in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma
of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose of 135 to 170
mg/m2 in most patients (>90%) administered over 24 hours by continuous infusion. Response
rates in these 2 studies were 22% (95% CI, 11–37%) and 30% (95% CI, 18–46%) with a total of
6 complete and 18 partial responses in 92 patients. The median duration of overall response in
these 2 studies measured from the first day of treatment was 7.2 months (range, 3.5–15.8
months) and 7.5 months (range, 5.3–17.4 months), respectively. The median survival was 8.1
months (range, 0.2–36.7 months) and 15.9 months (range, 1.8–34.5+ months).
The Phase 3 study had a bifactorial design and compared the efficacy and safety of TAXOL
(paclitaxel), administered at 2 different doses (135 or 175 mg/m2) and schedules (3- or 24-hour
infusion). The overall response rate for the 407 patients was 16.2% (95% CI, 12.8–20.2%), with
6 complete and 60 partial responses. Duration of response, measured from the first day of
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treatment was 8.3 months (range, 3.2–21.6 months). Median time to progression was 3.7 months
(range, 0.1+ to 25.1+ months). Median survival was 11.5 months (range, 0.2 to 26.3+ months).
Response rates, median survival, and median time to progression for the 4 arms are given in the
following table.
TABLE 3
EFFICACY IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY
175/3
175/24
135/3
135/24
(n=96)
(n=106)
(n=99)
(n=106)
•
Response
—rate (percent)
14.6
21.7
15.2
13.2
—95% Confidence Interval
(8.5–23.6)
(14.5–31.0)
(9.0–24.1)
(7.7–21.5)
•
Time to Progression
—median (months)
4.4
4.2
3.4
2.8
—95% Confidence Interval
(3.0–5.6)
(3.5–5.1)
(2.8–4.2)
(1.9–4.0)
•
Survival
—median (months)
11.5
11.8
13.1
10.7
—95% Confidence Interval
(8.4–14.4)
(8.9–14.6)
(9.1–14.6)
(8.1–13.6)
Analyses were performed as planned by the bifactorial study design described in the protocol, by
comparing the 2 doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the 2
schedules irrespective of dose. Patients receiving the 175 mg/m2 dose had a response rate similar
to that for those receiving the 135 mg/m2 dose: 18% versus 14% (p=0.28). No difference in
response rate was detected when comparing the 3-hour with the 24-hour infusion: 15% versus
17% (p=0.50). Patients receiving the 175 mg/m2 dose of TAXOL had a longer time to
progression than those receiving the 135 mg/m2 dose: median 4.2 versus 3.1 months (p=0.03).
The median time to progression for patients receiving the 3-hour versus the 24-hour infusion was
4.0 months versus 3.7 months, respectively. Median survival was 11.6 months in patients
receiving the 175 mg/m2 dose of TAXOL and 11.0 months in patients receiving the 135 mg/m2
dose (p=0.92). Median survival was 11.7 months for patients receiving the 3-hour infusion of
TAXOL and 11.2 months for patients receiving the 24-hour infusion (p=0.91). These statistical
analyses should be viewed with caution because of the multiple comparisons made.
TAXOL remained active in patients who had developed resistance to platinum-containing
therapy (defined as tumor progression while on, or tumor relapse within 6 months from
completion of, a platinum-containing regimen) with response rates of 14% in the Phase 3 study
and 31% in the Phase 1 and 2 clinical studies.
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The adverse event profile in this Phase 3 study was consistent with that seen for the pooled
analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse
events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE
REACTIONS section in tabular (TABLES 10 and 12) and narrative form.
The results of this randomized study support the use of TAXOL at doses of 135 to 175 mg/m2,
administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion
were more toxic. However, the study had insufficient power to determine whether a particular
dose and schedule produced superior efficacy.
Breast Carcinoma
Adjuvant Therapy
A Phase 3 Intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative
Oncology Group [ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest
Oncology Group [SWOG]) randomized 3170 patients with node-positive breast carcinoma to
adjuvant therapy with TAXOL or to no further chemotherapy following 4 courses of doxorubicin
and cyclophosphamide (AC). This multicenter trial was conducted in women with histologically
positive lymph nodes following either a mastectomy or segmental mastectomy and nodal
dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of 3 different
dose levels of doxorubicin (A) and to evaluate the effect of the addition of TAXOL administered
following the completion of AC therapy. After stratification for the number of positive lymph
nodes (1–3, 4–9, or 10+), patients were randomized to receive cyclophosphamide at a dose of
600 mg/m2 and doxorubicin at doses of either 60 mg/m2 (on day 1), 75 mg/m2 (in 2 divided
doses on days 1 and 2), or 90 mg/m2 (in 2 divided doses on days 1 and 2 with prophylactic
G-CSF support and ciprofloxacin) every 3 weeks for 4 courses and either TAXOL 175 mg/m2 as
a 3-hour infusion every 3 weeks for 4 additional courses or no additional chemotherapy. Patients
whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg daily for
5 years); patients who received segmental mastectomies prior to study were to receive breast
irradiation after recovery from treatment-related toxicities.
At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who
were hormone receptor positive, 93% received tamoxifen. The primary analyses of disease-free
survival and overall survival used multivariate Cox models, which included TAXOL
administration, doxorubicin dose, number of positive lymph nodes, tumor size, menopausal
status, and estrogen receptor status as factors. Based on the model for disease-free survival,
patients receiving AC followed by TAXOL had a 22% reduction in the risk of disease recurrence
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compared to patients randomized to AC alone (Hazard Ratio [HR]=0.78, 95% CI, 0.67–0.91,
p=0.0022). They also had a 26% reduction in the risk of death (HR=0.74, 95% CI, 0.60–0.92,
p=0.0065). For disease-free survival and overall survival, p-values were not adjusted for interim
analyses. Kaplan-Meier curves are shown in FIGURES 3 and 4. Increasing the dose of
doxorubicin higher than 60 mg/m2 had no effect on either disease-free survival or overall
survival.
FIGURE 3
DISEASE-FREE SURVIVAL: AC VERSUS AC+T graph
FIGURE 4
SURVIVAL: AC VERSUS AC+T graph
Subset analyses. Subsets defined by variables of known prognostic importance in adjuvant breast
carcinoma were examined, including number of positive lymph nodes, tumor size, hormone
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receptor status, and menopausal status. Such analyses must be interpreted with care, as the most
secure finding is the overall study result. In general, a reduction in hazard similar to the overall
reduction was seen with TAXOL (paclitaxel) for both disease-free and overall survival in all of
the larger subsets with one exception; patients with receptor-positive tumors had a smaller
reduction in hazard (HR=0.92) for disease-free survival with TAXOL than other groups. Results
of subset analyses are shown in TABLE 4.
TABLE 4
SUBSET ANALYSES—ADJUVANT BREAST CARCINOMA STUDY
Disease-Free Survival
Overall Survival
Patient Subset
No. of
No. of
Hazard Ratio
No. of
Hazard Ratio
Patients
Recurrences
(95% CI)
Deaths
(95% CI)
•
No. of Positive Nodes
1–3
1449
221
0.72
107
0.76
(0.55–0.94)
(0.52–1.12)
4–9
1310
274
0.78
148
0.66
(0.61–0.99)
(0.47–0.91)
10+
360
129
0.93
87
0.90
(0.66–1.31)
(0.59–1.36)
•
Tumor Size (cm)
≤2
1096
153
0.79
67
0.73
(0.57–1.08)
(0.45–1.18)
>2 and ≤5
1611
358
0.79
201
0.74
(0.64–0.97)
(0.56–0.98)
>5
397
111
0.75
72
0.73
(0.51–1.08)
(0.46–1.16)
•
Menopausal Status
Pre
1929
374
0.83
187
0.72
(0.67–1.01)
(0.54–0.97)
Post
1183
250
0.73
155
0.77
(0.57–0.93)
(0.56–1.06)
•
Receptor Status
Positivea
2066
293
0.92
126
0.83
Negative/Unknownb
1055
331
(0.73–1.16)
0.68
(0.55–0.85)
216
(0.59–1.18)
0.71
(0.54–0.93)
a Positive for either estrogen or progesterone receptors.
b Negative or missing for both estrogen and progesterone receptors (both missing: n=15).
These retrospective subgroup analyses suggest that the beneficial effect of TAXOL (paclitaxel)
is clearly established in the receptor-negative subgroup, but the benefit in receptor-positive
patients is not yet clear. With respect to menopausal status, the benefit of TAXOL is consistent
(see TABLE 4 and FIGURES 5–8).
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FIGURE 5
DISEASE-FREE SURVIVAL—RECEPTOR STATUS NEGATIVE/UNKNOWN
AC VERSUS AC+T graph
FIGURE 6
DISEASE-FREE SURVIVAL—RECEPTOR STATUS POSITIVE
AC VERSUS AC+T graph
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FIGURE 7
DISEASE-FREE SURVIVAL—PREMENOPAUSAL
AC VERSUS AC+T graph
FIGURE 8
DISEASE-FREE SURVIVAL—POSTMENOPAUSAL
AC VERSUS AC+T graph
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The adverse event profile for the patients who received TAXOL subsequent to AC was
consistent with that seen in the pooled analysis of data from 812 patients (TABLE 10) treated
with single-agent TAXOL in 10 clinical studies. These adverse events are described in the
ADVERSE REACTIONS section in tabular (TABLES 10 and 13) and narrative form.
After Failure of Initial Chemotherapy
Data from 83 patients accrued in 3, Phase 2 open-label studies and from 471 patients enrolled in
a Phase 3 randomized study were available to support the use of TAXOL in patients with
metastatic breast carcinoma.
Phase 2 open-label studies: Two studies were conducted in 53 patients previously treated with a
maximum of 1 prior chemotherapeutic regimen. TAXOL was administered in these 2 trials as a
24-hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The
response rates were 57% (95% CI, 37–75%) and 52% (95% CI, 32–72%), respectively. The third
Phase 2 study was conducted in extensively pretreated patients who had failed anthracycline
therapy and who had received a minimum of 2 chemotherapy regimens for the treatment of
metastatic disease. The dose of TAXOL was 200 mg/m2 as a 24-hour infusion with G-CSF
support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% CI, 15–
50%).
Phase 3 randomized study: This multicenter trial was conducted in patients previously treated
with 1 or 2 regimens of chemotherapy. Patients were randomized to receive TAXOL (paclitaxel)
at a dose of either 175 mg/m2 or 135 mg/m2 given as a 3-hour infusion. In the 471 patients
enrolled, 60% had symptomatic disease with impaired performance status at study entry, and
73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant
setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven percent of the patients
had been previously exposed to anthracyclines and 23% of them had disease considered resistant
to this class of agents.
The overall response rate for the 454 evaluable patients was 26% (95% CI, 22–30%), with 17
complete and 99 partial responses. The median duration of response, measured from the first day
of treatment, was 8.1 months (range, 3.4–18.1+ months). Overall for the 471 patients, the median
time to progression was 3.5 months (range, 0.03–17.1 months). Median survival was 11.7
months (range, 0–18.9 months).
Response rates, median survival and median time to progression for the 2 arms are given in the
following table.
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TABLE 5
EFFICACY IN BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR
WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY
175/3
135/3
(n=235)
(n=236)
•
Response
—rate (percent)
28
22
—p-value
0.135
•
Time to Progression
—median (months)
4.2
3.0
—p-value
0.027
•
Survival
—median (months)
11.7
10.5
—p-value
0.321
The adverse event profile of the patients who received single-agent TAXOL in the Phase 3 study
was consistent with that seen for the pooled analysis of data from 812 patients treated in 10
clinical studies. These adverse events and adverse events from the Phase 3 breast carcinoma
study are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 14)
and narrative form.
Non-Small Cell Lung Carcinoma (NSCLC)
In a Phase 3 open-label randomized study conducted by the ECOG, 599 patients were
randomized to either TAXOL (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin
(c) 75 mg/m2, TAXOL (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75
mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100
mg/m2 on days 1, 2, and 3 (control).
Response rates, median time to progression, median survival, and 1-year survival rates are given
in the following table. The reported p-values have not been adjusted for multiple comparisons.
There were statistically significant differences favoring each of the TAXOL plus cisplatin arms
for response rate and time to tumor progression. There was no statistically significant difference
in survival between either TAXOL plus cisplatin arm and the cisplatin plus etoposide arm.
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TABLE 6
EFFICACY PARAMETERS IN THE PHASE 3 FIRST-LINE NSCLC STUDY
T135/24
T250/24
VP100a
c75
c75
c75
(n=198)
(n=201)
(n=200)
•
Response
—rate (percent)
—p-valueb
25
0.001
23
<0.001
12
•
Time to Progression
—median (months)
—p-valueb
4.3
0.05
4.9
0.004
2.7
•
Survival
—median (months)
—p-valueb
9.3
0.12
10.0
0.08
7.4
•
1-Year Survival
—percent of patients
36
40
32
a Etoposide (VP) 100 mg/m2 was administered IV on days 1, 2, and 3.
b Compared to cisplatin/etoposide.
In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L)
questionnaire had 7 subscales that measured subjective assessment of treatment. Of the 7, the
Lung Cancer Specific Symptoms subscale favored the TAXOL 135 mg/m2/24 hour plus cisplatin
arm compared to the cisplatin/etoposide arm. For all other factors, there was no difference in the
treatment groups.
The adverse event profile for patients who received TAXOL in combination with cisplatin in this
study was generally consistent with that seen for the pooled analysis of data from 812 patients
treated with single-agent TAXOL in 10 clinical studies. These adverse events and adverse events
from the Phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS section
in tabular (TABLES 10 and 15) and narrative form.
AIDS-Related Kaposi’s Sarcoma
Data from 2, Phase 2 open-label studies support the use of TAXOL (paclitaxel) as second-line
therapy in patients with AIDS-related Kaposi’s sarcoma. Fifty-nine of the 85 patients enrolled in
these studies had previously received systemic therapy, including interferon alpha (32%),
DaunoXome® (31%), DOXIL® (2%), and doxorubicin containing chemotherapy (42%), with
64% having received prior anthracyclines. Eighty-five percent of the pretreated patients had
progressed on, or could not tolerate, prior systemic therapy.
DaunoXome® is a registered trademark of Gilead Sciences, Inc.
DOXIL® is a registered trademark of ALZA Corporation.
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In Study CA139-174, patients received TAXOL at 135 mg/m2 as a 3-hour infusion every 3
weeks (intended dose intensity 45 mg/m2/week). If no dose-limiting toxicity was observed,
patients were to receive 155 mg/m2 and 175 mg/m2 in subsequent courses. Hematopoietic
growth factors were not to be used initially. In Study CA139-281, patients received TAXOL at
100 mg/m2 as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m2/week). In this
study patients could be receiving hematopoietic growth factors before the start of TAXOL
therapy, or this support was to be initiated as indicated; the dose of TAXOL was not increased.
The dose intensity of TAXOL used in this patient population was lower than the dose intensity
recommended for other solid tumors.
All patients had widespread and poor-risk disease. Applying the ACTG staging criteria to
patients with prior systemic therapy, 93% were poor risk for extent of disease (T1), 88% had a
CD4 count <200 cells/mm3 (I1), and 97% had poor risk considering their systemic illness (S1).
All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in
Study CA139-281, there were 26 (46%) patients with a Karnofsky performance status of 70 or
worse at baseline.
TABLE 7
EXTENT OF DISEASE AT STUDY ENTRY
Percent of Patients
Prior Systemic Therapy
(n=59)
Visceral ± edema ± oral ± cutaneous
42
Edema or lymph nodes ± oral ± cutaneous
41
Oral ± cutaneous
10
Cutaneous only
7
Although the planned dose intensity in the 2 studies was slightly different (45 mg/m2/week in
Study CA139-174 and 50 mg/m2/week in Study CA139-281), delivered dose intensity was 38 to
39 mg/m2/week in both studies, with a similar range (20–24 to 51–61).
Efficacy: The efficacy of TAXOL was evaluated by assessing cutaneous tumor response
according to the amended ACTG criteria and by seeking evidence of clinical benefit in patients
in 6 domains of symptoms and/or conditions that are commonly related to AIDS-related
Kaposi’s sarcoma.
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Cutaneous Tumor Response (Amended ACTG Criteria): The objective response rate was 59%
(95% CI, 46–72%) (35 of 59 patients) in patients with prior systemic therapy. Cutaneous
responses were primarily defined as flattening of more than 50% of previously raised lesions.
TABLE 8
OVERALL BEST RESPONSE (AMENDED ACTG CRITERIA)
Percent of Patients
Prior Systemic Therapy
(n=59)
Complete response
3
Partial response
56
Stable disease
29
Progression
8
Early death/toxicity
3
The median time to response was 8.1 weeks and the median duration of response measured from
the first day of treatment was 10.4 months (95% CI, 7.0–11.0 months) for the patients who had
previously received systemic therapy. The median time to progression was 6.2 months (95% CI,
4.6–8.7 months).
Additional Clinical Benefit: Most data on patient benefit were assessed retrospectively (plans for
such analyses were not included in the study protocols). Nonetheless, clinical descriptions and
photographs indicated clear benefit in some patients, including instances of improved pulmonary
function in patients with pulmonary involvement, improved ambulation, resolution of ulcers, and
decreased analgesic requirements in patients with Kaposi’s sarcoma (KS) involving the feet and
resolution of facial lesions and edema in patients with KS involving the face, extremities, and
genitalia.
Safety: The adverse event profile of TAXOL administered to patients with advanced HIV disease
and poor-risk AIDS-related Kaposi’s sarcoma was generally similar to that seen in the pooled
analysis of data from 812 patients with solid tumors. These adverse events and adverse events
from the Phase 2 second-line Kaposi’s sarcoma studies are described in the ADVERSE
REACTIONS section in tabular (TABLES 10 and 16) and narrative form. In this
immunosuppressed patient population, however, a lower dose intensity of TAXOL and
supportive therapy including hematopoietic growth factors in patients with severe neutropenia
are recommended. Patients with AIDS-related Kaposi’s sarcoma may have more severe
hematologic toxicities than patients with solid tumors.
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Page 22
INDICATIONS AND USAGE
TAXOL is indicated as first-line and subsequent therapy for the treatment of advanced
carcinoma of the ovary. As first-line therapy, TAXOL is indicated in combination with cisplatin.
TAXOL is indicated for the adjuvant treatment of node-positive breast cancer administered
sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial,
there was an overall favorable effect on disease-free and overall survival in the total population
of patients with receptor-positive and receptor-negative tumors, but the benefit has been
specifically demonstrated by available data (median follow-up 30 months) only in the patients
with estrogen and progesterone receptor-negative tumors. (See CLINICAL STUDIES: Breast
Carcinoma.)
TAXOL is indicated for the treatment of breast cancer after failure of combination chemotherapy
for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should
have included an anthracycline unless clinically contraindicated.
TAXOL, in combination with cisplatin, is indicated for the first-line treatment of non-small cell
lung cancer in patients who are not candidates for potentially curative surgery and/or radiation
therapy.
TAXOL is indicated for the second-line treatment of AIDS-related Kaposi’s sarcoma.
CONTRAINDICATIONS
TAXOL is contraindicated in patients who have a history of hypersensitivity reactions to
TAXOL or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).
TAXOL should not be used in patients with solid tumors who have baseline neutrophil counts of
<1500 cells/mm3 or in patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil
counts of <1000 cells/mm3.
WARNINGS
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension
requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients
receiving TAXOL in clinical trials. Fatal reactions have occurred in patients despite
premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2
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Page 23
antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe
hypersensitivity reactions to TAXOL should not be rechallenged with the drug.
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting
toxicity. Neutrophil nadirs occurred at a median of 11 days. TAXOL should not be administered
to patients with baseline neutrophil counts of less than 1500 cells/mm3 (<1000 cells/mm3 for
patients with KS). Frequent monitoring of blood counts should be instituted during TAXOL
treatment. Patients should not be re-treated with subsequent cycles of TAXOL until neutrophils
recover to a level >1500 cells/mm3 (>1000 cells/mm3 for patients with KS) and platelets recover
to a level >100,000 cells/mm3.
Severe conduction abnormalities have been documented in <1% of patients during TAXOL
therapy and in some cases requiring pacemaker placement. If patients develop significant
conduction abnormalities during TAXOL infusion, appropriate therapy should be administered
and continuous cardiac monitoring should be performed during subsequent therapy with
TAXOL.
Pregnancy
TAXOL can cause fetal harm when administered to a pregnant woman. Administration of
paclitaxel during the period of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the
daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity,
as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal
toxicity was also observed at this dose. No teratogenic effects were observed at 1.0 mg/kg/day
(about 1/15 the daily maximum recommended human dose on a mg/m2 basis); teratogenic
potential could not be assessed at higher doses due to extensive fetal mortality.
There are no adequate and well-controlled studies in pregnant women. If TAXOL is used during
pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be
apprised of the potential hazard to the fetus. Women of childbearing potential should be advised
to avoid becoming pregnant.
PRECAUTIONS
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or
devices used to prepare solutions for infusion is not recommended. In order to minimize patient
exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC
infusion bags or sets, diluted TAXOL solutions should preferably be stored in bottles (glass,
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Page 24
polypropylene) or plastic bags (polypropylene, polyolefin) and administered through
polyethylene-lined administration sets.
TAXOL should be administered through an in-line filter with a microporous membrane not
greater than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short
inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.
Drug Interactions: In a Phase 1 trial using escalating doses of TAXOL (110–200 mg/m2) and
cisplatin (50 or 75 mg/m2) given as sequential infusions, myelosuppression was more profound
when TAXOL was given after cisplatin than with the alternate sequence (ie, TAXOL before
cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel
clearance of approximately 33% when TAXOL was administered following cisplatin.
The metabolism of TAXOL is catalyzed by cytochrome P450 isoenzymes CYP2C8 and
CYP3A4. Caution should be exercised when TAXOL is concomitantly administered with known
substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin,
and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and
carbamazepine) of CYP3A4. (See CLINICAL PHARMACOLOGY.)
Caution should also be exercised when TAXOL is concomitantly administered with known
substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg,
rifampin) of CYP2C8. (See CLINICAL PHARMACOLOGY.)
Potential interactions between TAXOL, a substrate of CYP3A4, and protease inhibitors
(ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of
CYP3A4, have not been evaluated in clinical trials.
Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite
doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination.
Hematology: TAXOL therapy should not be administered to patients with baseline neutrophil
counts of less than 1500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is
recommended that frequent peripheral blood cell counts be performed on all patients receiving
TAXOL. Patients should not be re-treated with subsequent cycles of TAXOL until neutrophils
recover to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the
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case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of TAXOL
therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.
For patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, TAXOL,
at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is
at least 1000 cells/mm3.
Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to
products containing Cremophor® EL (eg, cyclosporin for injection concentrate and teniposide for
injection concentrate) should not be treated with TAXOL. In order to avoid the occurrence of
severe hypersensitivity reactions, all patients treated with TAXOL should be premedicated with
corticosteroids (such as dexamethasone), diphenhydramine and H2 antagonists (such as
cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea,
hypotension, or tachycardia do not require interruption of therapy. However, severe reactions,
such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or
generalized urticaria require immediate discontinuation of TAXOL and aggressive symptomatic
therapy. Patients who have developed severe hypersensitivity reactions should not be
rechallenged with TAXOL.
Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during
administration of TAXOL, but generally do not require treatment. Occasionally TAXOL
infusions must be interrupted or discontinued because of initial or recurrent hypertension.
Frequent vital sign monitoring, particularly during the first hour of TAXOL infusion, is
recommended. Continuous cardiac monitoring is not required except for patients with serious
conduction abnormalities. (See WARNINGS.) When TAXOL is used in combination with
doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is
recommended. (See ADVERSE REACTIONS.)
Nervous System: Although the occurrence of peripheral neuropathy is frequent, the
development of severe symptomatology is unusual and requires a dose reduction of 20% for all
subsequent courses of TAXOL.
TAXOL contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to
possible CNS and other effects of alcohol. (See PRECAUTIONS: Pediatric Use.)
Hepatic: There is limited evidence that the myelotoxicity of TAXOL may be exacerbated in
patients with serum total bilirubin >2 times ULN (see CLINICAL PHARMACOLOGY).
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Extreme caution should be exercised when administering TAXOL to such patients, with dose
reduction as recommended in DOSAGE AND ADMINISTRATION, TABLE 17.
Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation,
were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the
injection site. These reactions have been observed more frequently with the 24-hour infusion
than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation
following administration of TAXOL at a different site, ie, “recall,” has been reported.
More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis
have been reported. In some cases the onset of the injection site reaction either occurred during a
prolonged infusion or was delayed by a week to 10 days.
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of
extravasation, it is advisable to closely monitor the infusion site for possible infiltration during
drug administration.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of TAXOL
(paclitaxel) has not been studied.
Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human
lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames
test or the CHO/HGPRT gene mutation assay.
Administration of paclitaxel prior to and during mating produced impairment of fertility in male
and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum
recommended human dose on a mg/m2 basis). At this dose, paclitaxel caused reduced fertility
and reproductive indices, and increased embryo- and fetotoxicity. (See WARNINGS.)
Pregnancy: Pregnancy Category D. (See WARNINGS.)
Nursing Mothers: It is not known whether the drug is excreted in human milk. Following
intravenous administration of carbon 14-labeled TAXOL to rats on days 9 to 10 postpartum,
concentrations of radioactivity in milk were higher than in plasma and declined in parallel with
the plasma concentrations. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants, it is recommended that nursing be
discontinued when receiving TAXOL therapy.
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Pediatric Use: The safety and effectiveness of TAXOL (paclitaxel) in pediatric patients have not
been established.
There have been reports of central nervous system (CNS) toxicity (rarely associated with death)
in a clinical trial in pediatric patients in which TAXOL was infused intravenously over 3 hours at
doses ranging from 350 mg/m2 to 420 mg/m2. The toxicity is most likely attributable to the high
dose of the ethanol component of the TAXOL vehicle given over a short infusion time. The use
of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel
itself cannot be discounted, the high doses used in this study (over twice the recommended adult
dosage) must be considered in assessing the safety of TAXOL for use in this population.
Geriatric Use: Of 2228 patients who received TAXOL in 8 clinical studies evaluating its safety
and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and
1570 patients who were randomized to receive TAXOL in the adjuvant breast cancer study, 649
patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most
studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe
neuropathy was more common in elderly patients. In 2 clinical studies in NSCLC, the elderly
patients treated with TAXOL had a higher incidence of cardiovascular events. Estimates of
efficacy appeared similar in elderly patients and in younger patients; however, comparative
efficacy cannot be determined with confidence due to the small number of elderly patients
studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median
survival than younger patients, but no other efficacy parameters favored the younger group.
TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical
studies according to age.
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c
NDA 020262/S-048
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TABLE 9
SELECTED ADVERSE EVENTS IN GERIATRIC PATIENTS RECEIVING TAXOL IN
CLINICAL STUDIES
Patients (n/total [%])
Neutropenia
Peripheral Neuropathy
(Grade IV)
(Grades III/IV)
INDICATION
Age (y)
Age (y)
(Study/Regimen)
≥65
<65
≥65
<65
•
OVARIAN Cancer
(Intergroup First-Line/T175/3 c75a)
34/83 (41)
78/252 (31)
24/84 (29)*b
46/255 (18)b
(GOG-111 First-Line/T135/24 c75a)
48/61 (79)
106/129 (82)
3/62 (5)
2/134 (1)
(Phase 3 Second-Line/T175/3c)
5/19 (26)
21/76 (28)
1/19 (5)
0/76 (0)
(Phase 3 Second-Line/T175/24c)
21/25 (84)
57/79 (72)
0/25 (0)
2/80 (3)
(Phase 3 Second-Line/T135/3c)
4/16 (25)
10/81 (12)
0/17 (0)
0/81 (0)
(Phase 3 Second-Line/T135/24c)
17/22 (77)
53/83 (64)
0/22 (0)
0/83 (0)
(Phase 3 Second-Line Pooled)
47/82 (57)*
141/319 (44)
1/83 (1)
2/320 (1)
•
Adjuvant BREAST Cancer
(Intergroup/AC followed by Td)
56/102 (55)
734/1468 (50)
5/102 (5)e
46/1468 (3)e
•
BREAST Cancer After Failure of Initial Therapy
(Phase 3/T175/3c)
7/24 (29)
56/200 (28)
3/25 (12)
12/204 (6)
(Phase 3/T135/3c)
7/20 (35)
37/207 (18)
0/20 (0)
6/209 (3)
•
Non-Small Cell LUNG Cancer
(ECOG/T135/24 c75a)
58/71 (82)
86/124 (69)
9/71 (13)f
16/124 (13)f
(Phase 3/T175/3 c80a)
37/89 (42)*
56/267 (21)
11/91 (12)*
11/271 (4)
* p<0.05
a TAXOL dose in mg/m2/infusion duration in hours; cisplatin doses in mg/m2.
b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-Line Ovarian Cancer
study (see TABLE 11).
TAXOL dose in mg/m2/infusion duration in hours.
d TAXOL (T) following 4 courses of doxorubicin and cyclophosphamide (AC) at a dose of 175 mg/m2/3 hours
every 3 weeks for 4 courses.
e Peripheral neuropathy reported as neurosensory toxicity in the Intergroup Adjuvant Breast Cancer study (see
TABLE 13).
f Peripheral neuropathy reported as neurosensory toxicity in the ECOG NSCLC study (see TABLE 15).
Information for Patients: (See Patient Information Leaflet.)
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ADVERSE REACTIONS
Pooled Analysis of Adverse Event Experiences from Single-Agent
Studies
Data in the following table are based on the experience of 812 patients (493 with ovarian
carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent
TAXOL. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with TAXOL
doses ranging from 135 to 300 mg/m2 administered over 24 hours (in 4 of these studies, G-CSF
was administered as hematopoietic support). Three hundred and one patients were treated in the
randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m2) and 2
schedules (3 or 24 hours) of TAXOL. Two hundred and thirty-six patients with breast carcinoma
received TAXOL (135 or 175 mg/m2) administered over 3 hours in a controlled study.
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TABLE 10
SUMMARYa OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING
SINGLE-AGENT TAXOL
Percent of Patients
(n=812)
•
Bone Marrow
—Neutropenia
<2000/mm3
<500/mm3
90
52
—Leukopenia
<4000/mm3
<1000/mm3
—Thrombocytopenia
<100,000/mm3
<50,000/mm3
—Anemia
<11 g/dL
<8 g/dL
—Infections
90
17
20
7
78
16
30
—Bleeding
—Red Cell Transfusions
14
25
—Platelet Transfusions
2
•
Hypersensitivity Reactionb
—All
41
—Severe†
2
•
Cardiovascular
—Vital Sign Changesc
—Bradycardia (n=537)
—Hypotension (n=532)
—Significant Cardiovascular Events
3
12
1
•
Abnormal ECG
—All Pts
23
—Pts with normal baseline (n=559)
14
•
Peripheral Neuropathy
—Any symptoms
—Severe symptoms†
60
3
•
Myalgia/Arthralgia
—Any symptoms
—Severe symptoms†
60
8
•
Gastrointestinal
—Nausea and vomiting
—Diarrhea
52
38
—Mucositis
31
•
•
•
Alopecia
Hepatic (Pts with normal baseline and on study data)
—Bilirubin elevations (n=765)
—Alkaline phosphatase elevations (n=575)
—AST (SGOT) elevations (n=591)
Injection Site Reaction
87
7
22
19
13
a
b
c
†
Based on worst course analysis.
All patients received premedication.
During the first 3 hours of infusion.
Severe events are defined as at least Grade III toxicity.
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Page 31
None of the observed toxicities were clearly influenced by age.
Disease-Specific Adverse Event Experiences
First-Line Ovary in Combination: For the 1084 patients who were evaluable for safety in the
Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of
important adverse events. For both studies, the analysis of safety was based on all courses of
therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).
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TABLE 11
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE
OVARIAN CARCINOMA STUDIES
Percent of Patients
Intergroup
T175/3b
C750c
GOG-111
T135/24b
C750c
c75c
c75c
c75c
c75c
(n=339)
(n=336)
(n=196)
(n=213)
•
Bone Marrow
—Neutropenia
—Thrombocytopenia
—Anemia
<2000/mm3
<500/mm3
<100,000/mm3e
<50,000/mm3
<11 g/dLf
<8 g/dL
91d
33d
21d
3d
96
3d
95d
43d
33d
7d
97
8d
96
81d
26
10
88
13
92
58d
30
9
86
9
—Infections
25
27
21
15
—Febrile Neutropenia
4
7
15d
4d
•
Hypersensitivity Reaction
—All
11d
6d
8d,g
1d,g
—Severe†
1
1
3d,g
—d,g
•
Neurotoxicityh
—Any symptoms
87d
52d
25
20
—Severe symptoms†
21d
2d
3d
— d
•
Nausea and Vomiting
—Any symptoms
—Severe symptoms†
88
18
93
24
65
10
69
11
•
Myalgia/Arthralgia
—Any symptoms
60d
27d
9d
2d
—Severe symptoms†
6d
1d
1
—
•
Diarrhea
—Any symptoms
37d
29d
16d
8d
—Severe symptoms†
2
3
4
1
•
Asthenia
—Any symptoms
NC
NC
17d
10d
—Severe symptoms†
NC
NC
1
1
•
Alopecia
—Any symptoms
96d
89d
55d
37d
—Severe symptoms†
51d
21d
6
8
a
Based on worst course analysis.
b
TAXOL (T) dose in mg/m2/infusion duration in hours.
Cyclophosphamide (C) or cisplatin (c) dose in mg/m2.
d
p<0.05 by Fisher exact test.
e
<130,000/mm3 in the Intergroup study.
f
<12 g/dL in the Intergroup study.
c
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c
NDA 020262/S-048
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g
All patients received premedication.
h
In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study,
neurotoxicity was collected as either neuromotor or neurosensory symptoms.
†
Severe events are defined as at least Grade III toxicity.
NC Not Collected
Second-Line Ovary: For the 403 patients who received single-agent TAXOL in the Phase 3
second-line ovarian carcinoma study, the following table shows the incidence of important
adverse events.
TABLE 12
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE
OVARIAN CARCINOMA STUDY
Percent of Patients
175/3b
175/24b
135/3b
135/24b
(n=95)
(n=105)
(n=98)
(n=105)
•
Bone Marrow
—Neutropenia
—Thrombocytopenia
<2000/mm3
<500/mm3
<100,000/mm3
<50,000/mm3
78
27
4
1
98
75
18
7
78
14
8
2
98
67
6
1
—Anemia
<11 g/dL
84
90
68
88
<8 g/dL
11
12
6
10
—Infections
26
29
20
18
•
Hypersensitivity Reactionc
—All
41
45
38
45
—Severe†
2
0
2
1
•
Peripheral Neuropathy
—Any symptoms
—Severe symptoms†
63
1
60
2
55
0
42
0
•
Mucositis
—Any symptoms
—Severe symptoms†
17
0
35
3
21
0
25
2
a Based on worst course analysis.
b TAXOL dose in mg/m2/infusion duration in hours.
All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
Myelosuppression was dose and schedule related, with the schedule effect being more
prominent. The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the
patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for
the HSRs. Peripheral neuropathy was clearly dose related, but schedule did not appear to affect
the incidence.
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Adjuvant Breast: For the Phase 3 adjuvant breast carcinoma study, the following table shows
the incidence of important severe adverse events for the 3121 patients (total population) who
were evaluable for safety as well as for a group of 325 patients (early population) who, per the
study protocol, were monitored more intensively than other patients.
TABLE 13
FREQUENCYa OF IMPORTANT SEVEREb ADVERSE EVENTS IN THE PHASE 3
ADJUVANT BREAST CARCINOMA STUDY
Percent of Patients
Early Population
Total Population
ACc
ACc followed by Td
ACc
ACc followed by Td
(n=166)
(n=159)
(n=1551)
(n=1570)
•
Bone Marrowe
79
76
—Neutropenia
<500/mm3
27
25
—Thrombocytopenia <50,000/mm3
—Anemia
<8 g/dL
17
21
—Infections
6
14
—Fever Without Infection
—
3
•
Hypersensitivity Reactionf
1
4
•
Cardiovascular Events
1
2
•
Neuromotor Toxicity
1
1
•
Neurosensory Toxicity
—
3
•
Myalgia/Arthralgia
—
2
•
Nausea/Vomiting
13
18
•
Mucositis
13
4
48
50
11
11
8
8
5
6
<1
1
1
2
1
2
<1
1
<1
3
<1
2
8
9
6
5
a Based on worst course analysis.
b Severe events are defined as at least Grade III toxicity.
c Patients received 600 mg/m2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m2, 75 mg/m2, or
90 mg/m2 (with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4 courses.
d TAXOL (T) following 4 courses of AC at a dose of 175 mg/m2/3 hours every 3 weeks for 4 courses.
e The incidence of febrile neutropenia was not reported in this study.
f All patients were to receive premedication.
The incidence of an adverse event for the total population likely represents an underestimation of
the actual incidence given that safety data were collected differently based on enrollment cohort.
However, since safety data were collected consistently across regimens, the safety of the
sequential addition of TAXOL (paclitaxel) following AC therapy may be compared with AC
therapy alone. Compared to patients who received AC alone, patients who received AC followed
by TAXOL experienced more Grade III/IV neurosensory toxicity, more Grade III/IV
myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-like
symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional
4 courses of treatment with TAXOL, 2 deaths (0.1%) were attributed to treatment. During
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TAXOL treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III
neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%.
The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events
increased with higher doses of doxorubicin.
Breast Cancer After Failure of Initial Chemotherapy: For the 458 patients who received
single-agent TAXOL in the Phase 3 breast carcinoma study, the following table shows the
incidence of important adverse events by treatment arm (each arm was administered by a 3-hour
infusion).
TABLE 14
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY OF
BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6
MONTHS OF ADJUVANT CHEMOTHERAPY
Percent of Patients
175/3b
135/3b
(n=229)
(n=229)
•
Bone Marrow
—Neutropenia
<2000/mm3
90
81
<500/mm3
28
19
—Thrombocytopenia <100,000/mm3
11
7
<50,000/mm3
3
2
—Anemia
<11 g/dL
55
47
<8 g/dL
4
2
—Infections
23
15
—Febrile Neutropenia
2
2
•
Hypersensitivity Reactionc
—All
36
31
—Severe†
0
<1
•
Peripheral Neuropathy
—Any symptoms
70
46
—Severe symptoms†
7
3
•
Mucositis
—Any symptoms
23
17
—Severe symptoms†
3
<1
a Based on worst course analysis.
b TAXOL dose in mg/m2/infusion duration in hours.
All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
Myelosuppression and peripheral neuropathy were dose related. There was one severe
hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2.
c
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First-Line NSCLC in Combination: In the study conducted by the Eastern Cooperative
Oncology Group (ECOG), patients were randomized to either TAXOL (T) 135 mg/m2 as a 24
hour infusion in combination with cisplatin (c) 75 mg/m2, TAXOL (T) 250 mg/m2 as a 24-hour
infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c)
75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control).
The following table shows the incidence of important adverse events.
TABLE 15
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY FOR
FIRST-LINE NSCLC
Percent of Patients
T135/24b
T250/24c
VP100d
c75
c75
c75
(n=195)
(n=197)
(n=196)
•
Bone Marrow
—Neutropenia
<2000/mm3
<500/mm3
89
74e
86
65
84
55
—Thrombocytopenia
< normal
<50,000/mm3
48
6
68
12
62
16
—Anemia
< normal
94
96
95
<8 g/dL
22
19
28
—Infections
38
31
35
•
Hypersensitivity Reactionf
—All
16
27
13
—Severe†
1
4e
1
•
Arthralgia/Myalgia
—Any symptoms
—Severe symptoms†
21e
3
42e
11
9
1
•
Nausea/Vomiting
—Any symptoms
—Severe symptoms†
85
27
87
29
81
22
•
Mucositis
—Any symptoms
—Severe symptoms†
18
1
28
4
16
2
•
Neuromotor Toxicity
—Any symptoms
—Severe symptoms†
37
6
47
12
44
7
•
Neurosensory Toxicity
—Any symptoms
—Severe symptoms†
48
13
61
28e
25
8
•
Cardiovascular Events
—Any symptoms
—Severe symptoms†
33
13
39
12
24
8
a Based on worst course analysis.
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c
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b TAXOL (T) dose in mg/m2/infusion duration in hours; cisplatin (c) dose in mg/m2.
TAXOL dose in mg/m2/infusion duration in hours with G-CSF support; cisplatin dose in mg/m2.
d Etoposide (VP) dose in mg/m2 was administered IV on days 1, 2, and 3; cisplatin dose in mg/m2.
e p<0.05.
f All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
Toxicity was generally more severe in the high-dose TAXOL treatment arm (T250/c75) than in
the low-dose TAXOL arm (T135/c75). Compared to the cisplatin/etoposide arm, patients in the
low-dose TAXOL arm experienced more arthralgia/myalgia of any grade and more severe
neutropenia. The incidence of febrile neutropenia was not reported in this study.
Kaposi’s Sarcoma: The following table shows the frequency of important adverse events in the
85 patients with KS treated with 2 different single-agent TAXOL (paclitaxel) regimens.
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TABLE 16
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSI’S
SARCOMA STUDIES
Percent of Patients
Study CA139-174
TAXOL 135/3b q 3 wk
(n=29)
Study CA139-281
TAXOL 100/3b q 2 wk
(n=56)
•
•
Bone Marrow
—Neutropenia
<2000/mm3
<500/mm3
—Thrombocytopenia
<100,000/mm3
<50,000/mm3
—Anemia
<11 g/dL
<8 g/dL
—Febrile Neutropenia
Opportunistic Infection
—Any
—Cytomegalovirus
—Herpes Simplex
—Pneumocystis carinii
—M. avium intracellulare
100
76
52
17
86
34
55
76
45
38
14
24
95
35
27
5
73
25
9
54
27
11
21
4
•
—Candidiasis, esophageal
—Cryptosporidiosis
—Cryptococcal meningitis
—Leukoencephalopathy
Hypersensitivity Reactionc
—All
7
7
3
—
14
9
7
2
2
9
•
Cardiovascular
•
—Hypotension
—Bradycardia
Peripheral Neuropathy
—Any
—Severe†
17
3
79
10
9
—
46
2
•
Myalgia/Arthralgia
—Any
—Severe†
93
14
48
16
•
Gastrointestinal
—Nausea and Vomiting
—Diarrhea
69
90
70
73
—Mucositis
45
20
•
Renal (creatinine elevation)
—Any
—Severe†
34
7
18
5
•
Discontinuation for drug toxicity
7
16
a Based on worst course analysis.
b TAXOL dose in mg/m2/infusion duration in hours.
All patients received premedication.
† Severe events are defined as at least Grade III toxicity.
c
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As demonstrated in this table, toxicity was more pronounced in the study utilizing TAXOL
(paclitaxel) at a dose of 135 mg/m2 every 3 weeks than in the study utilizing TAXOL at a dose
of 100 mg/m2 every 2 weeks. Notably, severe neutropenia (76% vs 35%), febrile neutropenia
(55% vs 9%), and opportunistic infections (76% vs 54%) were more common with the former
dose and schedule. The differences between the 2 studies with respect to dose escalation and use
of hematopoietic growth factors, as described above, should be taken into account. (See
CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma.) Note also that only 26% of the 85
patients in these studies received concomitant treatment with protease inhibitors, whose effect on
paclitaxel metabolism has not yet been studied.
Adverse Event Experiences by Body System
Unless otherwise noted, the following discussion refers to the overall safety database of 812
patients with solid tumors treated with single-agent TAXOL in clinical studies. Toxicities that
occurred with greater severity or frequency in previously untreated patients with ovarian
carcinoma or NSCLC who received TAXOL in combination with cisplatin or in patients with
breast cancer who received TAXOL after doxorubicin/cyclophosphamide in the adjuvant setting
and that occurred with a difference that was clinically significant in these populations are also
described. The frequency and severity of important adverse events for the Phase 3 ovarian
carcinoma, breast carcinoma, NSCLC, and the Phase 2 Kaposi’s sarcoma studies are presented
above in tabular form by treatment arm. In addition, rare events have been reported from
postmarketing experience or from other clinical studies. The frequency and severity of adverse
events have been generally similar for patients receiving TAXOL for the treatment of ovarian,
breast, or lung carcinoma or Kaposi’s sarcoma, but patients with AIDS-related Kaposi’s sarcoma
may have more frequent and severe hematologic toxicity, infections (including opportunistic
infections, see TABLE 16), and febrile neutropenia. These patients require a lower dose
intensity and supportive care. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma.)
Toxicities that were observed only in or were noted to have occurred with greater severity in the
population with Kaposi’s sarcoma and that occurred with a difference that was clinically
significant in this population are described. Elevated liver function tests and renal toxicity have a
higher incidence in KS patients as compared to patients with solid tumors.
Hematologic: Bone marrow suppression was the major dose-limiting toxicity of TAXOL.
Neutropenia, the most important hematologic toxicity, was dose and schedule dependent and was
generally rapidly reversible. Among patients treated in the Phase 3 second-line ovarian study
with a 3-hour infusion, neutrophil counts declined below 500 cells/mm3 in 14% of the patients
treated with a dose of 135 mg/m2 compared to 27% at a dose of 175 mg/m2 (p=0.05). In the same
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study, severe neutropenia (<500 cells/mm3) was more frequent with the 24-hour than with the 3
hour infusion; infusion duration had a greater impact on myelosuppression than dose.
Neutropenia did not appear to increase with cumulative exposure and did not appear to be more
frequent nor more severe for patients previously treated with radiation therapy.
In the study where TAXOL was administered to patients with ovarian carcinoma at a dose of 135
mg/m2/24 hours in combination with cisplatin versus the control arm of cyclophosphamide plus
cisplatin, the incidences of grade IV neutropenia and of febrile neutropenia were significantly
greater in the TAXOL plus cisplatin arm than in the control arm. Grade IV neutropenia occurred
in 81% on the TAXOL plus cisplatin arm versus 58% on the cyclophosphamide plus cisplatin
arm, and febrile neutropenia occurred in 15% and 4% respectively. On the TAXOL/cisplatin
arm, there were 35/1074 (3%) courses with fever in which Grade IV neutropenia was reported at
some time during the course. When TAXOL followed by cisplatin was administered to patients
with advanced NSCLC in the ECOG study, the incidences of Grade IV neutropenia were 74%
(TAXOL 135 mg/m2/24 hours followed by cisplatin) and 65% (TAXOL 250 mg/m2/24 hours
followed by cisplatin and G-CSF) compared with 55% in patients who received
cisplatin/etoposide.
Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all
patients and 9% of all courses; these episodes were fatal in 1% of all patients, and included
sepsis, pneumonia and peritonitis. In the Phase 3 second-line ovarian study, infectious episodes
were reported in 20% and 26% of the patients treated with a dose of 135 mg/m2 or 175 mg/m2
given as 3-hour infusions, respectively. Urinary tract infections and upper respiratory tract
infections were the most frequently reported infectious complications. In the immunosuppressed
patient population with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma,
61% of the patients reported at least one opportunistic infection. (See CLINICAL STUDIES:
AIDS-Related Kaposi’s Sarcoma.) The use of supportive therapy, including G-CSF, is
recommended for patients who have experienced severe neutropenia. (See DOSAGE AND
ADMINISTRATION.)
Thrombocytopenia was reported. Twenty percent of the patients experienced a drop in their
platelet count below 100,000 cells/mm3 at least once while on treatment; 7% had a platelet count
<50,000 cells/mm3 at the time of their worst nadir. Bleeding episodes were reported in 4% of all
courses and by 14% of all patients, but most of the hemorrhagic episodes were localized and the
frequency of these events was unrelated to the TAXOL dose and schedule. In the Phase 3
second-line ovarian study, bleeding episodes were reported in 10% of the patients; no patients
treated with the 3-hour infusion received platelet transfusions. In the adjuvant breast carcinoma
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trial, the incidence of severe thrombocytopenia and platelet transfusions increased with higher
doses of doxorubicin.
Anemia (Hb <11 g/dL) was observed in 78% of all patients and was severe (Hb <8 g/dL) in 16%
of the cases. No consistent relationship between dose or schedule and the frequency of anemia
was observed. Among all patients with normal baseline hemoglobin, 69% became anemic on
study but only 7% had severe anemia. Red cell transfusions were required in 25% of all patients
and in 12% of those with normal baseline hemoglobin levels.
Hypersensitivity Reactions (HSRs): All patients received premedication prior to TAXOL (see
WARNINGS and PRECAUTIONS: Hypersensitivity Reactions). The frequency and severity
of HSRs were not affected by the dose or schedule of TAXOL administration. In the Phase 3
second-line ovarian study, the 3-hour infusion was not associated with a greater increase in
HSRs when compared to the 24-hour infusion. Hypersensitivity reactions were observed in 20%
of all courses and in 41% of all patients. These reactions were severe in less than 2% of the
patients and 1% of the courses. No severe reactions were observed after course 3 and severe
symptoms occurred generally within the first hour of TAXOL infusion. The most frequent
symptoms observed during these severe reactions were dyspnea, flushing, chest pain, and
tachycardia. Abdominal pain, pain in the extremities, diaphoresis, and hypertension were also
noted.
The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%),
hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). The frequency of
hypersensitivity reactions remained relatively stable during the entire treatment period.
Chills, shock, and back pain in association with hypersensitivity reactions have been reported.
Cardiovascular: Hypotension, during the first 3 hours of infusion, occurred in 12% of all
patients and 3% of all courses administered. Bradycardia, during the first 3 hours of infusion,
occurred in 3% of all patients and 1% of all courses. In the Phase 3 second-line ovarian study,
neither dose nor schedule had an effect on the frequency of hypotension and bradycardia. These
vital sign changes most often caused no symptoms and required neither specific therapy nor
treatment discontinuation. The frequency of hypotension and bradycardia were not influenced by
prior anthracycline therapy.
Significant cardiovascular events possibly related to single-agent TAXOL (paclitaxel) occurred
in approximately 1% of all patients. These events included syncope, rhythm abnormalities,
hypertension, and venous thrombosis. One of the patients with syncope treated with TAXOL at
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175 mg/m2 over 24 hours had progressive hypotension and died. The arrhythmias included
asymptomatic ventricular tachycardia, bigeminy, and complete AV block requiring pacemaker
placement. Among patients with NSCLC treated with TAXOL in combination with cisplatin in
the Phase 3 study, significant cardiovascular events occurred in 12 to 13%. This apparent
increase in cardiovascular events is possibly due to an increase in cardiovascular risk factors in
patients with lung cancer.
Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG
abnormalities on study did not usually result in symptoms, were not dose-limiting, and required
no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a
normal ECG prior to study entry, 14% of all patients developed an abnormal tracing while on
study. The most frequently reported ECG modifications were non-specific repolarization
abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. Among patients with
normal ECGs at baseline, prior therapy with anthracyclines did not influence the frequency of
ECG abnormalities.
Cases of myocardial infarction have been reported. Congestive heart failure, including cardiac
dysfunction and reduction of left ventricular ejection fraction or ventricular failure, has been
reported typically in patients who have received other chemotherapy, notably anthracyclines.
(See PRECAUTIONS: Drug Interactions.)
Atrial fibrillation and supraventricular tachycardia have been reported.
Respiratory: Interstitial pneumonia, lung fibrosis, and pulmonary embolism have been reported.
Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.
Pleural effusion and respiratory failure have been reported.
Neurologic: The assessment of neurologic toxicity was conducted differently among the studies
as evident from the data reported in each individual study (see TABLES 10–16). Moreover, the
frequency and severity of neurologic manifestations were influenced by prior and/or concomitant
therapy with neurotoxic agents.
In general, the frequency and severity of neurologic manifestations were dose-dependent in
patients receiving single-agent TAXOL. Peripheral neuropathy was observed in 60% of all
patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy.
The frequency of peripheral neuropathy increased with cumulative dose. Paresthesia commonly
occurs in the form of hyperesthesia. Neurologic symptoms were observed in 27% of the patients
after the first course of treatment and in 34 to 51% from course 2 to 10. Peripheral neuropathy
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was the cause of TAXOL discontinuation in 1% of all patients. Sensory symptoms have usually
improved or resolved within several months of TAXOL discontinuation. Pre-existing
neuropathies resulting from prior therapies are not a contraindication for TAXOL therapy.
In the Intergroup first-line ovarian carcinoma study (see TABLE 11), neurotoxicity included
reports of neuromotor and neurosensory events. The regimen with TAXOL 175 mg/m2 given by
3-hour infusion plus cisplatin 75 mg/m2 resulted in greater incidence and severity of
neurotoxicity than the regimen containing cyclophosphamide and cisplatin, 87% (21% severe)
versus 52% (2% severe), respectively. The duration of grade III or IV neurotoxicity cannot be
determined with precision for the Intergroup study since the resolution dates of adverse events
were not collected in the case report forms for this trial and complete follow-up documentation
was available only in a minority of these patients. In the GOG first-line ovarian carcinoma study,
neurotoxicity was reported as peripheral neuropathy. The regimen with TAXOL 135 mg/m2
given by 24-hour infusion plus cisplatin 75 mg/m2 resulted in an incidence of neurotoxicity that
was similar to the regimen containing cyclophosphamide plus cisplatin, 25% (3% severe) versus
20% (0% severe), respectively. Cross-study comparison of neurotoxicity in the Intergroup and
GOG trials suggests that when TAXOL is given in combination with cisplatin 75 mg/m2, the
incidence of severe neurotoxicity is more common at a TAXOL dose of 175 mg/m2 given by 3
hour infusion (21%) than at a dose of 135 mg/m2 given by 24-hour infusion (3%).
In patients with NSCLC, administration of TAXOL followed by cisplatin resulted in a greater
incidence of severe neurotoxicity compared to the incidence in patients with ovarian or breast
cancer treated with single-agent TAXOL. Severe neurosensory symptoms were noted in 13% of
NSCLC patients receiving TAXOL 135 mg/m2 by 24-hour infusion followed by cisplatin 75
mg/m2 and 8% of NSCLC patients receiving cisplatin/etoposide (see TABLE 15).
Other than peripheral neuropathy, serious neurologic events following TAXOL administration
have been rare (<1%) and have included grand mal seizures, syncope, ataxia, and
neuroencephalopathy.
Autonomic neuropathy resulting in paralytic ileus has been reported. Optic nerve and/or visual
disturbances (scintillating scotomata) have also been reported, particularly in patients who have
received higher doses than those recommended. These effects generally have been reversible.
However, reports in the literature of abnormal visual evoked potentials in patients have
suggested persistent optic nerve damage. Postmarketing reports of ototoxicity (hearing loss and
tinnitus) have also been received.
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Convulsions, dizziness, and headache have been reported.
Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of TAXOL
and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated
experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually
transient, occurred 2 or 3 days after TAXOL administration, and resolved within a few days. The
frequency and severity of musculoskeletal symptoms remained unchanged throughout the
treatment period.
Hepatic: No relationship was observed between liver function abnormalities and either dose or
schedule of TAXOL administration. Among patients with normal baseline liver function 7%,
22%, and 19% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively.
Prolonged exposure to TAXOL was not associated with cumulative hepatic toxicity.
Hepatic necrosis and hepatic encephalopathy leading to death have been reported.
Renal: Among the patients treated for Kaposi’s sarcoma with TAXOL, 5 patients had renal
toxicity of grade III or IV severity. One patient with suspected HIV nephropathy of grade IV
severity had to discontinue therapy. The other 4 patients had renal insufficiency with reversible
elevations of serum creatinine.
Patients with gyneocological cancers treated with TAXOL and cisplatin may have an increased
risk of renal failure with the combination therapy of paclitaxel and cisplatin in gynecological
cancers as compared to cisplatin alone.
Gastrointestinal (GI): Nausea/vomiting, diarrhea, and mucositis were reported by 52%, 38%,
and 31% of all patients, respectively. These manifestations were usually mild to moderate.
Mucositis was schedule dependent and occurred more frequently with the 24-hour than with the
3-hour infusion.
In patients with poor-risk AIDS-related Kaposi’s sarcoma, nausea/vomiting, diarrhea, and
mucositis were reported by 69%, 79%, and 28% of patients, respectively. One-third of patients
with Kaposi’s sarcoma complained of diarrhea prior to study start. (See CLINICAL STUDIES:
AIDS-Related Kaposi’s Sarcoma.)
In the first-line Phase 3 ovarian carcinoma studies, the incidence of nausea and vomiting when
TAXOL was administered in combination with cisplatin appeared to be greater compared with
the database for single-agent TAXOL in ovarian and breast carcinoma. In addition, diarrhea of
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any grade was reported more frequently compared to the control arm, but there was no difference
for severe diarrhea in these studies.
Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, dehydration,
esophagitis, constipation, and ascites have been reported. Neutropenic enterocolitis (typhlitis),
despite the coadministration of G-CSF, was observed in patients treated with TAXOL alone and
in combination with other chemotherapeutic agents.
Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation,
were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the
injection site. These reactions have been observed more frequently with the 24-hour infusion
than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation
following administration of TAXOL at a different site, ie, “recall,” has been reported.
More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis
have been reported. In some cases the onset of the injection site reaction either occurred during a
prolonged infusion or was delayed by a week to 10 days.
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of
extravasation, it is advisable to closely monitor the infusion site for possible infiltration during
drug administration.
Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. Transient
skin changes due to TAXOL-related hypersensitivity reactions have been observed, but no other
skin toxicities were significantly associated with TAXOL administration. Nail changes (changes
in pigmentation or discoloration of nail bed) were uncommon (2%). Edema was reported in 21%
of all patients (17% of those without baseline edema); only 1% had severe edema and none of
these patients required treatment discontinuation. Edema was most commonly focal and disease-
related. Edema was observed in 5% of all courses for patients with normal baseline and did not
increase with time on study.
Skin abnormalities related to radiation recall as well as maculopapular rash, pruritus, Stevens-
Johnson syndrome, and toxic epidermal necrolysis have been reported.
Reports of asthenia and malaise have been received as part of the continuing surveillance of
TAXOL safety. In the Phase 3 trial of TAXOL 135 mg/m2 over 24 hours in combination with
cisplatin as first-line therapy of ovarian cancer, asthenia was reported in 17% of the patients,
significantly
greater
than
the
10%
incidence
observed
in
the
control
arm
of
cyclophosphamide/cisplatin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 46
Conjunctivitis, increased lacrimation, anorexia, confusional state, photopsia, visual floaters,
vertigo, and increase in blood creatinine have been reported.
Accidental Exposure: Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and
nausea have been reported. Following topical exposure, events have included tingling, burning,
and redness.
OVERDOSAGE
There is no known antidote for TAXOL (paclitaxel) overdosage. The primary anticipated
complications of overdosage would consist of bone marrow suppression, peripheral
neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute
ethanol toxicity (see PRECAUTIONS: Pediatric Use).
DOSAGE AND ADMINISTRATION
Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to
prepare solutions for infusion is not recommended. In order to minimize patient exposure to the
plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or
sets, diluted TAXOL solutions should be stored in bottles (glass, polypropylene) or plastic bags
(polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
All patients should be premedicated prior to TAXOL administration in order to prevent severe
hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO
administered approximately 12 and 6 hours before TAXOL, diphenhydramine (or its equivalent)
50 mg IV 30 to 60 minutes prior to TAXOL, and cimetidine (300 mg) or ranitidine (50 mg) IV
30 to 60 minutes before TAXOL.
For patients with carcinoma of the ovary, the following regimens are recommended (see
CLINICAL STUDIES: Ovarian Carcinoma):
1) For previously untreated patients with carcinoma of the ovary, one of the following
recommended regimens may be given every 3 weeks. In selecting the appropriate regimen,
differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS:
Disease-Specific Adverse Event Experiences).
a. TAXOL administered intravenously over 3 hours at a dose of 175 mg/m2 followed by
cisplatin at a dose of 75 mg/m2; or
b. TAXOL administered intravenously over 24 hours at a dose of 135 mg/m2 followed by
cisplatin at a dose of 75 mg/m2.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 47
2) In patients previously treated with chemotherapy for carcinoma of the ovary, TAXOL has
been used at several doses and schedules; however, the optimal regimen is not yet clear. The
recommended regimen is TAXOL 135 mg/m2 or 175 mg/m2 administered intravenously over
3 hours every 3 weeks.
For patients with carcinoma of the breast, the following regimens are recommended (see
CLINICAL STUDIES: Breast Carcinoma):
1) For the adjuvant treatment of node-positive breast cancer, the recommended regimen is
TAXOL, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses
administered sequentially to doxorubicin-containing combination chemotherapy. The clinical
trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES:
Breast Carcinoma).
2) After failure of initial chemotherapy for metastatic disease or relapse within 6 months of
adjuvant chemotherapy, TAXOL at a dose of 175 mg/m2 administered intravenously over 3
hours every 3 weeks has been shown to be effective.
For patients with non-small cell lung carcinoma, the recommended regimen, given every 3
weeks, is TAXOL administered intravenously over 24 hours at a dose of 135 mg/m2 followed by
cisplatin, 75 mg/m2.
For patients with AIDS-related Kaposi’s sarcoma, TAXOL administered at a dose of 135
mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given
intravenously over 3 hours every 2 weeks is recommended (dose intensity 45–50 mg/m2/week).
In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related
Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the
latter. In addition, all patients with low performance status were treated with the latter schedule
(100 mg/m2 every 2 weeks).
Based upon the immunosuppression in patients with advanced HIV disease, the following
modifications are recommended in these patients:
1) Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of
20 mg PO);
2) Initiate or repeat treatment with TAXOL only if the neutrophil count is at least 1000
cells/mm3;
3) Reduce the dose of subsequent courses of TAXOL by 20% for patients who experience
severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 48
4) Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.
For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of TAXOL
should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count
is at least 100,000 cells/mm3. TAXOL should not be given to patients with AIDS-related
Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3.
Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or
severe peripheral neuropathy during TAXOL therapy should have dosage reduced by 20% for
subsequent courses of TAXOL. The incidence of neurotoxicity and the severity of neutropenia
increase with dose.
Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity,
particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and
PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of
therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in
subsequent courses should be based on individual tolerance. Patients should be monitored
closely for the development of profound myelosuppression.
TABLE 17
RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT
BASED ON CLINICAL TRIAL DATAa
Degree of Hepatic Impairment
Transaminase Levels
Bilirubin Levelsb
Recommended TAXOL Dosec
24-hour infusion
<2 × ULN
and
≤1.5 mg/dL
135 mg/m2
2 to <10 × ULN
and
≤1.5 mg/dL
100 mg/m2
<10 × ULN
and
1.6–7.5 mg/dL
50 mg/m2
≥10 × ULN
or
>7.5 mg/dL
Not recommended
3-hour infusion
<10 × ULN
and
≤1.25 × ULN
175 mg/m2
<10 × ULN
and
1.26–2.0 × ULN
135 mg/m2
<10 × ULN
and
2.01–5.0 × ULN
90 mg/m2
≥10 × ULN
or
>5.0 × ULN
Not recommended
a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24
hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other
regimens (eg, for AIDS-related Kaposi’s sarcoma).
b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical
trial design.
Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should
be based on individual tolerance.
c
This label may not be the latest approved by FDA.
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NDA 020262/S-048
Page 49
Preparation and Administration Precautions
Procedures for proper handling and disposal of anticancer drugs should be considered. Several
guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure,
always wear impervious gloves when handling vials containing TAXOL Injection. If TAXOL
solution contacts the skin, wash the skin immediately and thoroughly with soap and water.
Following topical exposure, events have included tingling, burning, and redness. If TAXOL
contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon
inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for
possible infiltration during drug administration (see PRECAUTIONS: Injection Site
Reaction).
Preparation for Intravenous Administration
TAXOL (paclitaxel) Injection must be diluted prior to infusion. TAXOL should be diluted in
0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9%
Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of
0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at
ambient temperature (approximately 25° C) and room lighting conditions. Parenteral drug
products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle.
No significant losses in potency have been noted following simulated delivery of the solution
through IV tubing containing an in-line (0.22 micron) filter.
Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate]
show that levels increase with time and concentration when dilutions are prepared in PVC
containers. Consequently, the use of plasticized PVC containers and administration sets is not
recommended. TAXOL solutions should be prepared and stored in glass, polypropylene, or
polyolefin containers. Non-PVC containing administration sets, such as those which are
polyethylene-lined, should be used.
TAXOL should be administered through an in-line filter with a microporous membrane not
greater than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short
inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 50
The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials
of TAXOL since they can cause the stopper to collapse resulting in loss of sterile integrity of the
TAXOL solution.
Stability
Unopened vials of TAXOL (paclitaxel) Injection are stable until the date indicated on the
package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing
nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in
the TAXOL vial may precipitate, but will redissolve upon reaching room temperature with little
or no agitation. There is no impact on product quality under these circumstances. If the solution
remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for
infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and
lighting conditions for up to 27 hours.
HOW SUPPLIED
NDC 0015-3475-30
30 mg/5 mL multidose vial individually packaged in a carton.
NDC 0015-3476-30
100 mg/16.7 mL multidose vial individually packaged in a carton.
NDC 0015-3479-11
300 mg/50 mL multidose vial individually packaged in a carton.
Storage
Store the vials in original cartons between 20°–25° C (68°–77° F). Retain in the original package
to protect from light.
Handling and Disposal
See DOSAGE AND ADMINISTRATION: Preparation and Administration Precautions.
REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs
in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health
Service, Centers for Disease Control and Prevention, National Institute for Occupational
Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
Chemo Dispensing Pin™ is a trademark of B. Braun Medical Incorporated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 51
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational
exposure to hazardous drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous
drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines
and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Rev August 2010
Patient Information
TAXOL® (TAX all)
(paclitaxel)
Injection
Read this patient information leaflet before you start taking TAXOL. There may be new
information. This information does not take the place of talking to your healthcare provider
about your medical condition or your treatment.
What is the most important information I should know about TAXOL?
TAXOL can cause serious side effects including death.
Serious allergic reactions (anaphylaxis) can happen in people who receive TAXOL. Anaphylaxis
is a serious medical emergency that can lead to death and must be treated right away.
Tell your healthcare provider right away if you have any of these signs of an allergic reaction:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 52
• trouble breathing
• sudden swelling of your face, lips, tongue, throat, or trouble swallowing
• hives (raised bumps) or rash
Your healthcare provider will give you medicines to lessen your chance of having an allergic
reaction.
What is TAXOL?
TAXOL is a prescription medicine used to treat some forms of:
• ovarian cancer
• breast cancer
• lung cancer
• Kaposi’s sarcoma
It is not known if TAXOL is safe or effective in children.
Who should not receive TAXOL?
Do not receive TAXOL if:
• you are allergic to any of the ingredients in TAXOL. See the end of this leaflet for a
complete list of ingredients in TAXOL.
• are allergic to medicines containing Cremophor® EL* (polyoxyethylated castor oil).
• you have low white blood cell counts.
What should I tell my healthcare provider before receiving TAXOL?
Before receiving TAXOL, tell your healthcare provider about all your medical conditions,
including if you:
• have liver problems
• have heart problems
• are pregnant or plan to become pregnant. TAXOL can harm your unborn baby. Talk to your
healthcare provider if you are pregnant or plan to become pregnant.
• are breast-feeding or plan to breast-feed. It is not known if TAXOL passes into your breast
milk. You and your healthcare provider should decide if you will receive TAXOL or breast-
feed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 53
Tell your healthcare provider about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist when you get a new medicine.
How will I receive TAXOL?
• TAXOL is injected into a vein (intravenous [IV] infusion) by your healthcare provider.
Your healthcare provider will do certain tests while you receive TAXOL.
What are the possible side effects of TAXOL?
Tell your healthcare provider right away if you have:
• severe stomach pain
• severe diarrhea
The most common side effects of TAXOL include:
• low red blood cell count (anemia) feeling weak or tired
• hair loss
• numbness, tingling, or burning in your hands or feet (neuropathy)
• joint and muscle pain
• nausea and vomiting
• hypersensitivity reaction - trouble breathing; sudden swelling of your face, lips, tongue,
throat, or trouble swallowing; hives (raised bumps) or rash
• diarrhea
• mouth or lip sores (mucositis)
• infections - if you have a fever (temperature above 100.4°F) or other sign of infection, tell
your healthcare provider right away
• swelling of your hands, face, or feet
• bleeding events
• irritation at the injection site
• low blood pressure (hypotension)
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 54
These are not all the possible side effects of TAXOL. 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 TAXOL.
Medicines are sometimes prescribed for purposes other than those listed in a patient information
leaflet. Do not use TAXOL for a condition for which it was not prescribed. Do not give TAXOL
to other people, even if they have the same symptoms that you have. It may harm them.
This patient information leaflet summarizes the most important information about TAXOL. If
you would like more information, talk with your healthcare provider. You can ask your
pharmacist or healthcare provider for information about TAXOL that is written for health
professionals. For more information call 1-800-321-1335 or go to www.bms.com.
What are the ingredients in TAXOL?
Active ingredient: paclitaxel.
Inactive ingredients include: purified Cremophor® EL (polyoxyethylated castor oil) and
dehydrated alcohol, USP.
What is cancer?
Under normal conditions, the cells in your body divide and grow in an orderly, controlled way.
Cell division and growth are necessary for the human body to perform its functions and to repair
itself, when necessary. Cancer cells are different from normal cells because they are not able to
control their own growth. The reasons for this abnormal growth are not yet fully understood.
A tumor is a mass of unhealthy cells that are dividing and growing fast and in an uncontrolled
way. When a tumor invades surrounding healthy body tissue, it is known as a malignant tumor.
A malignant tumor can spread (metastasize) from its original site to other parts of the body if not
found and treated early.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020262/S-048
Page 55
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
*Cremophor® EL is the registered trademark of BASF Aktiengesellschaft.
Cremophor® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.
Rev August 2010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf', 'application_number': 20262, 'submission_type': 'SUPPL ', 'submission_number': 48}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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.
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|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20588s05lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 9}
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1
JANSSEN
PHARMACEUTICA
PRODUCTS, L.P.
RISPERDAL®
(RISPERIDONE)
TABLETS/ORAL SOLUTION
RISPERDAL® M-TAB™
(RISPERIDONE)
ORALLY DISINTEGRATING TABLETS
DESCRIPTION
RISPERDAL® (risperidone) is a psychotropic agent belonging to the chemical class of
benzisoxazole
derivatives.
The
chemical
designation
is
3-[2-[4-(6-fluoro-
1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-
pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular
weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely
soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg
(white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. Inactive ingredients are
colloidal silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline
cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn). Tablets of 0.25, 0.5,
2, 3, and 4 mg also contain talc and titanium dioxide. The 0.25 mg tablets contain yellow
iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg tablets contain FD&C
Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C Yellow No. 10; the
4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
RISPERDAL® is also available as a 1 mg/mL oral solution. The inactive ingredients for
this solution are tartaric acid, benzoic acid, sodium hydroxide, and purified water.
RISPERDAL® M-TAB™ Orally Disintegrating Tablets are available in 0.5 mg, 1.0 mg,
and 2.0 mg strengths and are light coral in color.
RISPERDAL® M-TAB™ Orally Disintegrating Tablets contain the following inactive
ingredients: Amberlite® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium
hydroxide, aspartame, red ferric oxide, and peppermint oil.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of RISPERDAL (risperidone), as with other drugs used to treat
schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic
activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and
serotonin Type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and
5HT2 may explain some of the other effects of RISPERDAL.
RISPERDAL is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to
7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and
H1 histaminergic receptors. RISPERDAL acts as an antagonist at other receptors, but with
lower potency. RISPERDAL has low to moderate affinity (Ki of 47 to 253 nM) for the
serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the
dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at
concentrations >10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70%
(CV=25%). The relative oral bioavailability of risperidone from a tablet is 94%
(CV=10%) when compared to a solution.
Pharmacokinetic studies showed that RISPERDAL M-TAB™ Orally Disintegrating
Tablets are bioequivalent to RISPERDAL Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to
16 mg daily (0.5 to 8 mg BID). Following oral administration of solution or tablet, mean
peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in
poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in
extensive metabolizers and would be expected to reach steady state in about 5 days in poor
metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days
(measured in extensive metabolizers).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus,
risperidone can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma,
risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of
risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%.
Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding
sites. High therapeutic concentrations of sulfamethazine (100 µg/mL), warfarin (10 µg/mL),
and carbamazepine (10 µg/mL) caused only a slight increase in the free fraction of
risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown
clinical significance.
Metabolism
Risperidone is extensively metabolized in the liver. The main metabolic pathway is
through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A
minor metabolic pathway is through N-dealkylation. The main metabolite,
9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently,
the clinical effect of the drug (i.e., the active moiety) results from the combined
concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism
of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is
subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage
of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a
variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6
metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP
2D6 metabolizers convert it much more slowly. Although extensive metabolizers have
lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers,
the pharmacokinetics of the active moiety, after single and multiple doses, are similar in
extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions (see Drug Interactions
under PRECAUTIONS). First, inhibitors of CYP 2D6 interfere with conversion of
risperidone to 9-hydroxyrisperidone. This occurs with quinidine, giving essentially all
recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The
therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have
not been evaluated, but observations in a modest number (n≅70) of poor metabolizers
given risperidone do not suggest important differences between poor and extensive
metabolizers. Second, co-administration of known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with risperidone may cause a decrease in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone. It would also be possible
for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6.
Relatively weak binding of risperidone to the enzyme suggests this is unlikely.
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In a drug interaction study in schizophrenic patients, 11 subjects received risperidone
titrated to 6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine
for an additional 3 weeks. During co-administration, the plasma concentrations of
risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone, were
decreased by about 50%. Plasma concentrations of carbamazepine did not appear to be
affected. Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and
phenobarbital) with risperidone may cause similar decreases in the combined plasma
concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of risperidone treatment.
Fluoxetine (20 mg QD) has been shown to increase the plasma concentration of risperidone
2.5-2.8 fold, while the plasma concentration of 9-hydroxyrisperidone was not affected.
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak
plasma concentrations (Cmax) of lithium (n=13).
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided
doses) compared to placebo (n=21). However, there was a 20% increase in valproate
peak plasma concentration (Cmax) after concomitant administration of risperidone.
There were no significant interactions between risperidone (1 mg QD) and erythromycin
(500 mg QID) (see Drug Interactions under PRECAUTIONS).
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent,
via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of
14C-risperidone administered as solution to three healthy male volunteers, total recovery of
radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone
was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of the active moiety, after single and multiple doses,
were similar in extensive and poor metabolizers, with an overall mean elimination half-life
of about 20 hours.
Special Populations
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and
its active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL®
doses should be reduced in patients with renal disease (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).
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Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable
to those in young healthy subjects, the mean free fraction of risperidone in plasma was
increased by about 35% because of the diminished concentration of both albumin and
α1-acid glycoprotein. RISPERDAL® doses should be reduced in patients with liver
disease (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Elderly
In healthy elderly subjects renal clearance of both risperidone and 9-hydroxyrisperidone
was decreased, and elimination half-lives were prolonged compared to young healthy
subjects. Dosing should be modified accordingly in the elderly patients (see DOSAGE
AND ADMINISTRATION).
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects,
but a population pharmacokinetic analysis did not identify important differences in the
disposition of risperidone due to gender (whether corrected for body weight or not) or
race.
Clinical Trials
Schizophrenia
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four
short-term (4 to 8-week) controlled trials of psychotic inpatients who met DSM-III-R
criteria for schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these
studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of
general psychopathology traditionally used to evaluate the effects of drug treatment in
schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory
behavior, suspiciousness, and unusual thought content) is considered a particularly useful
subset for assessing actively psychotic schizophrenic patients. A second traditional
assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled
observer, fully familiar with the manifestations of schizophrenia, about the overall clinical
state of the patient. In addition, two more recently developed, but less well evaluated
scales, were employed; these included the Positive and Negative Syndrome Scale
(PANSS) and the Scale for Assessing Negative Symptoms (SANS).
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in
doses up to 10 mg/day (BID schedule), RISPERDAL® was generally superior to placebo
on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to
placebo on the SANS.
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(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of
RISPERDAL® (2, 6, 10, and 16 mg/day, on a BID schedule), all 4 RISPERDAL® groups
were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and
CGI severity score; the 3 highest RISPERDAL® dose groups were generally superior to
placebo on the PANSS negative subscale. The most consistently positive responses on all
measures were seen for the 6 mg dose group, and there was no suggestion of increased
benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of
RISPERDAL® (1, 4, 8, 12, and 16 mg/day, on a BID schedule), the four highest
RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL® dose group
on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose
groups were superior to the 1 mg group on the PANSS negative subscale. The most
consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed
doses of RISPERDAL® (4 and 8 mg/day on a QD schedule), both RISPERDAL® dose
groups were generally superior to placebo on several PANSS measures, including a
response measure (>20% reduction in PANSS total score), PANSS total score, and the
BPRS psychosis cluster (derived from PANSS). The results were generally stronger for
the 8 mg than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator,
for 1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
significantly longer time to relapse over this time period compared to those receiving the
active comparator.
Bipolar Mania
Monotherapy — The efficacy of Risperdal in the treatment of acute manic or mixed
episodes was established in 2 short-term (3-week) placebo-controlled trials in patients
who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These
trials included patients with or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the
Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to
assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior,
sleep, elevated mood, speech, increased activity, sexual interest, language/thought
disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to
60 (maximum score). The primary outcome in these trials was change from baseline in the
Y-MRS total score. The results of the trials follow:
• In one 3-week placebo-controlled trial (n=246), limited to patients with manic
episodes, which involved a dose range of Risperdal 1-6 mg/day, once daily, starting at
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3 mg/day (mean modal dose was 4.1 mg/day), Risperdal was superior to placebo in
the reduction of Y-MRS total score.
• In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1-
6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
Risperdal was superior to placebo in the reduction of Y-MRS total score.
Combination Therapy — The efficacy of risperidone with concomitant lithium or valproate
in the treatment of acute manic or mixed episodes was established in one controlled trial in
patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients
with or without psychotic features and with or without a rapid-cycling course.
• In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium
or valproate therapy with inadequately controlled manic or mixed symptoms were
randomized to receive Risperdal, placebo, or an active comparator, in combination
with their original therapy. Risperdal, in a dose range of 1-6 mg/day, once daily,
starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or
valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 µg/mL to
125 µg/mL, respectively) was superior to lithium or valproate alone in the reduction of
Y-MRS total score.
• In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on
lithium, valproate, or carbamazepine therapy with inadequately controlled manic or
mixed symptoms were randomized to receive Risperdal or placebo, in combination
with their original therapy. Risperdal, in a dose range of 1-6 mg/day, once daily,
starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium,
valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for
lithium, 50 µg/mL to 125 µg/mL for valproate, or 4-12 µg/mL for carbamazepine,
respectively) was not superior to lithium, valproate, or carbamazepine alone in the
reduction of Y-MRS total score. A possible explanation for the failure of this trial was
induction of risperidone and 9-hydroxy risperidone clearance by carbamazepine,
leading to subtherapeutic levels of risperidone and 9-hydroxy risperidone.
INDICATIONS AND USAGE
Schizophrenia
RISPERDAL (risperidone) is indicated for the treatment of schizophrenia.
The efficacy of RISPERDAL® in schizophrenia was established in short-term (6 to
8 weeks) controlled trials of schizophrenic inpatients (see CLINICAL
PHARMACOLOGY).
The efficacy of RISPERDAL® in delaying relapse was demonstrated in schizophrenic
patients who had been clinically stable for at least 4 weeks before initiation of treatment
with RISPERDAL® or an active comparator and who were then observed for relapse
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during a period of 1 to 2 years (see Clinical Trials, under CLINICAL
PHARMACOLOGY). Nevertheless, the physician who elects to use RISPERDAL® for
extended periods should periodically re-evaluate the long-term usefulness of the drug for
the individual patient (see DOSAGE AND ADMINISTRATION).
Bipolar Mania
Monotherapy — RISPERDAL® is indicated for the short-term treatment of acute manic or
mixed episodes associated with Bipolar I Disorder.
The efficacy of RISPERDAL® was established in two placebo-controlled trials (3-week)
with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an
acute manic or mixed episode with or without psychotic features (see CLINICAL
PHARMACOLOGY).
Combination Therapy — The combination of RISPERDAL® with lithium or valproate is
indicated for the short-term treatment of acute manic or mixed episodes associated with
Bipolar I Disorder.
The efficacy of RISPERDAL® in combination with lithium or valproate was established in
one placebo-controlled (3-week) trial with patients meeting DSM-IV criteria for Bipolar I
Disorder who currently displayed an acute manic or mixed episode with or without
psychotic features (see CLINICAL PHARMACOLOGY).
The effectiveness of RISPERDAL® for longer-term use, that is, for more than 3 weeks of
treatment of an acute episode, and for prophylactic use in mania, has not been
systematically evaluated in controlled clinical trials. Therefore, physicians who elect to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks
and benefits of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
CONTRAINDICATIONS
RISPERDAL® (risperidone) is contraindicated in patients with a known hypersensitivity to
the product.
WARNINGS
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and
evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,
diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine
phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both
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serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or
inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic
drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic
treatment and medical monitoring; and (3) treatment of any concomitant serious medical
problems for which specific treatments are available. There is no general agreement about
specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be
carefully monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears
to be highest among the elderly, especially elderly women, it is impossible to rely upon
prevalence estimates to predict, at the inception of antipsychotic treatment, which patients
are likely to develop the syndrome. Whether antipsychotic drug products differ in their
potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total cumulative
dose of antipsychotic drugs administered to the patient increase. However, the syndrome
can develop, although much less commonly, after relatively brief treatment periods at low
doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and
symptoms of the syndrome and thereby may possibly mask the underlying process. The
effect that symptomatic suppression has upon the long-term course of the syndrome is
unknown.
Given these considerations, RISPERDAL® (risperidone) should be prescribed in a manner
that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness that
(1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally
effective, but potentially less harmful treatments are not available or appropriate. In
patients who do require chronic treatment, the smallest dose and the shortest duration of
treatment producing a satisfactory clinical response should be sought. The need for
continued treatment should be reassessed periodically.
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If signs and symptoms of tardive dyskinesia appear in a patient treated on RISPERDAL®,
drug discontinuation should be considered. However, some patients may require treatment
with RISPERDAL® despite the presence of the syndrome.
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients With
Dementia
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including
fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of
risperidone in elderly patients with dementia-related psychosis. In placebo-controlled
trials, there was a significantly higher incidence of cerebrovascular adverse events in
patients treated with risperidone compared to patients treated with placebo. RISPERDAL®
is not approved for the treatment of patients with dementia-related psychosis.
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar
coma or death, has been reported in patients treated with atypical antipsychotics including
RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes
mellitus in the general population. Given these confounders, the relationship between
atypical antipsychotic use and hyperglycemia-related adverse events is not completely
understood. However, epidemiological studies suggest an increased risk of treatment-
emergent hyperglycemia-related adverse events in patients treated with the atypical
antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients
treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients
with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are
starting treatment with atypical antipsychotics should undergo fasting blood glucose testing
at the beginning of treatment and periodically during treatment. Any patient treated with
atypical antipsychotics should be monitored for symptoms of hyperglycemia including
polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of
hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood
glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic
was discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of the suspect drug.
PRECAUTIONS
General
Orthostatic Hypotension
RISPERDAL® (risperidone) may induce orthostatic hypotension associated with dizziness,
tachycardia, and in some patients, syncope, especially during the initial dose-titration
period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was
reported in 0.2% (6/2607) of RISPERDAL®-treated patients in Phase 2-3 studies. The risk
of orthostatic hypotension and syncope may be minimized by limiting the initial dose to
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2 mg total (either QD or 1 mg BID) in normal adults and 0.5 mg BID in the elderly and
patients with renal or hepatic impairment (see DOSAGE AND ADMINISTRATION).
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL®
should be used with particular caution in patients with known cardiovascular disease
(history of myocardial infarction or ischemia, heart failure, or conduction abnormalities),
cerebrovascular disease, and conditions which would predispose patients to hypotension,
e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed
with concomitant use of RISPERDAL® and antihypertensive medication.
Seizures
During premarketing testing, seizures occurred in 0.3% (9/2607) of RISPERDAL®-treated
patients, two in association with hyponatremia. RISPERDAL® should be used cautiously in
patients with a history of seizures.
Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with
advanced Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be
used cautiously in patients at risk for aspiration pneumonia.
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin
levels and the elevation persists during chronic administration. Tissue culture experiments
indicate that approximately one-third of human breast cancers are prolactin dependent in
vitro, a factor of potential importance if the prescription of these drugs is contemplated in a
patient with previously detected breast cancer. Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating
compounds, the clinical significance of elevated serum prolactin levels is unknown for
most patients. As is common with compounds which increase prolactin release, an increase
in pituitary gland, mammary gland, and pancreatic islet cell hyperplasia and/or neoplasia
was observed in the risperidone carcinogenicity studies conducted in mice and rats (see
CARCINOGENESIS). However, neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class
of drugs and tumorigenesis in humans; the available evidence is considered too limited to
be conclusive at this time.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL®
treatment, especially when ascertained by direct questioning of patients. This adverse
event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of
the high dose patients (RISPERDAL® 16 mg/day) reported somnolence compared to 16%
of placebo patients. Direct questioning is more sensitive for detecting adverse events than
spontaneous reporting, by which 8% of RISPERDAL® 16 mg/day patients and 1% of
placebo patients reported somnolence as an adverse event. Since RISPERDAL® has the
potential to impair judgment, thinking, or motor skills, patients should be cautioned about
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operating hazardous machinery, including automobiles, until they are reasonably certain
that RISPERDAL® therapy does not affect them adversely.
Priapism
Rare cases of priapism have been reported. While the relationship of the events to
RISPERDAL® use has not been established, other drugs with alpha-adrenergic blocking
effects have been reported to induce priapism, and it is possible that RISPERDAL® may
share this capacity. Severe priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving
RISPERDAL® in a large, open premarketing experience (approximately 1300 patients).
She experienced jaundice, fever, and bruising, but eventually recovered after receiving
plasmapheresis. The relationship to RISPERDAL® therapy is unknown.
Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and
may mask signs and symptoms of overdosage with certain drugs or of conditions such as
intestinal obstruction, Reye’s syndrome, and brain tumor.
Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL
use. Caution is advised when prescribing for patients who will be exposed to temperature
extremes.
Suicide
The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of
high-risk patients should accompany drug therapy. Prescriptions for RISPERDAL® should
be written for the smallest quantity of tablets, consistent with good patient management, in
order to reduce the risk of overdose.
Use in Patients With Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic
illnesses is limited. Caution is advisable in using RISPERDAL® in patients with diseases
or conditions that could affect metabolism or hemodynamic responses.
RISPERDAL® has not been evaluated or used to any appreciable extent in patients with a
recent history of myocardial infarction or unstable heart disease. Patients with these
diagnoses were excluded from clinical studies during the product's premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients
with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase
in the free fraction of risperidone is seen in patients with severe hepatic impairment. A
lower starting dose should be used in such patients (see DOSAGE AND
ADMINISTRATION).
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Information for Patients
Physicians are advised to discuss the following issues with patients for whom they
prescribe RISPERDAL®:
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the
period of initial dose titration.
Interference With Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they
are reasonably certain that RISPERDAL® therapy does not affect them adversely.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL®.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL®.
Phenylketonurics
Phenylalanine is a component of aspartame. Each 2 mg RISPERDAL M-TAB™ Orally
Disintegrating Tablet contains 0.56 mg phenylalanine; each 1 mg RISPERDAL M-TAB™
Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL M-TAB™ Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Laboratory Tests
No specific laboratory tests are recommended.
Drug Interactions
The interactions of RISPERDAL® and other drugs have not been systematically evaluated.
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL®
is taken in combination with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, RISPERDAL® may enhance the
hypotensive effects of other therapeutic agents with this potential.
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
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Chronic administration of clozapine with risperidone may decrease the clearance of
risperidone.
Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone
titrated to 6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine
for an additional 3 weeks. During co-administration, the plasma concentrations of
risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone, were
decreased by about 50%. Plasma concentrations of carbamazepine did not appear to be
affected. The dose of risperidone may need to be titrated accordingly for patients receiving
carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy.
Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and
phenobarbital) with risperidone may cause similar decreases in the combined plasma
concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of risperidone treatment.
Fluoxetine
Fluoxetine (20 mg QD) has been shown to increase the plasma concentration of risperidone
2.5-2.8 fold, while the plasma concentration of 9-hydroxyrisperidone was not affected.
When concomitant fluoxetine is initiated or discontinued, the physician should re-evaluate
the dosing of RISPERDAL. The effects of discontinuation of concomitant fluoxetine
therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been
studied.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak
plasma concentrations (Cmax) of lithium (n=13).
Valproate
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided
doses) compared to placebo (n=21). However, there was a 20% increase in valproate
peak plasma concentration (Cmax) after concomitant administration of risperidone.
Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and
other drugs (see CLINICAL PHARMACOLOGY). Drug interactions that reduce the
metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma
concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone.
Analysis of clinical studies involving a modest number of poor metabolizers (n≅70) does
not suggest that poor and extensive metabolizers have different rates of adverse effects. No
comparison of effectiveness in the two groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1,
1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
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There were no significant interactions between risperidone and erythromycin (see
CLINICAL PHARMACOLOGY).
Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6.
Therefore, RISPERDAL® is not expected to substantially inhibit the clearance of drugs that
are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not
significantly affect the pharmacokinetics of donepezil and galantamine, which are
metabolized by CYP2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone
was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and
for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times
the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. A maximum
tolerated dose was not achieved in male mice. There were statistically significant
increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland
adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents.
Serum prolactin levels were not measured during the risperidone carcinogenicity studies;
however, measurements during subchronic toxicity studies showed that risperidone
elevated serum prolactin levels 5 to 6 fold in mice and rats at the same doses used in the
carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas
neoplasms has been found in rodents after chronic administration of other antipsychotic
drugs and is considered to be prolactin-mediated. The relevance for human risk of the
findings of prolactin-mediated endocrine tumors in rodents is unknown (see
Hyperprolactinemia under PRECAUTIONS, GENERAL).
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Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse
mutation test, mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo
micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the
chromosomal aberration test in human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats
in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to
3 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect
appeared to be in females, since impaired mating behavior was not noted in the Segment I
study in which males only were treated. In a subchronic study in Beagle dogs in which
risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration
were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 basis. Dose-related
decreases were also noted in serum testosterone at the same doses. Serum testosterone and
sperm parameters partially recovered, but remained decreased after treatment was
discontinued. No no-effect doses were noted in either rat or dog.
Pregnancy
Pregnancy Category C
The teratogenic potential of risperidone was studied in three Segment II studies in
Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum
recommended human dose [MRHD] on a mg/m2 basis) and in one Segment II study in New
Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The
incidence of malformations was not increased compared to control in offspring of rats or
rabbits given 0.4 to 6 times the MRHD on a mg/m2 basis. In three reproductive studies in
rats (two Segment III and a multigenerational study), there was an increase in pup deaths
during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on
a mg/m2 basis. It is not known whether these deaths were due to a direct effect on the
fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there
was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a
mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as
evidenced by a decrease in the number of live pups and an increase in the number of dead
pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were
observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated
dams, regardless of whether or not the pups were cross-fostered. Risperidone also
appeared to impair maternal behavior in that pup body weight gain and survival (from Day
1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams.
These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times
the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and
well-controlled studies in pregnant women. However, there was one report of a case of
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agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal
relationship to RISPERDAL® therapy is unknown.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone
and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women
receiving risperidone should not breast-feed.
Pediatric Use
Safety and effectiveness in children have not been established.
Geriatric Use
Clinical studies of RISPERDAL® did not include sufficient numbers of patients aged
65 and over to determine whether or not they respond differently than younger patients.
Other reported clinical experience has not identified differences in responses between
elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as
a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy (see CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION). While elderly patients exhibit a greater tendency to orthostatic
hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg
BID followed by careful titration (see PRECAUTIONS). Monitoring of orthostatic vital
signs should be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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
The following findings are based on the short-term, placebo-controlled, North American,
premarketing trials for schizophrenia and acute bipolar mania. In patients with Bipolar I
disorder, treatment-emergent adverse events are presented separately for risperidone as
monotherapy and as adjunctive therapy to mood stabilizers.
Certain portions of the discussion below relating to objective or numeric safety
parameters, namely, dose-dependent adverse events, vital sign changes, weight gain,
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laboratory changes, and ECG changes are derived from studies in patients with
schizophrenia. However, this information is also generally applicable to bipolar mania.
Associated With Discontinuation of Treatment
Schizophrenia: Approximately 9% (244/2607) of RISPERDAL® (risperidone)-treated
patients in Phase 2-3 studies discontinued treatment due to an adverse event, compared
with about 7% on placebo and 10% on active control drugs. The more common events
(≥0.3%) associated with discontinuation and considered to be possibly or probably drug-
related included:
Adverse Event
RISPERDAL®
Placebo
Extrapyramidal symptoms
2.1%
0%
Dizziness
0.7%
0%
Hyperkinesia
0.6%
0%
Somnolence
0.5%
0%
Nausea
0.3%
0%
Suicide attempt was associated with discontinuation in 1.2% of RISPERDAL®-treated
patients compared to 0.6% of placebo patients, but, given the almost 40-fold greater
exposure time in RISPERDAL® compared to placebo patients, it is unlikely that suicide
attempt is a RISPERDAL® related adverse event (see PRECAUTIONS). Discontinuation
for extrapyramidal symptoms was 0% in placebo patients, but 3.8% in active-control
patients in the Phase 2-3 trials.
Bipolar Mania: In the US placebo-controlled trial with risperidone as monotherapy,
approximately 8% (10/134) of RISPERDAL-treated patients discontinued treatment due
to an adverse event, compared with approximately 6% (7/125) of placebo-treated patients.
The adverse events associated with discontinuation and considered to be possibly,
probably, or very likely drug-related included: paroniria, somnolence, dizziness,
extrapyramidal disorder, and muscle contractions involuntary. Each of these events
occurred in one RISPERDAL-treated patient (0.7%) and in no placebo-treated patients
(0%).
In the US placebo-controlled trial with risperidone as adjunctive therapy to mood
stabilizers, there was no overall difference in the incidence of discontinuation due to
adverse events (4% for RISPERDAL vs 4% for placebo).
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Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
Schizophrenia: In two 6 to 8-week placebo-controlled trials, spontaneously-reported,
treatment-emergent adverse events with an incidence of 5% or greater in at least one of the
RISPERDAL® groups and at least twice that of placebo were: anxiety, somnolence,
extrapyramidal symptoms, dizziness, constipation, nausea, dyspepsia, rhinitis, rash, and
tachycardia.
Adverse events were also elicited in one of these two trials (i.e., in the fixed-dose trial
comparing RISPERDAL® at doses of 2, 6, 10, and 16 mg/day with placebo) utilizing a
checklist for detecting adverse events, a method that is more sensitive than spontaneous
reporting. By this method, the following additional common and drug-related adverse
events occurred at an incidence of at least 5% and twice the rate of placebo: increased
dream activity, increased duration of sleep, accommodation disturbances, reduced
salivation, micturition disturbances, diarrhea, weight gain, menorrhagia, diminished sexual
desire, erectile dysfunction, ejaculatory dysfunction, and orgastic dysfunction.
Bipolar Mania: In the US placebo-controlled trial with risperidone as monotherapy, the
most commonly observed adverse events associated with the use of RISPERDAL
(incidence of 5% or greater and at least twice that of placebo) were somnolence, dystonia,
akathisia, dyspepsia, nausea, parkinsonism, vision abnormal, and saliva increased. In the
US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, the
most commonly observed adverse events associated with the use of RISPERDAL were
somnolence, dizziness, parkinsonism, saliva increased, akathisia, abdominal pain, and
urinary incontinence.
Adverse Events Occurring at an Incidence of 1% or More Among
RISPERDAL®-Treated Patients - Schizophrenia: The table that follows enumerates
adverse events that occurred at an incidence of 1% or more, and were more frequent
among RISPERDAL®-treated patients treated at doses of ≤10 mg/day than among
placebo-treated patients in the pooled results of two 6 to 8-week controlled trials. Patients
received RISPERDAL® doses of 2, 6, 10, or 16 mg/day in the dose comparison trial, or up
to a maximum dose of 10 mg/day in the titration study. This table shows the percentage of
patients in each dose group (≤10 mg/day or 16 mg/day) who spontaneously reported at
least one episode of an event at some time during their treatment. Patients given doses of 2,
6, or 10 mg did not differ materially in these rates. Reported adverse events were
classified using the World Health Organization preferred terms.
The prescriber should be aware that these figures cannot be used to predict the incidence
of side effects in the course of usual medical practice where patient characteristics and
other factors differ from those which prevailed in this clinical trial. Similarly, the cited
frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses and investigators. The cited figures, however, do
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provide the prescribing physician with some basis for estimating the relative contribution
of drug and non-drug factors to the side effect incidence rate in the population studied.
Table 1. Incidence of Treatment-Emergent Adverse Events in 6 to 8-Week
Controlled Clinical Trials1
RISPERDAL
Body System/
Preferred Term
≤10 mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(N=142)
Psychiatric
Insomnia
26%
23%
19%
Agitation
22%
26%
20%
Anxiety
12%
20%
9%
Somnolence
3%
8%
1%
Aggressive reaction
1%
3%
1%
Central & peripheral nervous system
Extrapyramidal symptoms2
17%
34%
16%
Headache
14%
12%
12%
Dizziness
4%
7%
1%
Gastrointestinal
Constipation
7%
13%
3%
Nausea
6%
4%
3%
Dyspepsia
5%
10%
4%
Vomiting
5%
7%
4%
Abdominal pain
4%
1%
0%
Saliva increased
2%
0%
1%
Toothache
2%
0%
0%
Respiratory system
Rhinitis
10%
8%
4%
Coughing
3%
3%
1%
Sinusitis
2%
1%
1%
Pharyngitis
2%
3%
0%
Dyspnea
1%
0%
0%
Body as a whole - general
Back pain
2%
0%
1%
Chest pain
2%
3%
1%
Fever
2%
3%
0%
Dermatological
Rash
2%
5%
1%
Dry skin
2%
4%
0%
Seborrhea
1%
0%
0%
Infections
Upper respiratory
3%
3%
1%
Visual
Abnormal vision
2%
1%
1%
Musculo-Skeletal
Arthralgia
2%
3%
0%
(continued)
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Table 1. Incidence of Treatment-Emergent Adverse Events in 6 to 8-Week
Controlled Clinical Trials1
RISPERDAL
Body System/
Preferred Term
≤10 mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(N=142)
Cardiovascular
Tachycardia
3%
5%
0%
1
Events reported by at least 1% of patients treated with RISPERDAL®
≤10 mg/day are included, and are rounded to the nearest %. Comparative rates
for RISPERDAL® 16 mg/day and placebo are provided as well. Events for
which the RISPERDAL® incidence (in both dose groups) was equal to or less
than placebo are not listed in the table, but included the following:
nervousness, injury, and fungal infection.
2
Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculogyric
crisis, ataxia, abnormal gait, involuntary muscle contractions, hyporeflexia,
akathisia, and extrapyramidal disorders. Although the incidence of
'extrapyramidal symptoms' does not appear to differ for the '≤10 mg/day' group
and placebo, the data for individual dose groups in fixed dose trials do suggest a
dose/response relationship (see DOSE DEPENDENCY OF ADVERSE
EVENTS).
Adverse Events Occurring at an Incidence of 2% or More Among
RISPERDAL®-Treated Patients - Bipolar Mania: Tables 2 and 3 display adverse
events that occurred at an incidence of 2% or more, and were more frequent among patients
treated with flexible doses of RISPERDAL (1-6 mg daily as monotherapy and as
adjunctive therapy to mood stabilizers, respectively) than among patients treated with
placebo. Reported adverse events were classified using the World Health Organization
preferred terms.
Table 2. Incidence of Treatment-Emergent Adverse Events in a
3-Week, Placebo-Controlled Trial - Monotherapy in Bipolar
Mania1
Body System/
RISPERDAL
Placebo
Preferred Term
N = 134
N = 125
Central & peripheral nervous system
Dystonia
18%
6%
Akathisia
16%
6%
Dizziness
11%
9%
Parkinsonism
6%
3%
Hypoaesthesia
2%
1%
Psychiatric
Somnolence
28%
7%
Agitation
8%
6%
Manic reaction
8%
6%
Anxiety
4%
2%
Concentration impaired
2%
1%
Gastrointestinal system
Dyspepsia
11%
6%
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Table 2. Incidence of Treatment-Emergent Adverse Events in a
3-Week, Placebo-Controlled Trial - Monotherapy in Bipolar
Mania1
Body System/
RISPERDAL
Placebo
Preferred Term
N = 134
N = 125
Nausea
11%
2%
Saliva increased
5%
1%
Mouth dry
3%
2%
Body as a whole - general
Pain
5%
3%
Fatigue
4%
2%
Injury
2%
0%
Respiratory system
Sinusitis
4%
1%
Rhinitis
3%
2%
Coughing
2%
2%
Skin and appendage
Acne
2%
0%
Pruritus
2%
1%
Musculoskeletal
Myalgia
5%
2%
Skeletal pain
2%
1%
Metabolic and nutritional
Weight increase
2%
0%
Vision disorders
Vision abnormal
6%
2%
Cardiovascular, general
Hypertension
3%
1%
Hypotension
2%
0%
Heart rate and rhythm
Tachycardia
3%
2%
1Events reported by at least 2% of patients treated with RISPERDAL® are
included, and are rounded to the nearest %. Events reported by at least
2% of patients treated with RISPERDAL® that were less than the
incidence reported by patients treated with placebo are not listed in the
table, but included the following: headache, tremor, insomnia,
constipation, back pain, upper respiratory tract infection, pharyngitis, and
arthralgia.
Table 3. Incidence of Treatment-Emergent Adverse Events in a
3-Week, Placebo-Controlled Trial - Adjunctive Therapy in Bipolar Mania1
Body system/
RISPERDAL
+mood stabilizer
Placebo
+ mood stabilizer
Preferred term
N = 52
N = 51
Gastrointestinal system
Saliva increased
10%
0%
Diarrhea
8%
4%
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Table 3. Incidence of Treatment-Emergent Adverse Events in a
3-Week, Placebo-Controlled Trial - Adjunctive Therapy in Bipolar Mania1
Body system/
RISPERDAL
+mood stabilizer
Placebo
+ mood stabilizer
Preferred term
N = 52
N = 51
Abdominal pain
6%
0%
Constipation
6%
4%
Mouth dry
6%
4%
Tooth ache
4%
0%
Tooth disorder
4%
0%
Central & peripheral nervous system
Dizziness
14%
2%
Parkinsonism
14%
4%
Akathisia
8%
0%
Dystonia
6%
4%
Psychiatric
Somnolence
25%
12%
Anxiety
6%
4%
Confusion
4%
0%
Respiratory system
Rhinitis
8%
4%
Pharyngitis
6%
4%
Coughing
4%
0%
Body as a whole - general
Asthenia
4%
2%
Urinary system
Urinary incontinence
6%
2%
Heart rate and rhythm
Tachycardia
4%
2%
Metabolic and nutritional
Weight increase
4%
2%
Skin and appendages
Rash
4%
2%
1Events reported by at least 2% of patients treated with RISPERDAL® are included, and
are rounded to the nearest %. Events reported by at least 2% of patients treated with
RISPERDAL® that were less than the incidence reported by patients treated with placebo
are not listed in the table, but included the following: dyspepsia, nausea, vomiting,
headache, tremor, insomnia, chest pain, fatigue, pain, skeletal pain, hypertension, and
vision abnormal.
Dose Dependency of Adverse Events
Extrapyramidal Symptoms
Data from two fixed-dose trials provided evidence of dose-relatedness for extrapyramidal
symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a
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parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
Ris 2
Ris 6
Ris 10
Ris 16
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
13%
16%
20%
31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups
Ris 1
Ris 4
Ris 8
Ris 12
Ris 16
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
18%
18%
21%
Other Adverse Events
Adverse event data elicited by a checklist for side effects from a large study comparing 5
fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-
relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a
positive trend (p<0.05) for the following adverse events: sleepiness, increased duration of
sleep, accommodation disturbances, orthostatic dizziness, palpitations, weight gain,
erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction,
asthenia/lassitude/increased fatigability, and increased pigmentation.
Vital Sign Changes
RISPERDAL® is associated with orthostatic hypotension and tachycardia (see
PRECAUTIONS).
Weight Changes
The proportions of RISPERDAL® and placebo-treated patients meeting a weight gain
criterion of ≥7% of body weight were compared in a pool of 6 to 8-week, placebo-
controlled trials, revealing a statistically significantly greater incidence of weight gain for
RISPERDAL® (18%) compared to placebo (9%).
Laboratory Changes
A between-group comparison for 6 to 8-week placebo-controlled trials revealed no
statistically significant RISPERDAL®/placebo differences in the proportions of patients
experiencing potentially important changes in routine serum chemistry, hematology, or
urinalysis parameters. Similarly, there were no RISPERDAL®/placebo differences in the
incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis.
However, RISPERDAL® administration was associated with increases in serum prolactin
(see PRECAUTIONS).
ECG Changes
Between-group comparisons for pooled placebo-controlled trials revealed no statistically
significant differences between risperidone and placebo in mean changes from baseline in
ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
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RISPERDAL® doses were pooled from randomized controlled trials in several
indications, there was a mean increase in heart rate of 1 beat per minute compared to no
change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone
(8-16 mg/day) were associated with a higher mean increase in heart rate compared to
placebo (4-6 beats per minute).
Other Events Observed During the Premarketing Evaluation of RISPERDAL
During its premarketing assessment, multiple doses of RISPERDAL® (risperidone) were
administered to 2607 patients in Phase 2 and 3 studies. The conditions and duration of
exposure to RISPERDAL® varied greatly, and included (in overlapping categories)
open-label and double-blind studies, uncontrolled and controlled studies, inpatient and
outpatient studies, fixed-dose and titration studies, and short-term or longer-term exposure.
In most studies, untoward events associated with this exposure were obtained by
spontaneous report and recorded by clinical investigators using terminology of their own
choosing. Consequently, it is not possible to provide a meaningful estimate of the
proportion of individuals experiencing adverse events without first grouping similar types
of untoward events into a smaller number of standardized event categories. In two large
studies, adverse events were also elicited utilizing the UKU (direct questioning) side effect
rating scale, and these events were not further categorized using standard terminology.
(Note: These events are marked with an asterisk in the listings that follow.)
In the listings that follow, spontaneously reported adverse events were classified using
World Health Organization (WHO) preferred terms. The frequencies presented, therefore,
represent the proportion of the 2607 patients exposed to multiple doses of RISPERDAL®
who experienced an event of the type cited on at least one occasion while receiving
RISPERDAL®. All reported events are included, except those already listed in Table 1,
those events for which a drug cause was remote, and those event terms which were so
general as to be uninformative. It is important to emphasize that, although the events
reported occurred during treatment with RISPERDAL®, they were not necessarily caused
by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring in at
least 1/100 patients (only those not already listed in the tabulated results from
placebo-controlled trials appear in this listing); infrequent adverse events are those
occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than
1/1000 patients.
Psychiatric Disorders
Frequent: increased dream activity*, diminished sexual desire*, nervousness.
Infrequent: impaired concentration, depression, apathy, catatonic reaction, euphoria,
increased libido, amnesia. Rare: emotional lability, nightmares, delirium, withdrawal
syndrome, yawning.
Central and Peripheral Nervous System Disorders
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Frequent: increased sleep duration*. Infrequent: dysarthria, vertigo, stupor,
paraesthesia, confusion. Rare: aphasia, cholinergic syndrome, hypoesthesia, tongue
paralysis, leg cramps, torticollis, hypotonia, coma, migraine, hyperreflexia,
choreoathetosis.
Gastrointestinal Disorders
Frequent: anorexia, reduced salivation*. Infrequent: flatulence, diarrhea, increased
appetite, stomatitis, melena, dysphagia, hemorrhoids, gastritis. Rare: fecal incontinence,
eructation, gastroesophageal reflux, gastroenteritis, esophagitis, tongue discoloration,
cholelithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage,
hematemesis.
Body as a Whole/General Disorders
Frequent: fatigue. Infrequent: edema, rigors, malaise, influenza-like symptoms.
Rare: pallor, enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing.
Respiratory System Disorders
Infrequent: hyperventilation, bronchospasm, pneumonia, stridor. Rare: asthma, increased
sputum, aspiration.
Skin and Appendage Disorders
Frequent: increased pigmentation*, photosensitivity*. Infrequent: increased sweating,
acne, decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation.
Rare: bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca,
dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria.
Cardiovascular Disorders
Infrequent: palpitation, hypertension, hypotension, AV block, myocardial infarction.
Rare: ventricular tachycardia, angina pectoris, premature atrial contractions, T wave
inversions, ventricular extrasystoles, ST depression, myocarditis.
Vision Disorders
Infrequent: abnormal accommodation, xerophthalmia. Rare: diplopia, eye pain,
blepharitis, photopsia, photophobia, abnormal lacrimation.
Metabolic and Nutritional Disorders
Infrequent: hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight
decrease, diabetes mellitus. Rare: decreased serum iron, cachexia, dehydration,
hypokalemia, hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia,
hypoglycemia.
Urinary System Disorders
Frequent: polyuria/polydipsia*. Infrequent: urinary incontinence, hematuria, dysuria.
Rare: urinary retention, cystitis, renal insufficiency.
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27
Musculo-Skeletal System Disorders
Infrequent: myalgia. Rare: arthrosis, synostosis, bursitis, arthritis, skeletal pain.
Reproductive Disorders, Female
Frequent: menorrhagia*, orgastic dysfunction*, dry vagina*. Infrequent: nonpuerperal
lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female
perineal pain, intermenstrual bleeding, vaginal hemorrhage.
Liver and Biliary System Disorders
Infrequent: increased SGOT, increased SGPT. Rare: hepatic failure, cholestatic
hepatitis, cholecystitis, cholelithiasis, hepatitis, hepatocellular damage.
Platelet, Bleeding, and Clotting Disorders
Infrequent: epistaxis, purpura. Rare: hemorrhage, superficial phlebitis, thrombophlebitis,
thrombocytopenia.
Hearing and Vestibular Disorders
Rare: tinnitus, hyperacusis, decreased hearing.
Red Blood Cell Disorders
Infrequent: anemia, hypochromic anemia. Rare: normocytic anemia.
Reproductive Disorders, Male
Frequent: erectile dysfunction*. Infrequent: ejaculation failure.
White Cell and Resistance Disorders
Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly.
Endocrine Disorders
Rare: gynecomastia, male breast pain, antidiuretic hormone disorder.
Special Senses
Rare: bitter taste.
* Incidence based on elicited reports.
Postintroduction Reports
Adverse events reported since market introduction which were temporally (but not
necessarily causally) related to RISPERDAL® therapy, include the following: anaphylactic
reaction, angioedema, apnea, atrial fibrillation, cerebrovascular disorder, including
cerebrovascular accident, hyperglycemia, diabetes mellitus aggravated, including diabetic
ketoacidosis, intestinal obstruction, jaundice, mania, pancreatitis, Parkinson's disease
aggravated, pulmonary embolism. There have been rare reports of sudden death and/or
cardiopulmonary arrest in patients receiving RISPERDAL®. A causal relationship with
RISPERDAL® has not been established. It is important to note that sudden and unexpected
This label may not be the latest approved by FDA.
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28
death may occur in psychotic patients whether they remain untreated or whether they are
treated with other antipsychotic drugs.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
RISPERDAL® (risperidone) is not a controlled substance.
Physical and Psychologic Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential
for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any
tendency for any drug-seeking behavior, these observations were not systematic and it is
not possible to predict on the basis of this limited experience the extent to which a
CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
patients should be evaluated carefully for a history of drug abuse, and such patients should
be observed closely for signs of RISPERDAL® misuse or abuse (e.g., development of
tolerance, increases in dose, drug-seeking behavior).
OVERDOSAGE
Human Experience
Premarketing experience included eight reports of acute RISPERDAL® (risperidone)
overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general,
reported signs and symptoms were those resulting from an exaggeration of the drug's known
pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and
extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was
associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another
case, involving an estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with
estimated doses of up to 360 mg. In general, the most frequently reported signs and
symptoms are those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms.
Other adverse events reported since market introduction which were temporally (but not
necessarily causally) related to RISPERDAL® overdose, include torsade de pointes,
prolonged QT interval, convulsions, cardiopulmonary arrest, and rare fatality associated
with multiple drug overdose.
Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate
oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and
administration of activated charcoal together with a laxative should be considered.
Because of the rapid disintegration of risperidone orally disintegrating tablets, pill
fragments may not appear in gastric contents obtained with lavage.
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29
The possibility of obtundation, seizures, or dystonic reaction of the head and neck
following overdose may create a risk of aspiration with induced emesis. Cardiovascular
monitoring should commence immediately and should include continuous
electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is
administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-
prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable
to expect that the alpha-blocking properties of bretylium might be additive to those of
risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive
measures should be instituted. The possibility of multiple drug involvement should be
considered. Hypotension and circulatory collapse should be treated with appropriate
measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and
dopamine should not be used, since beta stimulation may worsen hypotension in the setting
of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms,
anticholinergic medication should be administered. Close medical supervision and
monitoring should continue until the patient recovers.
DOSAGE AND ADMINISTRATION
Schizophrenia
Usual Initial Dose
RISPERDAL® (risperidone) can be administered on either a BID or a QD schedule. In
early clinical trials, RISPERDAL® was generally administered at 1 mg BID initially, with
increases in increments of 1 mg BID on the second and third day, as tolerated, to a target
dose of 3 mg BID by the third day. Subsequent controlled trials have indicated that total
daily risperidone doses of up to 8 mg on a QD regimen are also safe and effective.
However, regardless of which regimen is employed, in some patients a slower titration
may be medically appropriate. Further dosage adjustments, if indicated, should generally
occur at intervals of not less than 1 week, since steady state for the active metabolite
would not be achieved for approximately 1 week in the typical patient. When dosage
adjustments are necessary, small dose increments/decrements of 1-2 mg are recommended.
Efficacy in schizophrenia was demonstrated in a dose range of 4 to 16 mg/day in the
clinical trials supporting effectiveness of RISPERDAL®; however, maximal effect was
generally seen in a range of 4 to 8 mg/day. Doses above 6 mg/day for BID dosing were not
demonstrated to be more efficacious than lower doses, were associated with more
extrapyramidal symptoms and other adverse effects, and are not generally recommended. In
a single study supporting QD dosing, the efficacy results were generally stronger for 8 mg
than for 4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical
trials.
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30
Maintenance Therapy
While there is no body of evidence available to answer the question of how long the
schizophrenic patient treated with RISPERDAL® should remain on it, the effectiveness of
RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled
trial in patients who had been clinically stable for at least 4 weeks and were then followed
for a period of 1 to 2 years. In this trial, RISPERDAL® was administered on a QD
schedule, at 1 mg QD initially, with increases to 2 mg QD on the second day, and to a
target dose of 4 mg QD on the third day (see Clinical Trials, under CLINICAL
PHARMACOLOGY). Nevertheless, patients should be periodically reassessed to
determine the need for maintenance treatment with an appropriate dose.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is
recommended that when restarting patients who have had an interval off RISPERDAL®, the
initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or concerning concomitant
administration with other antipsychotics. While immediate discontinuation of the previous
antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual
discontinuation may be most appropriate for others. In all cases, the period of overlapping
antipsychotic administration should be minimized. When switching schizophrenic patients
from depot antipsychotics, if medically appropriate, initiate RISPERDAL® therapy in
place of the next scheduled injection. The need for continuing existing EPS medication
should be re-evaluated periodically.
Bipolar Mania
Usual Dose
Risperidone should be administered on a once daily schedule, starting with 2 mg to 3mg
per day. Dosage adjustments, if indicated, should occur at intervals of not less than
24 hours and in dosage increments/decrements of 1 mg per day, as studied in the
short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic
efficacy was demonstrated in a flexible dosage range of 1-6 mg per day (see Clinical
Trials, under CLINICAL PHARMACOLOGY). RISPERDAL doses higher than 6 mg per
day were not studied.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the
longer-term management of a patient who improves during treatment of an acute manic
episode with risperidone. While it is generally agreed that pharmacological treatment
beyond an acute response in mania is desirable, both for maintenance of the initial
response and for prevention of new manic episodes, there are no systematically obtained
data to support the use of risperidone in such longer-term treatment (i.e., beyond 3weeks).
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31
Pediatric Use
Safety and effectiveness of RISPERDAL in pediatric patients with schizophrenia or acute
mania associated with Bipolar I disorder have not been established.
Dosage in Special Populations
The recommended initial dose is 0.5 mg BID in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to
hypotension or for whom hypotension would pose a risk. Dosage increases in these
patients should be in increments of no more than 0.5 mg BID. Increases to dosages above
1.5 mg BID should generally occur at intervals of at least 1 week. In some patients, slower
titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may
have increases in the free fraction of risperidone, possibly resulting in an enhanced effect
(see CLINICAL PHARMACOLOGY). Patients with a predisposition to hypotensive
reactions or for whom such reactions would pose a particular risk likewise need to be
titrated cautiously and carefully monitored (see PRECAUTIONS). If a once-a-day dosing
regimen in the elderly or debilitated patient is being considered, it is recommended that the
patient be titrated on a twice-a-day regimen for 2-3 days at the target dose. Subsequent
switches to a once-a-day dosing regimen can be done thereafter.
Co-Administration of RISPERDAL® with Certain Other
Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with risperidone would be expected to cause decreases in the plasma
concentrations of active moiety (the sum of risperidone and 9-hydroxyrisperidone), which
could lead to decreased efficacy of risperidone treatment. The dose of risperidone needs to
be titrated accordingly for patients receiving these enzyme inducers, especially during
initiation or discontinuation of therapy with these inducers (See CLINICAL
PHARMACOLOGY and PRECAUTIONS).
Fluoxetine has been shown to increase the plasma concentration of risperidone 2.5-2.8
fold, while the plasma concentration of 9-hydroxyrisperidone was not affected. The dose
of risperidone needs to be titrated accordingly when fluoxetine, is co-administered (See
CLINICAL PHARMACOLOGY and PRECAUTIONS).
Directions for Use of RISPERDAL® M-TAB™ Orally
Disintegrating Tablets
RISPERDAL® M-TAB™ Orally Disintegrating Tablets are supplied in blister packs of 4
tablet units each.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Tablet Accessing
Do not open the blister until ready to administer. For single tablet removal, separate one
of the four blister units by tearing apart at the perforations. Bend the corner where
indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil
because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB™ Orally Disintegrating Tablet on the tongue. The RISPERDAL®
M-TAB™ Orally Disintegrating Tablet should be consumed immediately, as the tablet
cannot be stored once removed from the blister unit. RISPERDAL® M-TAB™ Orally
Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed
subsequently with or without liquid. Patients should not attempt to split or to chew the
tablet.
HOW SUPPLIED
RISPERDAL® (risperidone) tablets are imprinted "JANSSEN", and either “Ris” and the
strength “0.25”, “0.5”, or "R" and the strength "1", "2", "3", or "4".
0.25 mg dark yellow tablet: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50.
0.5 mg red-brown tablet: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50.
1 mg white tablet: bottles of 60 NDC 50458-300-06, blister pack of 100
NDC 50458-300-01, bottles of 500 NDC 50458-300-50.
2 mg orange tablet: bottles of 60 NDC 50458-320-06, blister pack of 100
NDC 50458-320-01, bottles of 500 NDC 50458-320-50.
3 mg yellow tablet: bottles of 60 NDC 50458-330-06, blister pack of 100
NDC 50458-330-01, bottles of 500 NDC 50458-330-50.
4 mg green tablet: bottles of 60 NDC 50458-350-06, blister pack of 100
NDC 50458-350-01.
RISPERDAL® (risperidone) 1 mg/mL oral solution (NDC 50458-305-03) is supplied in
30 mL bottles with a calibrated (in milligrams and milliliters) pipette. The minimum
calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL.
Tests indicate that RISPERDAL® (risperidone) oral solution is compatible in the following
beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either
cola or tea, however.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
RISPERDAL® M-TAB™ (risperidone) Orally Disintegrating Tablets are etched on one
side with R0.5, R1, and R2, respectively, and are packaged in blister packs of 4 (2 X 2)
tablets.
0.5 mg light coral, round, biconvex tablets: 7 blister packages per box,
NDC 50458-395-28, bingo card of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages per box,
NDC 50458-315-28, bingo card of 30 tablets NDC 50458-315-30.
2 mg light coral, round, biconvex tablets: 7 blister packages per box,
NDC 50458-325-28.
Storage and Handling
RISPERDAL® tablets should be stored at controlled room temperature 15o-25oC
(59o-77oF). Protect from light and moisture.
Keep out of reach of children.
RISPERDAL® 1 mg/mL oral solution should be stored at controlled room temperature 15o-
25oC (59o-77oF). Protect from light and freezing.
Keep out of reach of children.
RISPERDAL® M-TAB™ Orally Disintegrating Tablets should be stored at controlled
room temperature 15o-25oC (59o-77oF).
Keep out of reach of children.
7503223
US Patent 4,804,663
December 2003
©Janssen 2003
RISPERDAL® tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico or
Janssen-Cilag, SpA, Latina, Italy
RISPERDAL® oral solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB™ Orally Disintegrating Tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
RISPERDAL® tablets, RISPERDAL® M-TAB™ Orally Disintegrating Tablets, and oral
solution are distributed by:
Janssen Pharmaceutica Products, L.P.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:17.043866
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20272s-26,27,20588s-17,18,21444s-2,3_risperdal_lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
12,398
|
NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
1
JANSSEN, L.P.
RISPERDAL®
(risperidone)
TABLETS/ORAL SOLUTION
RISPERDAL® M-TAB®
(risperidone)
ORALLY DISINTEGRATING TABLETS
Increased Mortality in Elderly Patients with Dementia –Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. Analyses of seventeen placebo
controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in
the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients.
Over the course of a typical 10 week controlled trial, the rate of death in drug-treated
patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. RISPERDAL®
(risperidone) is not approved for the treatment of patients with Dementia-Related
Psychosis.
DESCRIPTION
RISPERDAL® (risperidone) is a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
2
RISPERDAL® tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. Inactive ingredients are colloidal
silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene
glycol, sodium lauryl sulfate, and starch (corn). Tablets of 0.25, 0.5, 2, 3, and 4 mg also contain
talc and titanium dioxide. The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets
contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg
and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No.
2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. The inactive ingredients for this
solution are tartaric acid, benzoic acid, sodium hydroxide, and purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (light coral), 3 mg (coral), and 4 mg (coral) strengths.
RISPERDAL® M-TAB® Orally Disintegrating Tablets contain the following inactive
ingredients: Amberlite® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium
hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition, the 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets contain xanthan gum.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of RISPERDAL® (risperidone), as with other drugs used to treat
schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in
schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2
(5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some
of the other effects of RISPERDAL®.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the
dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations
>10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
3
Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
daily (0.5 to 8 mg BID). Following oral administration of solution or tablet, mean peak plasma
concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-
hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can
be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is 90%,
and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-
hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
4
(e.g., the active moiety) results from the combined concentrations of risperidone plus 9-
hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active
moiety, after single and multiple doses, are similar in extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions (see PRECAUTIONS –
Drug Interactions). First, inhibitors of CYP 2D6 interfere with conversion of risperidone to
9-hydroxyrisperidone. This occurs with quinidine, giving essentially all recipients a risperidone
pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse
effects of risperidone in patients receiving quinidine have not been evaluated, but observations in
a modest number (n≅70) of poor metabolizers given risperidone do not suggest important
differences between poor and extensive metabolizers. Second, co-administration of known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone. It
would also be possible for risperidone to interfere with metabolism of other drugs metabolized
by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely.
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone titrated to
6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional
3 weeks. During co-administration, the plasma concentrations of risperidone and its
pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%.
Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of
other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone
may cause similar decreases in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment (see
PRECAUTIONS – Drug Interactions and DOSAGE AND ADMINISTRATION – Co-
Administration of RISPERDAL® with Certain Other Medications).
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the plasma
concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the
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5
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-
hydroxyrisperidone by about 10% (see PRECAUTIONS -Drug Interactions and DOSAGE AND
ADMINISTRATION – Co-Administration of RISPERDAL® with Certain Other Medications).
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma
concentrations (Cmax) of lithium (n=13) (see PRECAUTIONS – Drug Interactions).
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma
concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared
to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration
(Cmax) after concomitant administration of risperidone (see PRECAUTIONS – Drug
Interactions).
There were no significant interactions between risperidone (1 mg QD) and erythromycin (500
mg QID) (see PRECAUTIONS – Drug Interactions).
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%,
respectively. However, cimetidine did not affect the AUC of the active moiety, whereas
ranitidine increased the AUC of the active moiety by 20%.
Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety.
In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of
donepezil and galantamine, which are metabolized by CYP 2D6.
RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics
of digoxin.
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at 1
week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of the active moiety, after single and multiple doses, were
similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20
hours.
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6
Special Populations
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION).
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients (see DOSAGE AND
ADMINISTRATION).
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
CLINICAL TRIALS SCHIZOPHRENIA
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
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7
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (BID schedule), RISPERDAL® was generally superior to placebo on the
BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the
SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL® (2,
6, 10, and 16 mg/day, on a BID schedule), all 4 RISPERDAL® groups were generally
superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score;
the 3 highest RISPERDAL® dose groups were generally superior to placebo on the PANSS
negative subscale. The most consistently positive responses on all measures were seen for the
6 mg dose group, and there was no suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL® (1,
4, 8, 12, and 16 mg/day, on a BID schedule), the four highest RISPERDAL® dose groups
were generally superior to the 1 mg RISPERDAL® dose group on BPRS total score, BPRS
psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg
group on the PANSS negative subscale. The most consistently positive responses were seen
for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a QD schedule), both RISPERDAL® dose groups were
generally superior to placebo on several PANSS measures, including a response measure
(>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster
(derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg
dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
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8
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for 1 to
2 years of observation for relapse. Patients receiving RISPERDAL® experienced a significantly
longer time to relapse over this time period compared to those receiving the active comparator.
Bipolar Mania
Monotherapy
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in 2 short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the Y-MRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of Y-MRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1-6
mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), RISPERDAL®
was superior to placebo in the reduction of Y-MRS total score.
Combination Therapy
The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic
or mixed episodes was established in one controlled trial in patients who met the DSM-IV
criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and
with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2
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9
mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of Y-MRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in
therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of Y-MRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-
hydroxyrisperidone.
Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to
16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were
under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
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10
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5
to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01
mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent
to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this
open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL®
of 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as
≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very
much improved’) during the 4-6 month open-label treatment phase for about 140 days, on
average, were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
INDICATIONS AND USAGE
Schizophrenia
RISPERDAL® (risperidone) is indicated for the treatment of schizophrenia.
The efficacy of RISPERDAL® in schizophrenia was established in short-term (6- to 8-weeks)
controlled trials of schizophrenic inpatients (see CLINICAL PHARMACOLOGY).
The efficacy of RISPERDAL® in delaying relapse was demonstrated in schizophrenic patients
who had been clinically stable for at least 4 weeks before initiation of treatment with
RISPERDAL® or an active comparator and who were then observed for relapse during a period
of 1 to 2 years (see CLINICAL PHARMACOLOGY -Clinical Trials). Nevertheless, the
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11
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Bipolar Mania
Monotherapy
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder.
The efficacy of RISPERDAL® was established in two placebo-controlled trials (3-week) with
patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic
or mixed episode with or without psychotic features (see CLINICAL PHARMACOLOGY).
Combination Therapy
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder.
The efficacy of RISPERDAL® in combination with lithium or valproate was established in one
placebo-controlled (3-week) trial with patients meeting DSM-IV criteria for Bipolar I Disorder
who currently displayed an acute manic or mixed episode with or without psychotic features (see
CLINICAL PHARMACOLOGY).
The effectiveness of RISPERDAL® for longer-term use, that is, for more than 3 weeks of
treatment of an acute episode, and for prophylactic use in mania, has not been systematically
evaluated in controlled clinical trials. Therefore, physicians who elect to use RISPERDAL® for
extended periods should periodically re-evaluate the long-term risks and benefits of the drug for
the individual patient (see DOSAGE AND ADMINISTRATION).
Irritability Associated with Autistic Disorder
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents, including symptoms of aggression towards others, deliberate self-
injuriousness, temper tantrums, and quickly changing moods.
The efficacy of RISPERDAL® was established in two 8-week, placebo-controlled trials in
children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder.
The benefit of maintaining patients with irritability associated with autistic disorder on therapy
with RISPERDAL® after achieving a responder status for an average duration of about 140 days
was demonstrated in a controlled trial (see CLINICAL PHARMACOLOGY - Clinical Trials.)
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12
Physicians who elect to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
CONTRAINDICATIONS
RISPERDAL® (risperidone) is contraindicated in patients with a known hypersensitivity to the
product.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. RISPERDAL®(risperidone) is not
approved for the treatment of dementia-related psychosis (see Boxed Warning).
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional
signs
may
include
elevated
creatinine
phosphokinase,
myoglobinuria
(rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia
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A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® (risperidone) should be prescribed in a manner that is
most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment
should generally be reserved for patients who suffer from a chronic illness that: (1) is known to
respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially
less harmful treatments are not available or appropriate. In patients who do require chronic
treatment, the smallest dose and the shortest duration of treatment producing a satisfactory
clinical response should be sought. The need for continued treatment should be reassessed
periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients With
Dementia-Related Psychosis
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Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis (See also Boxed WARNING, WARNINGS: Increased Mortality
in Elderly Patients with Dementia-Related Psychosis.)
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma
or death, has been reported in patients treated with atypical antipsychotics including
RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and glucose
abnormalities is complicated by the possibility of an increased background risk of diabetes
mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the
general population. Given these confounders, the relationship between atypical antipsychotic use
and hyperglycemia-related adverse events is not completely understood. However,
epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related
adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for
hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not
available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has
resolved when the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
PRECAUTIONS
General
Orthostatic Hypotension
RISPERDAL® (risperidone) may induce orthostatic hypotension associated with dizziness,
tachycardia, and in some patients, syncope, especially during the initial dose-titration period,
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15
probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2%
(6/2607) of RISPERDAL®-treated patients in Phase 2 and 3 studies. The risk of orthostatic
hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either QD
or 1 mg BID) in normal adults and 0.5 mg BID in the elderly and patients with renal or hepatic
impairment (see DOSAGE AND ADMINISTRATION). Monitoring of orthostatic vital signs
should be considered in patients for whom this is of concern. A dose reduction should be
considered if hypotension occurs. RISPERDAL® should be used with particular caution in
patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart
failure, or conduction abnormalities), cerebrovascular disease, and conditions which would
predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant
hypotension has been observed with concomitant use of RISPERDAL® and antihypertensive
medication.
Seizures
During premarketing testing, seizures occurred in 0.3% (9/2607) of RISPERDAL®-treated
patients, two in association with hyponatremia. RISPERDAL® should be used cautiously in
patients with a history of seizures.
Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. (See also Boxed WARNING, WARNINGS:
Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels
and the elevation persists during chronic administration. Risperidone is associated with higher
levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
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16
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats (see PRECAUTIONS – Carcinogenesis, Mutagenesis, Impairment of Fertility). Neither
clinical studies nor epidemiologic studies conducted to date have shown an association between
chronic administration of this class of drugs and tumorigenesis in humans; the available evidence
is considered too limited to be conclusive at this time.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
Priapism
Rare cases of priapism have been reported. While the relationship of the events to RISPERDAL®
use has not been established, other drugs with alpha-adrenergic blocking effects have been
reported to induce priapism, and it is possible that RISPERDAL® may share this capacity.
Severe priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving RISPERDAL® in a
large, open premarketing experience (approximately 1300 patients). She experienced jaundice,
fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
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17
Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
Use in Patients With Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to
include confusion, obtundation, postural instability with frequent falls, extrapyramidal
symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration.
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18
Interference With Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy.
Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL®.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL®.
Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M-
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Laboratory Tests
No specific laboratory tests are recommended.
Drug Interactions
The interactions of RISPERDAL® and other drugs have not been systematically evaluated.
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
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19
Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety. Cimetidine
and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively.
However, cimetidine did not affect the AUC of the active moiety, whereas ranitidine increased
the AUC of the active moiety by 20%.
Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.
Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone titrated to 6
mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3
weeks. During co-administration, the plasma concentrations of risperidone and its
pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%.
Plasma concentrations of carbamazepine did not appear to be affected. The dose of risperidone
may need to be titrated accordingly for patients receiving carbamazepine, particularly during
initiation or discontinuation of carbamazepine therapy. Co-administration of other known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause
similar
decreases
in
the
combined
plasma
concentrations
of risperidone
and
9-
hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment.
Fluoxetine and Paroxetine
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the plasma
concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-
hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated
or discontinued, the physician should re-evaluate the dosing of RISPERDAL®. The effects of
discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics
of risperidone and 9-hydroxyrisperidone have not been studied.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma
concentrations (Cmax) of lithium (n=13).
Valproate
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma
concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared
to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration
(Cmax) after concomitant administration of risperidone.
Digoxin
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RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics
of digoxin.
Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs (see CLINICAL PHARMACOLOGY). Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
There were no significant interactions between risperidone and erythromycin (see CLINICAL
PHARMACOLOGY).
Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the
pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25
months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2,
0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis.
A maximum tolerated dose was not achieved in male mice. There were statistically significant
increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland
adenocarcinomas. The following table summarizes the multiples of the human dose on a mg/m2
(mg/kg) basis at which these tumors occurred.
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21
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown (see PRECAUTIONS, General -Hyperprolactinemia).
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
Pregnancy
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22
Pregnancy Category C
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits (0.31-5
mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations was not
increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a
mg/m2 basis. In three reproductive studies in rats (two Segment III and a multigenerational
study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5
mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether these deaths were
due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of risperidone during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-
hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
risperidone should not breast-feed.
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23
Pediatric Use
The safety and effectiveness of RISPERDAL® in pediatric patients with schizophrenia or bipolar
mania have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, placebo-controlled trials in 156 children and adolescent
patients, aged 5 to 16 years (see CLINICAL PHARMACOLOGY - Clinical Trials,
INDICATIONS AND USAGE, and ADVERSE REACTIONS). Additional safety information
was also assessed in a long-term study in patients with autistic disorder, or in short- and long-
term studies in more than 1200 pediatric patients with other psychiatric disorders who were of
similar age and weight, and who received similar dosages of RISPERDAL® as patients who were
treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric
disorders treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia,
which resolved on discontinuation of risperidone treatment (see WARNINGS – Tardive
Dyskinesia).
Weight Gain
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index. When treating patients with RISPERDAL®,
weight gain should be assessed against that expected with normal growth. (See also ADVERSE
REACTIONS.)
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. (See also ADVERSE REACTIONS.) Patients
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24
experiencing persistent somnolence may benefit from a change in dosing regimen (see DOSAGE
AND ADMINISTRATION – Irritability Associated with Autistic Disorder).
Hyperprolactinemia, Growth, and Sexual Maturation
Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in
adults (see PRECAUTIONS - Hyperprolactinemia). In double-blind, placebo-controlled studies
of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) 49% of patients who
received risperidone had elevated prolactin levels compared to 2% of patients who received
placebo.
In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric
disorders treated with risperidone, galactorrhea was reported in 0.8% of risperidone-treated
patients and gynecomastia was reported in 2.3% of risperidone-treated patients.
The long-term effects of risperidone on growth and sexual maturation have not been fully
evaluated.
Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other
drug
therapy
(see CLINICAL PHARMACOLOGY
and
DOSAGE
AND
ADMINISTRATION). While elderly patients exhibit a greater tendency to orthostatic
hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg BID
followed by careful titration (see PRECAUTIONS). Monitoring of orthostatic vital signs should
be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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).
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus risperidone
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25
when compared to patients treated with risperidone alone or with placebo plus furosemide. No
pathological mechanism has been identified to explain this finding, and no consistent pattern for
cause of death was observed. An increase of mortality in elderly patients with dementia-related
psychosis was seen with the use of RISPERDAL® regardless of concomitant use with
furosemide. RISPERDAL® is not approved for the treatment of patients with dementia-related
psychosis. (See Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients
with Dementia-Related Psychosis.)
ADVERSE REACTIONS
The following findings are based on the short-term, placebo-controlled, North American,
premarketing trials for schizophrenia and acute bipolar mania, and are followed by a description
of adverse events and other safety measures in short-term, placebo-controlled trials in pediatric
patients treated for irritability associated with autistic disorder. In patients with Bipolar I
Disorder, treatment-emergent adverse events are presented separately for risperidone as
monotherapy and as adjunctive therapy to mood stabilizers.
Certain portions of the discussion below relating to objective or numeric safety parameters,
namely dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and
ECG changes are derived from studies in patients with schizophrenia. However, this information
is also generally applicable to bipolar mania and pediatric patients with autistic disorder.
Associated With Discontinuation of Treatment
Schizophrenia
Approximately 9% (244/2607) of RISPERDAL® (risperidone)-treated patients in Phase 2 and 3
studies discontinued treatment due to an adverse event, compared with about 7% on placebo and
10% on active control drugs. The more common events (≥ 0.3%) associated with discontinuation
and considered to be possibly or probably drug-related included:
Adverse Event
RISPERDAL®
Placebo
Extrapyramidal symptoms
2.1%
0%
Dizziness
0.7%
0%
Hyperkinesia
0.6%
0%
Somnolence
0.5%
0%
Nausea
0.3%
0%
Suicide attempt was associated with discontinuation in 1.2% of RISPERDAL®-treated patients
compared to 0.6% of placebo patients, but, given the almost 40-fold greater exposure time in
RISPERDAL® compared to placebo patients, it is unlikely that suicide attempt is a
RISPERDAL®-related adverse event (see PRECAUTIONS). Discontinuation for extrapyramidal
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26
symptoms was 0% in placebo patients, but 3.8% in active-control patients in the Phase 2 and 3
trials.
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, approximately 8% (10/134)
of RISPERDAL®-treated patients discontinued treatment due to an adverse event, compared with
approximately 6% (7/125) of placebo-treated patients. The adverse events associated with
discontinuation and considered to be possibly, probably, or very likely drug-related included
paroniria, somnolence, dizziness, extrapyramidal disorder, and muscle contractions involuntary.
Each of these events occurred in one RISPERDAL®-treated patient (0.7%) and in no placebo-
treated patients (0%).
In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers,
there was no overall difference in the incidence of discontinuation due to adverse events (4% for
RISPERDAL® vs. 4% for placebo).
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
Schizophrenia
In two 6- to 8-week placebo-controlled trials, spontaneously-reported, treatment-emergent
adverse events with an incidence of 5% or greater in at least one of the RISPERDAL® groups
and at least twice that of placebo were anxiety, somnolence, extrapyramidal symptoms,
dizziness, constipation, nausea, dyspepsia, rhinitis, rash, and tachycardia.
Adverse events were also elicited in one of these two trials (i.e., in the fixed-dose trial comparing
RISPERDAL® at doses of 2, 6, 10, and 16 mg/day with placebo) utilizing a checklist for
detecting adverse events, a method that is more sensitive than spontaneous reporting. By this
method, the following additional common and drug-related adverse events occurred at an
incidence of at least 5% and twice the rate of placebo: increased dream activity, increased
duration of sleep, accommodation disturbances, reduced salivation, micturition disturbances,
diarrhea, weight gain, menorrhagia, diminished sexual desire, erectile dysfunction, ejaculatory
dysfunction, and orgastic dysfunction.
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27
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, the most commonly
observed adverse events associated with the use of RISPERDAL® (incidence of 5% or greater
and at least twice that of placebo) were somnolence, dystonia, akathisia, dyspepsia, nausea,
parkinsonism, vision abnormal, and saliva increased. In the US placebo-controlled trial with
risperidone as adjunctive therapy to mood stabilizers, the most commonly observed adverse
events associated with the use of RISPERDAL® were somnolence, dizziness, parkinsonism,
saliva increased, akathisia, abdominal pain, and urinary incontinence.
Adverse Events Occurring at an Incidence of 1% or More Among RISPERDAL®-Treated
Patients - Schizophrenia
The table that follows enumerates adverse events that occurred at an incidence of 1% or more,
and were more frequent among RISPERDAL®-treated patients treated at doses of ≤10 mg/day
than among placebo-treated patients in the pooled results of two 6- to 8-week controlled trials.
Patients received RISPERDAL® doses of 2, 6, 10, or 16 mg/day in the dose comparison trial, or
up to a maximum dose of 10 mg/day in the titration study. This table shows the percentage of
patients in each dose group (≤10 mg/day or 16 mg/day) who spontaneously reported at least one
episode of an event at some time during their treatment. Patients given doses of 2, 6, or 10 mg
did not differ materially in these rates. Reported adverse events were classified using the World
Health Organization preferred terms.
The prescriber should be aware that these figures cannot be used to predict the incidence of side
effects in the course of usual medical practice where patient characteristics and other factors
differ from those which prevailed in this clinical trial. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving different treatments,
uses, and investigators. The cited figures, however, do provide the prescribing physician with
some basis for estimating the relative contribution of drug and non-drug factors to the side effect
incidence rate in the population studied.
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28
Table 1: Incidence of Treatment-Emergent Adverse Events in 6- to 8-Week Controlled Clinical Trials in
Schizophrenia 1
RISPERDAL®
Body System/
Preferred Term
<10mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(N=142)
Psychiatric
Insomnia
26%
23%
19%
Agitation
22%
26%
20%
Anxiety
12%
20%
9%
Somnolence
3%
8%
1%
Aggressive reaction
1%
3%
1%
Central & peripheral nervous system
Extrapyramidal symptoms2
17%
34%
16%
Headache
14%
12%
12%
Dizziness
4%
7%
1%
Gastrointestinal
Constipation
7%
13%
3%
Nausea
6%
4%
3%
Dyspepsia
5%
10%
4%
Vomiting
5%
7%
4%
Abdominal pain
4%
1%
0%
Saliva increased
2%
0%
1%
Toothache
2%
0%
0%
Respiratory system
Rhinitis
10%
8%
4%
Coughing
3%
3%
1%
Sinusitis
2%
1%
1%
Pharyngitis
2%
3%
0%
Dyspnea
1%
0%
0%
Body as a whole – general
Back pain
2%
0%
1%
Chest pain
2%
3%
1%
Fever
2%
3%
0%
Dermatological
Rash
2%
5%
1%
Dry skin
2%
4%
0%
Seborrhea
1%
0%
0%
Infections
Upper respiratory
3%
3%
1%
Visual
Abnormal vision
2%
1%
1%
Musculo-Skeletal
Arthralgia
2%
3%
0%
Cardiovascular
Tachycardia
3%
5%
0%
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1 Events reported by at least 1% of patients treated with RISPERDAL® ≤10 mg/day are included,
and are rounded to the nearest %. Comparative rates for RISPERDAL® 16 mg/day and placebo
are provided as well. Events for which the RISPERDAL® incidence (in both dose groups) was
equal to or less than placebo are not listed in the table, but included the following: nervousness,
injury, and fungal infection.
2 Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculogyric crisis, ataxia,
abnormal gait, involuntary muscle contractions, hyporeflexia, akathisia, and extrapyramidal
disorders. Although the incidence of 'extrapyramidal symptoms' does not appear to differ for the
'10 mg/day' group and placebo, the data for individual dose groups in fixed dose trials do suggest
a dose/response relationship (see ADVERSE REACTIONS – Dose Dependency of Adverse
Events).
Adverse Events Occurring at an Incidence of 2% or More Among RISPERDAL®-Treated
Patients - Bipolar Mania
Tables 2 and 3 display adverse events that occurred at an incidence of 2% or more, and were
more frequent among patients treated with flexible doses of RISPERDAL® (1-6 mg daily as
monotherapy and as adjunctive therapy to mood stabilizers, respectively) than among patients
treated with placebo. Reported adverse events were classified using the World Health
Organization preferred terms.
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Table 2: Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Monotherapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL®
(N=134)
Placebo
(N=125)
Central & peripheral nervous system
Dystonia
18%
6%
Akathisia
16%
6%
Dizziness
11%
9%
Parkinsonism
6%
3%
Hypoaesthesia
2%
1%
Psychiatric
Somnolence
28%
7%
Agitation
8%
6%
Manic reaction
8%
6%
Anxiety
4%
2%
Concentration impaired
2%
1%
Gastrointestinal system
Dyspepsia
11%
6%
Nausea
11%
2%
Saliva increased
5%
1%
Mouth dry
3%
2%
Body as a whole - general
Pain
5%
3%
Fatigue
4%
2%
Injury
2%
0%
Respiratory system
Sinusitis
4%
1%
Rhinitis
3%
2%
Coughing
2%
2%
Skin and appendages
Acne
2%
0%
Pruritus
2%
1%
Musculo-Skeletal
Myalgia
5%
2%
Skeletal pain
2%
1%
Metabolic and nutritional
Weight increase
2%
0%
Vision disorders
Vision abnormal
6%
2%
Cardiovascular, general
Hypertension
3%
1%
Hypotension
2%
0%
Heart rate and rhythm
Tachycardia
3%
2%
1 Events reported by at least 2% of patients treated with RISPERDAL® are included and are
rounded to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL®
that were less than the incidence reported by patients treated with placebo are not listed in the
table, but included the following: headache, tremor, insomnia, constipation, back pain, upper
respiratory tract infection, pharyngitis, and arthralgia.
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Table 3: Incidence of Treatment-Emergent Adverse Events in a 3-Week, Placebo-Controlled Trial -
Adjunctive Therapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL®
+ Mood Stabilizer
(N=52)
Placebo
+ Mood Stabilizer
(N=51)
Gastrointestinal system
Saliva increased
10%
0%
Diarrhea
8%
4%
Abdominal pain
6%
0%
Constipation
6%
4%
Mouth dry
6%
4%
Tooth ache
4%
0%
Tooth disorder
4%
0%
Central & peripheral nervous system
Dizziness
14%
2%
Parkinsonism
14%
4%
Akathisia
8%
0%
Dystonia
6%
4%
Psychiatric
Somnolence
25%
12%
Anxiety
6%
4%
Confusion
4%
0%
Respiratory system
Rhinitis
8%
4%
Pharyngitis
6%
4%
Coughing
4%
0%
Body as a whole - general
Asthenia
4%
2%
Urinary system
Urinary incontinence
6%
2%
Heart rate and rhythm
Tachycardia
4%
2%
Metabolic and nutritional
Weight increase
4%
2%
Skin and appendages
Rash
4%
2%
1 Events reported by at least 2% of patients treated with RISPERDAL® are included and are
rounded to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL®
that were less than the incidence reported by patients treated with placebo are not listed in the
table, but included the following: dyspepsia, nausea, vomiting, headache, tremor, insomnia,
chest pain, fatigue, pain, skeletal pain, hypertension, and vision abnormal.
Dose Dependency of Adverse Events
Extrapyramidal Symptoms
Data from two fixed-dose trials provided evidence of dose-relatedness for extrapyramidal
symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a parkinsonism
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score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2)
incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
Ris 2
Ris 6
Ris 10
Ris 16
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
13%
16%
20%
31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups
Ris 1
Ris 4
Ris 8
Ris 12
Ris 16
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
18%
18%
21%
Other Adverse Events
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse events: sleepiness, increased duration of sleep,
accommodation disturbances, orthostatic dizziness, palpitations, weight gain, erectile
dysfunction,
ejaculatory
dysfunction,
orgastic
dysfunction,
asthenia/lassitude/increased
fatigability, and increased pigmentation.
Vital Sign Changes
RISPERDAL®
is
associated
with
orthostatic
hypotension
and
tachycardia
(see PRECAUTIONS).
Weight Changes
The proportions of RISPERDAL® and placebo-treated patients meeting a weight gain criterion
of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials,
revealing a statistically significantly greater incidence of weight gain for RISPERDAL® (18%)
compared to placebo (9%).
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Laboratory Changes
A between-group comparison for 6- to 8-week placebo-controlled trials revealed no statistically
significant RISPERDAL®/placebo differences in the proportions of patients experiencing
potentially important changes in routine serum chemistry, hematology, or urinalysis parameters.
Similarly, there were no RISPERDAL®/placebo differences in the incidence of discontinuations
for changes in serum chemistry, hematology, or urinalysis. However, RISPERDAL®
administration was associated with increases in serum prolactin (see PRECAUTIONS).
ECG Changes
Between-group comparisons for pooled placebo-controlled trials revealed no statistically
significant differences between risperidone and placebo in mean changes from baseline in ECG
parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL® doses
were pooled from randomized controlled trials in several indications, there was a mean increase
in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term
schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher
mean increase in heart rate compared to placebo (4-6 beats per minute).
Adverse Events and Other Safety Measures in Pediatric Patients With Autistic
Disorder
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n=156), two patients (one treated with RISPERDAL® and one treated with
placebo) discontinued treatment due to an adverse event.
In addition to spontaneous reporting, in one of the studies, adverse events were also elicited from
a checklist for detecting selected events, a method that is more sensitive than spontaneous
reporting.
The most common adverse events with RISPERDAL® that occurred at an incidence equal to or
greater than 5% and at a rate of at least twice that of placebo are shown in Table 4.
Table 4
Incidence of Treatment-Emergent Adverse Events in Two 8-Week, Placebo-Controlled
Trials in Pediatric Patients with Autistic Disorder
Body System
Preferred Term
RISPERDAL®
(n=76)
Placebo
(n=80)
Psychiatric
Somnolence
67%
23%
Appetite increased
49%
19%
Confusion
5%
0%
Gastrointestinal
Saliva increased
22%
6%
Constipation
21%
8%
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Dry mouth
13%
6%
Body as a whole - general
Fatigue
42%
13%
Central & peripheral
nervous system
Tremor
12%
1%
Dystonia
12%
6%
Dizziness
9%
3%
Automatism
7%
1%
Dyskinesia
7%
0%
Parkinsonism
8%
0%
Respiratory
Upper respiratory tract
infection
34%
15%
Metabolic and nutritional
Weight increase
5%
0%
Heart rate and rhythm
Tachycardia
7%
0%
Weight increase was reported more frequently with RISPERDAL® than with placebo. The
average weight increase over 8 weeks was 2.6 kg in patients treated with RISPERDAL®
compared with 0.9 kg in patients treated with placebo. (See also PRECAUTIONS – Pediatric
Use – Weight Gain.)
There was a higher incidence of adverse events reflecting extrapyramidal symptoms (EPS) in the
RISPERDAL® group (27.6%) compared with the placebo group (10.0%). In addition, between-
group comparison of the severity of EPS were assessed objectively by the following rating
instruments: the Simpson-Angus Rating Scale (SARS) and the Abnormal Involuntary Movement
Scale (AIMS) in one study, and the Extrapyramidal Symptom Rating Scale (ESRS) in the other
study. The mean changes between baseline and endpoint in the total ESRS score were –0.3 in the
RISPERDAL® group and –0.4 in the placebo group. The median change from baseline to
endpoint was 0 in both treatment groups for each EPS rating scale.
Somnolence was the most frequent adverse event, and was reported at a higher incidence in the
RISPERDAL® group compared with the placebo group. The vast majority of cases (96%) were
either mild or moderate in severity. These events were most often of early onset with peak
incidence occurring during the first 2 weeks of treatment, and median duration was 16 days.
Patients experiencing persistent somnolence may benefit from a change in dosing regimen (see
DOSAGE AND ADMINISTRATION – Irritability Associated with Autistic Disorder –
Pediatrics [Children and Adolescents]).
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Other Events Observed During the Premarketing Evaluation of RISPERDAL®
During its premarketing assessment, multiple doses of RISPERDAL® were administered to 2607
adult patients with schizophrenia and 1923 pediatric patients in Phase 2 and 3 studies. The
conditions and duration of exposure to RISPERDAL® varied greatly, and included (in
overlapping categories) open-label and double-blind studies, uncontrolled and controlled studies,
inpatient and outpatient studies, fixed-dose and titration studies, and short-term or longer-term
exposure. In most studies, untoward events associated with this exposure were obtained by
spontaneous report and recorded by clinical investigators using terminology of their own
choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of
individuals experiencing adverse events without first grouping similar types of untoward events
into a smaller number of standardized event categories. In two large studies, adverse events were
also elicited utilizing the UKU (direct questioning) side effect rating scale, and these events were
not further categorized using standard terminology. (Note: These events are marked with an
asterisk in the listings that follow.)
In the listings that follow, spontaneously reported adverse events were classified using World
Health Organization (WHO) preferred terms. The frequencies presented, therefore, represent the
proportion of the 2607 adult or 1923 pediatric patients exposed to multiple doses of
RISPERDAL® who experienced an event of the type cited on at least one occasion while
receiving RISPERDAL®. All reported events are included, except those already listed in Table 1,
those events for which a drug cause was remote, and those event terms which were so general as
to be uninformative. It is important to emphasize that, although the events reported occurred
during treatment with RISPERDAL®, they were not necessarily caused by it. Serious adverse
reactions experienced by the pediatric population were similar to those seen in the adult
population (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS).
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring in at least
1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials
appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients;
rare events are those occurring in fewer than 1/1000 patients.
Psychiatric Disorders
Frequent: increased dream activity∗, diminished sexual desire∗, nervousness. Infrequent:
impaired concentration, depression, apathy, catatonic reaction, euphoria, increased libido,
amnesia. Rare: emotional lability, nightmares, delirium, withdrawal syndrome, yawning.
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Central and Peripheral Nervous System Disorders
Frequent: increased sleep duration∗. Infrequent: dysarthria, vertigo, stupor, paraesthesia,
confusion. Rare: aphasia, cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps,
torticollis, hypotonia, coma, migraine, hyperreflexia, choreoathetosis.
Gastrointestinal Disorders
Frequent: anorexia, reduced salivation∗. Infrequent: flatulence, diarrhea, increased appetite,
stomatitis, melena, dysphagia, hemorrhoids, gastritis. Rare: fecal incontinence, eructation,
gastroesophageal reflux, gastroenteritis, esophagitis, tongue discoloration, cholelithiasis, tongue
edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis.
Body as a Whole/General Disorders
Frequent: fatigue. Infrequent: edema, rigors, malaise, influenza-like symptoms. Rare: pallor,
enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing.
Respiratory System Disorders
Infrequent: hyperventilation, bronchospasm, pneumonia, stridor. Rare: asthma, increased
sputum, aspiration.
Skin and Appendage Disorders
Frequent: increased pigmentation∗, photosensitivity∗ Infrequent: increased sweating, acne,
decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation. Rare: bullous eruption,
skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis,
genital pruritus, urticaria.
Cardiovascular Disorders
Infrequent: palpitation, hypertension, hypotension, AV block, myocardial infarction. Rare:
ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversions,
ventricular extrasystoles, ST depression, myocarditis.
Vision Disorders
Infrequent: abnormal accommodation, xerophthalmia. Rare: diplopia, eye pain, blepharitis,
photopsia, photophobia, abnormal lacrimation.
Metabolic and Nutritional Disorders
Infrequent: hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight
decrease, diabetes mellitus. Rare: decreased serum iron, cachexia, dehydration, hypokalemia,
hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia.
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Urinary System Disorders
Frequent: polyuria/polydipsia∗. Infrequent: urinary incontinence, hematuria, dysuria. Rare:
urinary retention, cystitis, renal insufficiency.
Musculo-Skeletal System Disorders
Infrequent: myalgia. Rare: arthrosis, synostosis, bursitis, arthritis, skeletal pain.
Reproductive Disorders, Female
Frequent: menorrhagia∗, orgastic dysfunction∗, dry vagina∗ Infrequent: nonpuerperal lactation,
amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain,
intermenstrual bleeding, vaginal hemorrhage.
Liver and Biliary System Disorders
Infrequent: increased SGOT, increased SGPT. Rare: hepatic failure, cholestatic hepatitis,
cholecystitis, cholelithiasis, hepatitis, hepatocellular damage.
Platelet, Bleeding, and Clotting Disorders
Infrequent: epistaxis, purpura. Rare: hemorrhage, superficial phlebitis, thrombophlebitis,
thrombocytopenia.
Hearing and Vestibular Disorders
Rare: tinnitus, hyperacusis, decreased hearing.
Red Blood Cell Disorders
Infrequent: anemia, hypochromic anemia. Rare: normocytic anemia.
Reproductive Disorders, Male
Frequent: erectile dysfunction∗ Infrequent: ejaculation failure.
White Cell and Resistance Disorders
Infrequent: granulocytopenia. Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet
anomaly.
Endocrine Disorders
Rare: gynecomastia, male breast pain, antidiuretic hormone disorder.
Special Senses
Rare: bitter taste.
∗ Incidence based on elicited reports.
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Postintroduction Reports
Adverse events reported since market introduction which were temporally (but not necessarily
causally) related to RISPERDAL® therapy, include the following: anaphylactic reaction,
angioedema, apnea, atrial fibrillation, cerebrovascular disorder, including cerebrovascular
accident, diabetes mellitus aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal
obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated, pituitary adenomas,
pulmonary embolism, and precocious puberty. There have been rare reports of sudden death
and/or cardiopulmonary arrest in patients receiving RISPERDAL®. A causal relationship with
RISPERDAL® has not been established. It is important to note that sudden and unexpected death
may occur in psychotic patients whether they remain untreated or whether they are treated with
other antipsychotic drugs.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
RISPERDAL® (risperidone) is not a controlled substance.
Physical and Psychological Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for
any drug-seeking behavior, these observations were not systematic and it is not possible to
predict on the basis of this limited experience the extent to which a CNS-active drug will be
misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated
carefully for a history of drug abuse, and such patients should be observed closely for signs of
RISPERDAL® misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking
behavior).
OVERDOSAGE
Human Experience
Premarketing experience included eight reports of acute RISPERDAL® (risperidone) overdosage
with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
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Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse events reported
since market introduction which were temporally (but not necessarily causally) related to
RISPERDAL® overdose, include torsade de pointes, prolonged QT interval, convulsions,
cardiopulmonary arrest, and rare fatality associated with multiple drug overdose.
Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
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DOSAGE AND ADMINISTRATION
Schizophrenia
Usual Initial Dose
RISPERDAL® (risperidone) can be administered on either a BID or a QD schedule. In early
clinical trials, RISPERDAL® was generally administered at 1 mg BID initially, with increases in
increments of 1 mg BID on the second and third day, as tolerated, to a target dose of 3 mg BID
by the third day. Subsequent controlled trials have indicated that total daily risperidone doses of
up to 8 mg on a QD regimen are also safe and effective. However, regardless of which regimen
is employed, in some patients a slower titration may be medically appropriate. Further dosage
adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady
state for the active metabolite would not be achieved for approximately 1 week in the typical
patient. When dosage adjustments are necessary, small dose increments/decrements of 1-2 mg
are recommended.
Efficacy in schizophrenia was demonstrated in a dose range of 4 to 16 mg/day in the clinical
trials supporting effectiveness of RISPERDAL®; however, maximal effect was generally seen in
a range of 4 to 8 mg/day. Doses above 6 mg/day for BID dosing were not demonstrated to be
more efficacious than lower doses, were associated with more extrapyramidal symptoms and
other adverse effects, and are not generally recommended. In a single study supporting QD
dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses
above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While there is no body of evidence available to answer the question of how long the
schizophrenic patient treated with RISPERDAL® should remain on it, the effectiveness of
RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial
in patients who had been clinically stable for at least 4 weeks and were then followed for a
period of 1 to 2 years. In this trial, RISPERDAL® was administered on a QD schedule, at 1 mg
QD initially, with increases to 2 mg QD on the second day, and to a target dose of 4 mg QD on
the third day (see CLINICAL PHARMACOLOGY – Clinical Trials). Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment with an
appropriate dose.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that when restarting patients who have had an interval off RISPERDAL®, the initial titration
schedule should be followed.
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Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or concerning concomitant administration
with other antipsychotics. While immediate discontinuation of the previous antipsychotic
treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may
be most appropriate for others. In all cases, the period of overlapping antipsychotic
administration should be minimized. When switching schizophrenic patients from depot
antipsychotics, if medically appropriate, initiate RISPERDAL® therapy in place of the next
scheduled injection. The need for continuing existing EPS medication should be re-evaluated
periodically.
Pediatric Use
The safety and effectiveness of RISPERDAL® in pediatric patients with schizophrenia have not
been established.
Bipolar Mania
Usual Dose
Risperidone should be administered on a once daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day (see CLINICAL PHARMACOLOGY – Clinical Trials).
RISPERDAL® doses higher than 6 mg per day were not studied.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
risperidone. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of risperidone
in such longer-term treatment (i.e., beyond 3 weeks).
Pediatric Use
The safety and effectiveness of RISPERDAL® in pediatric patients with bipolar mania have not
been established.
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
42
Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weighed less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, see CLINICAL PHARMACOLOGY – Clinical Trials) received doses of RISPERDAL®
between 0.5 mg and 2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the
pivotal trials, when the therapeutic effect reached plateau, was 1.0 mg in patients < 20 kg, 2.5 mg
in patients ≥ 20 kg, or 3.0 mg in patients > 45 kg. No dosing data are available for children who
weigh less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
Dosage in Special Populations
The recommended initial dose is 0.5 mg BID in patients who are elderly or debilitated, patients
with severe renal or hepatic impairment, and patients either predisposed to hypotension or for
whom hypotension would pose a risk. Dosage increases in these patients should be in increments
of no more than 0.5 mg BID. Increases to dosages above 1.5 mg BID should generally occur at
intervals of at least 1 week. In some patients, slower titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
43
increases in the free fraction of risperidone, possibly resulting in an enhanced effect (see
CLINICAL PHARMACOLOGY). Patients with a predisposition to hypotensive reactions or for
whom such reactions would pose a particular risk likewise need to be titrated cautiously and
carefully monitored (see PRECAUTIONS). If a once-a-day dosing regimen in the elderly or
debilitated patient is being considered, it is recommended that the patient be titrated on a twice-a-
day regimen for 2-3 days at the target dose. Subsequent switches to a once-a-day dosing regimen
can be done thereafter.
Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with risperidone would be expected to cause decreases in the plasma
concentrations of active moiety (the sum of risperidone and 9-hydroxyrisperidone), which could
lead to decreased efficacy of risperidone treatment. The dose of risperidone needs to be titrated
accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers (see CLINICAL PHARMACOLOGY and
PRECAUTIONS).
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-
hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is
co-administered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-
resistant pouch containing a blister with 1 tablet each.
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
44
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M-
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
HOW SUPPLIED
RISPERDAL® (risperidone) tablets are imprinted "JANSSEN", and either “Ris” and the strength
“0.25”, “0.5”, or "R" and the strength "1", "2", "3", or "4".
0.25 mg dark yellow tablet: bottles of 60 NDC 50458-301-04, bottles of 500 NDC 50458-301-
50, hospital unit dose packs of 100 NDC 50458-301-01.
0.5 mg red-brown tablet: bottles of 60 NDC 50458-302-06, bottles of 500 NDC 50458-302-50,
hospital unit dose packs of 100 NDC 50458-302-01.
1 mg white tablet: bottles of 60 NDC 50458-300-06, blister pack of 100 NDC 50458-300-01,
bottles of 500 NDC 50458-300-50.
2 mg orange tablet: bottles of 60 NDC 50458-320-06, blister pack of 100 NDC 50458-320-01,
bottles of 500 NDC 50458-320-50.
3 mg yellow tablet: bottles of 60 NDC 50458-330-06, blister pack of 100 NDC 50458-330-01,
bottles of 500 NDC 50458-330-50.
4 mg green tablet: bottles of 60 NDC 50458-350-06, blister pack of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) 1 mg/mL oral solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
Tests indicate that RISPERDAL® (risperidone) oral solution is compatible in the following
beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or
tea, however.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
45
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, and “R4”, respectively. RISPERDAL® M-TAB® Orally
Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of 4 (2 X 2) tablets.
Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant pouch containing a
blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC 50458-395-28,
long-term care packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages per box, NDC 50458-315-28, long-
term care packaging of 30 tablets NDC 50458-315-30.
2 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
Keep out of reach of children.
RISPERDAL® 1 mg/mL oral solution should be stored at controlled room temperature 15°-25°C
(59°-77°F). Protect from light and freezing.
Keep out of reach of children.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
[INSERT NEW COMPONENT CODE]
Revised October 2006
©Janssen 2003
RISPERDAL® tablets are manufactured by:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
46
JOLLC, Gurabo, Puerto Rico or
Janssen-Cilag, SpA, Latina, Italy
RISPERDAL® oral solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico
RISPERDAL® tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and oral solution
are distributed by:
Janssen, L.P.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:17.264613
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021444s008s015,020588s024s028s029,020272s036s041lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 41}
|
12,397
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
1
JANSSEN, L.P.
RISPERDAL®
(risperidone)
TABLETS/ORAL SOLUTION
RISPERDAL® M-TAB®
(risperidone)
ORALLY DISINTEGRATING TABLETS
Increased Mortality in Elderly Patients with Dementia –Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. Analyses of seventeen placebo
controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in
the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients.
Over the course of a typical 10 week controlled trial, the rate of death in drug-treated
patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. RISPERDAL®
(risperidone) is not approved for the treatment of patients with Dementia-Related
Psychosis.
DESCRIPTION
RISPERDAL® (risperidone) is a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
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2
RISPERDAL® tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. Inactive ingredients are colloidal
silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene
glycol, sodium lauryl sulfate, and starch (corn). Tablets of 0.25, 0.5, 2, 3, and 4 mg also contain
talc and titanium dioxide. The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets
contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg
and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No.
2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. The inactive ingredients for this
solution are tartaric acid, benzoic acid, sodium hydroxide, and purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (light coral), 3 mg (coral), and 4 mg (coral) strengths.
RISPERDAL® M-TAB® Orally Disintegrating Tablets contain the following inactive
ingredients: Amberlite® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium
hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition, the 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets contain xanthan gum.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of RISPERDAL® (risperidone), as with other drugs used to treat
schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in
schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2
(5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some
of the other effects of RISPERDAL®.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the
dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations
>10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
3
Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
daily (0.5 to 8 mg BID). Following oral administration of solution or tablet, mean peak plasma
concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-
hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can
be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is 90%,
and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-
hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
4
(e.g., the active moiety) results from the combined concentrations of risperidone plus 9-
hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active
moiety, after single and multiple doses, are similar in extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions (see PRECAUTIONS –
Drug Interactions). First, inhibitors of CYP 2D6 interfere with conversion of risperidone to
9-hydroxyrisperidone. This occurs with quinidine, giving essentially all recipients a risperidone
pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse
effects of risperidone in patients receiving quinidine have not been evaluated, but observations in
a modest number (n≅70) of poor metabolizers given risperidone do not suggest important
differences between poor and extensive metabolizers. Second, co-administration of known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone. It
would also be possible for risperidone to interfere with metabolism of other drugs metabolized
by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely.
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone titrated to
6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional
3 weeks. During co-administration, the plasma concentrations of risperidone and its
pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%.
Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of
other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone
may cause similar decreases in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment (see
PRECAUTIONS – Drug Interactions and DOSAGE AND ADMINISTRATION – Co-
Administration of RISPERDAL® with Certain Other Medications).
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the plasma
concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
5
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-
hydroxyrisperidone by about 10% (see PRECAUTIONS -Drug Interactions and DOSAGE AND
ADMINISTRATION – Co-Administration of RISPERDAL® with Certain Other Medications).
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma
concentrations (Cmax) of lithium (n=13) (see PRECAUTIONS – Drug Interactions).
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma
concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared
to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration
(Cmax) after concomitant administration of risperidone (see PRECAUTIONS – Drug
Interactions).
There were no significant interactions between risperidone (1 mg QD) and erythromycin (500
mg QID) (see PRECAUTIONS – Drug Interactions).
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%,
respectively. However, cimetidine did not affect the AUC of the active moiety, whereas
ranitidine increased the AUC of the active moiety by 20%.
Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety.
In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of
donepezil and galantamine, which are metabolized by CYP 2D6.
RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics
of digoxin.
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at 1
week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of the active moiety, after single and multiple doses, were
similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20
hours.
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
6
Special Populations
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION).
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients (see DOSAGE AND
ADMINISTRATION).
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
CLINICAL TRIALS SCHIZOPHRENIA
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
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NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
7
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (BID schedule), RISPERDAL® was generally superior to placebo on the
BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the
SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL® (2,
6, 10, and 16 mg/day, on a BID schedule), all 4 RISPERDAL® groups were generally
superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score;
the 3 highest RISPERDAL® dose groups were generally superior to placebo on the PANSS
negative subscale. The most consistently positive responses on all measures were seen for the
6 mg dose group, and there was no suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL® (1,
4, 8, 12, and 16 mg/day, on a BID schedule), the four highest RISPERDAL® dose groups
were generally superior to the 1 mg RISPERDAL® dose group on BPRS total score, BPRS
psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg
group on the PANSS negative subscale. The most consistently positive responses were seen
for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a QD schedule), both RISPERDAL® dose groups were
generally superior to placebo on several PANSS measures, including a response measure
(>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster
(derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg
dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
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8
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for 1 to
2 years of observation for relapse. Patients receiving RISPERDAL® experienced a significantly
longer time to relapse over this time period compared to those receiving the active comparator.
Bipolar Mania
Monotherapy
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in 2 short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the Y-MRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of Y-MRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1-6
mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), RISPERDAL®
was superior to placebo in the reduction of Y-MRS total score.
Combination Therapy
The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic
or mixed episodes was established in one controlled trial in patients who met the DSM-IV
criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and
with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2
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9
mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of Y-MRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in
therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of Y-MRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-
hydroxyrisperidone.
Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to
16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were
under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
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10
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5
to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01
mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent
to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this
open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL®
of 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as
≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very
much improved’) during the 4-6 month open-label treatment phase for about 140 days, on
average, were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
INDICATIONS AND USAGE
Schizophrenia
RISPERDAL® (risperidone) is indicated for the treatment of schizophrenia.
The efficacy of RISPERDAL® in schizophrenia was established in short-term (6- to 8-weeks)
controlled trials of schizophrenic inpatients (see CLINICAL PHARMACOLOGY).
The efficacy of RISPERDAL® in delaying relapse was demonstrated in schizophrenic patients
who had been clinically stable for at least 4 weeks before initiation of treatment with
RISPERDAL® or an active comparator and who were then observed for relapse during a period
of 1 to 2 years (see CLINICAL PHARMACOLOGY -Clinical Trials). Nevertheless, the
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11
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Bipolar Mania
Monotherapy
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder.
The efficacy of RISPERDAL® was established in two placebo-controlled trials (3-week) with
patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic
or mixed episode with or without psychotic features (see CLINICAL PHARMACOLOGY).
Combination Therapy
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder.
The efficacy of RISPERDAL® in combination with lithium or valproate was established in one
placebo-controlled (3-week) trial with patients meeting DSM-IV criteria for Bipolar I Disorder
who currently displayed an acute manic or mixed episode with or without psychotic features (see
CLINICAL PHARMACOLOGY).
The effectiveness of RISPERDAL® for longer-term use, that is, for more than 3 weeks of
treatment of an acute episode, and for prophylactic use in mania, has not been systematically
evaluated in controlled clinical trials. Therefore, physicians who elect to use RISPERDAL® for
extended periods should periodically re-evaluate the long-term risks and benefits of the drug for
the individual patient (see DOSAGE AND ADMINISTRATION).
Irritability Associated with Autistic Disorder
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents, including symptoms of aggression towards others, deliberate self-
injuriousness, temper tantrums, and quickly changing moods.
The efficacy of RISPERDAL® was established in two 8-week, placebo-controlled trials in
children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder.
The benefit of maintaining patients with irritability associated with autistic disorder on therapy
with RISPERDAL® after achieving a responder status for an average duration of about 140 days
was demonstrated in a controlled trial (see CLINICAL PHARMACOLOGY - Clinical Trials.)
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12
Physicians who elect to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
CONTRAINDICATIONS
RISPERDAL® (risperidone) is contraindicated in patients with a known hypersensitivity to the
product.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. RISPERDAL®(risperidone) is not
approved for the treatment of dementia-related psychosis (see Boxed Warning).
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional
signs
may
include
elevated
creatinine
phosphokinase,
myoglobinuria
(rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia
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13
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® (risperidone) should be prescribed in a manner that is
most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment
should generally be reserved for patients who suffer from a chronic illness that: (1) is known to
respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially
less harmful treatments are not available or appropriate. In patients who do require chronic
treatment, the smallest dose and the shortest duration of treatment producing a satisfactory
clinical response should be sought. The need for continued treatment should be reassessed
periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients With
Dementia-Related Psychosis
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14
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis (See also Boxed WARNING, WARNINGS: Increased Mortality
in Elderly Patients with Dementia-Related Psychosis.)
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma
or death, has been reported in patients treated with atypical antipsychotics including
RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and glucose
abnormalities is complicated by the possibility of an increased background risk of diabetes
mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the
general population. Given these confounders, the relationship between atypical antipsychotic use
and hyperglycemia-related adverse events is not completely understood. However,
epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related
adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for
hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not
available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has
resolved when the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
PRECAUTIONS
General
Orthostatic Hypotension
RISPERDAL® (risperidone) may induce orthostatic hypotension associated with dizziness,
tachycardia, and in some patients, syncope, especially during the initial dose-titration period,
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15
probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2%
(6/2607) of RISPERDAL®-treated patients in Phase 2 and 3 studies. The risk of orthostatic
hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either QD
or 1 mg BID) in normal adults and 0.5 mg BID in the elderly and patients with renal or hepatic
impairment (see DOSAGE AND ADMINISTRATION). Monitoring of orthostatic vital signs
should be considered in patients for whom this is of concern. A dose reduction should be
considered if hypotension occurs. RISPERDAL® should be used with particular caution in
patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart
failure, or conduction abnormalities), cerebrovascular disease, and conditions which would
predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant
hypotension has been observed with concomitant use of RISPERDAL® and antihypertensive
medication.
Seizures
During premarketing testing, seizures occurred in 0.3% (9/2607) of RISPERDAL®-treated
patients, two in association with hyponatremia. RISPERDAL® should be used cautiously in
patients with a history of seizures.
Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. (See also Boxed WARNING, WARNINGS:
Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels
and the elevation persists during chronic administration. Risperidone is associated with higher
levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
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16
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats (see PRECAUTIONS – Carcinogenesis, Mutagenesis, Impairment of Fertility). Neither
clinical studies nor epidemiologic studies conducted to date have shown an association between
chronic administration of this class of drugs and tumorigenesis in humans; the available evidence
is considered too limited to be conclusive at this time.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
Priapism
Rare cases of priapism have been reported. While the relationship of the events to RISPERDAL®
use has not been established, other drugs with alpha-adrenergic blocking effects have been
reported to induce priapism, and it is possible that RISPERDAL® may share this capacity.
Severe priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving RISPERDAL® in a
large, open premarketing experience (approximately 1300 patients). She experienced jaundice,
fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
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17
Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
Use in Patients With Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to
include confusion, obtundation, postural instability with frequent falls, extrapyramidal
symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration.
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18
Interference With Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy.
Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL®.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL®.
Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M-
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Laboratory Tests
No specific laboratory tests are recommended.
Drug Interactions
The interactions of RISPERDAL® and other drugs have not been systematically evaluated.
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
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19
Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety. Cimetidine
and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively.
However, cimetidine did not affect the AUC of the active moiety, whereas ranitidine increased
the AUC of the active moiety by 20%.
Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.
Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone titrated to 6
mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3
weeks. During co-administration, the plasma concentrations of risperidone and its
pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%.
Plasma concentrations of carbamazepine did not appear to be affected. The dose of risperidone
may need to be titrated accordingly for patients receiving carbamazepine, particularly during
initiation or discontinuation of carbamazepine therapy. Co-administration of other known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause
similar
decreases
in
the
combined
plasma
concentrations
of risperidone
and
9-
hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment.
Fluoxetine and Paroxetine
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the plasma
concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-
hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated
or discontinued, the physician should re-evaluate the dosing of RISPERDAL®. The effects of
discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics
of risperidone and 9-hydroxyrisperidone have not been studied.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma
concentrations (Cmax) of lithium (n=13).
Valproate
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma
concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared
to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration
(Cmax) after concomitant administration of risperidone.
Digoxin
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20
RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics
of digoxin.
Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs (see CLINICAL PHARMACOLOGY). Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
There were no significant interactions between risperidone and erythromycin (see CLINICAL
PHARMACOLOGY).
Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the
pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25
months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2,
0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis.
A maximum tolerated dose was not achieved in male mice. There were statistically significant
increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland
adenocarcinomas. The following table summarizes the multiples of the human dose on a mg/m2
(mg/kg) basis at which these tumors occurred.
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Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown (see PRECAUTIONS, General -Hyperprolactinemia).
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
Pregnancy
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Pregnancy Category C
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits (0.31-5
mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations was not
increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a
mg/m2 basis. In three reproductive studies in rats (two Segment III and a multigenerational
study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5
mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether these deaths were
due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of risperidone during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-
hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
risperidone should not breast-feed.
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Pediatric Use
The safety and effectiveness of RISPERDAL® in pediatric patients with schizophrenia or bipolar
mania have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, placebo-controlled trials in 156 children and adolescent
patients, aged 5 to 16 years (see CLINICAL PHARMACOLOGY - Clinical Trials,
INDICATIONS AND USAGE, and ADVERSE REACTIONS). Additional safety information
was also assessed in a long-term study in patients with autistic disorder, or in short- and long-
term studies in more than 1200 pediatric patients with other psychiatric disorders who were of
similar age and weight, and who received similar dosages of RISPERDAL® as patients who were
treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric
disorders treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia,
which resolved on discontinuation of risperidone treatment (see WARNINGS – Tardive
Dyskinesia).
Weight Gain
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index. When treating patients with RISPERDAL®,
weight gain should be assessed against that expected with normal growth. (See also ADVERSE
REACTIONS.)
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. (See also ADVERSE REACTIONS.) Patients
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24
experiencing persistent somnolence may benefit from a change in dosing regimen (see DOSAGE
AND ADMINISTRATION – Irritability Associated with Autistic Disorder).
Hyperprolactinemia, Growth, and Sexual Maturation
Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in
adults (see PRECAUTIONS - Hyperprolactinemia). In double-blind, placebo-controlled studies
of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) 49% of patients who
received risperidone had elevated prolactin levels compared to 2% of patients who received
placebo.
In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric
disorders treated with risperidone, galactorrhea was reported in 0.8% of risperidone-treated
patients and gynecomastia was reported in 2.3% of risperidone-treated patients.
The long-term effects of risperidone on growth and sexual maturation have not been fully
evaluated.
Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other
drug
therapy
(see CLINICAL PHARMACOLOGY
and
DOSAGE
AND
ADMINISTRATION). While elderly patients exhibit a greater tendency to orthostatic
hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg BID
followed by careful titration (see PRECAUTIONS). Monitoring of orthostatic vital signs should
be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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).
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus risperidone
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when compared to patients treated with risperidone alone or with placebo plus furosemide. No
pathological mechanism has been identified to explain this finding, and no consistent pattern for
cause of death was observed. An increase of mortality in elderly patients with dementia-related
psychosis was seen with the use of RISPERDAL® regardless of concomitant use with
furosemide. RISPERDAL® is not approved for the treatment of patients with dementia-related
psychosis. (See Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients
with Dementia-Related Psychosis.)
ADVERSE REACTIONS
The following findings are based on the short-term, placebo-controlled, North American,
premarketing trials for schizophrenia and acute bipolar mania, and are followed by a description
of adverse events and other safety measures in short-term, placebo-controlled trials in pediatric
patients treated for irritability associated with autistic disorder. In patients with Bipolar I
Disorder, treatment-emergent adverse events are presented separately for risperidone as
monotherapy and as adjunctive therapy to mood stabilizers.
Certain portions of the discussion below relating to objective or numeric safety parameters,
namely dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and
ECG changes are derived from studies in patients with schizophrenia. However, this information
is also generally applicable to bipolar mania and pediatric patients with autistic disorder.
Associated With Discontinuation of Treatment
Schizophrenia
Approximately 9% (244/2607) of RISPERDAL® (risperidone)-treated patients in Phase 2 and 3
studies discontinued treatment due to an adverse event, compared with about 7% on placebo and
10% on active control drugs. The more common events (≥ 0.3%) associated with discontinuation
and considered to be possibly or probably drug-related included:
Adverse Event
RISPERDAL®
Placebo
Extrapyramidal symptoms
2.1%
0%
Dizziness
0.7%
0%
Hyperkinesia
0.6%
0%
Somnolence
0.5%
0%
Nausea
0.3%
0%
Suicide attempt was associated with discontinuation in 1.2% of RISPERDAL®-treated patients
compared to 0.6% of placebo patients, but, given the almost 40-fold greater exposure time in
RISPERDAL® compared to placebo patients, it is unlikely that suicide attempt is a
RISPERDAL®-related adverse event (see PRECAUTIONS). Discontinuation for extrapyramidal
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26
symptoms was 0% in placebo patients, but 3.8% in active-control patients in the Phase 2 and 3
trials.
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, approximately 8% (10/134)
of RISPERDAL®-treated patients discontinued treatment due to an adverse event, compared with
approximately 6% (7/125) of placebo-treated patients. The adverse events associated with
discontinuation and considered to be possibly, probably, or very likely drug-related included
paroniria, somnolence, dizziness, extrapyramidal disorder, and muscle contractions involuntary.
Each of these events occurred in one RISPERDAL®-treated patient (0.7%) and in no placebo-
treated patients (0%).
In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers,
there was no overall difference in the incidence of discontinuation due to adverse events (4% for
RISPERDAL® vs. 4% for placebo).
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
Schizophrenia
In two 6- to 8-week placebo-controlled trials, spontaneously-reported, treatment-emergent
adverse events with an incidence of 5% or greater in at least one of the RISPERDAL® groups
and at least twice that of placebo were anxiety, somnolence, extrapyramidal symptoms,
dizziness, constipation, nausea, dyspepsia, rhinitis, rash, and tachycardia.
Adverse events were also elicited in one of these two trials (i.e., in the fixed-dose trial comparing
RISPERDAL® at doses of 2, 6, 10, and 16 mg/day with placebo) utilizing a checklist for
detecting adverse events, a method that is more sensitive than spontaneous reporting. By this
method, the following additional common and drug-related adverse events occurred at an
incidence of at least 5% and twice the rate of placebo: increased dream activity, increased
duration of sleep, accommodation disturbances, reduced salivation, micturition disturbances,
diarrhea, weight gain, menorrhagia, diminished sexual desire, erectile dysfunction, ejaculatory
dysfunction, and orgastic dysfunction.
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Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, the most commonly
observed adverse events associated with the use of RISPERDAL® (incidence of 5% or greater
and at least twice that of placebo) were somnolence, dystonia, akathisia, dyspepsia, nausea,
parkinsonism, vision abnormal, and saliva increased. In the US placebo-controlled trial with
risperidone as adjunctive therapy to mood stabilizers, the most commonly observed adverse
events associated with the use of RISPERDAL® were somnolence, dizziness, parkinsonism,
saliva increased, akathisia, abdominal pain, and urinary incontinence.
Adverse Events Occurring at an Incidence of 1% or More Among RISPERDAL®-Treated
Patients - Schizophrenia
The table that follows enumerates adverse events that occurred at an incidence of 1% or more,
and were more frequent among RISPERDAL®-treated patients treated at doses of ≤10 mg/day
than among placebo-treated patients in the pooled results of two 6- to 8-week controlled trials.
Patients received RISPERDAL® doses of 2, 6, 10, or 16 mg/day in the dose comparison trial, or
up to a maximum dose of 10 mg/day in the titration study. This table shows the percentage of
patients in each dose group (≤10 mg/day or 16 mg/day) who spontaneously reported at least one
episode of an event at some time during their treatment. Patients given doses of 2, 6, or 10 mg
did not differ materially in these rates. Reported adverse events were classified using the World
Health Organization preferred terms.
The prescriber should be aware that these figures cannot be used to predict the incidence of side
effects in the course of usual medical practice where patient characteristics and other factors
differ from those which prevailed in this clinical trial. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving different treatments,
uses, and investigators. The cited figures, however, do provide the prescribing physician with
some basis for estimating the relative contribution of drug and non-drug factors to the side effect
incidence rate in the population studied.
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Table 1: Incidence of Treatment-Emergent Adverse Events in 6- to 8-Week Controlled Clinical Trials in
Schizophrenia 1
RISPERDAL®
Body System/
Preferred Term
<10mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(N=142)
Psychiatric
Insomnia
26%
23%
19%
Agitation
22%
26%
20%
Anxiety
12%
20%
9%
Somnolence
3%
8%
1%
Aggressive reaction
1%
3%
1%
Central & peripheral nervous system
Extrapyramidal symptoms2
17%
34%
16%
Headache
14%
12%
12%
Dizziness
4%
7%
1%
Gastrointestinal
Constipation
7%
13%
3%
Nausea
6%
4%
3%
Dyspepsia
5%
10%
4%
Vomiting
5%
7%
4%
Abdominal pain
4%
1%
0%
Saliva increased
2%
0%
1%
Toothache
2%
0%
0%
Respiratory system
Rhinitis
10%
8%
4%
Coughing
3%
3%
1%
Sinusitis
2%
1%
1%
Pharyngitis
2%
3%
0%
Dyspnea
1%
0%
0%
Body as a whole – general
Back pain
2%
0%
1%
Chest pain
2%
3%
1%
Fever
2%
3%
0%
Dermatological
Rash
2%
5%
1%
Dry skin
2%
4%
0%
Seborrhea
1%
0%
0%
Infections
Upper respiratory
3%
3%
1%
Visual
Abnormal vision
2%
1%
1%
Musculo-Skeletal
Arthralgia
2%
3%
0%
Cardiovascular
Tachycardia
3%
5%
0%
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1 Events reported by at least 1% of patients treated with RISPERDAL® ≤10 mg/day are included,
and are rounded to the nearest %. Comparative rates for RISPERDAL® 16 mg/day and placebo
are provided as well. Events for which the RISPERDAL® incidence (in both dose groups) was
equal to or less than placebo are not listed in the table, but included the following: nervousness,
injury, and fungal infection.
2 Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculogyric crisis, ataxia,
abnormal gait, involuntary muscle contractions, hyporeflexia, akathisia, and extrapyramidal
disorders. Although the incidence of 'extrapyramidal symptoms' does not appear to differ for the
'10 mg/day' group and placebo, the data for individual dose groups in fixed dose trials do suggest
a dose/response relationship (see ADVERSE REACTIONS – Dose Dependency of Adverse
Events).
Adverse Events Occurring at an Incidence of 2% or More Among RISPERDAL®-Treated
Patients - Bipolar Mania
Tables 2 and 3 display adverse events that occurred at an incidence of 2% or more, and were
more frequent among patients treated with flexible doses of RISPERDAL® (1-6 mg daily as
monotherapy and as adjunctive therapy to mood stabilizers, respectively) than among patients
treated with placebo. Reported adverse events were classified using the World Health
Organization preferred terms.
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Table 2: Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Monotherapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL®
(N=134)
Placebo
(N=125)
Central & peripheral nervous system
Dystonia
18%
6%
Akathisia
16%
6%
Dizziness
11%
9%
Parkinsonism
6%
3%
Hypoaesthesia
2%
1%
Psychiatric
Somnolence
28%
7%
Agitation
8%
6%
Manic reaction
8%
6%
Anxiety
4%
2%
Concentration impaired
2%
1%
Gastrointestinal system
Dyspepsia
11%
6%
Nausea
11%
2%
Saliva increased
5%
1%
Mouth dry
3%
2%
Body as a whole - general
Pain
5%
3%
Fatigue
4%
2%
Injury
2%
0%
Respiratory system
Sinusitis
4%
1%
Rhinitis
3%
2%
Coughing
2%
2%
Skin and appendages
Acne
2%
0%
Pruritus
2%
1%
Musculo-Skeletal
Myalgia
5%
2%
Skeletal pain
2%
1%
Metabolic and nutritional
Weight increase
2%
0%
Vision disorders
Vision abnormal
6%
2%
Cardiovascular, general
Hypertension
3%
1%
Hypotension
2%
0%
Heart rate and rhythm
Tachycardia
3%
2%
1 Events reported by at least 2% of patients treated with RISPERDAL® are included and are
rounded to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL®
that were less than the incidence reported by patients treated with placebo are not listed in the
table, but included the following: headache, tremor, insomnia, constipation, back pain, upper
respiratory tract infection, pharyngitis, and arthralgia.
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Table 3: Incidence of Treatment-Emergent Adverse Events in a 3-Week, Placebo-Controlled Trial -
Adjunctive Therapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL®
+ Mood Stabilizer
(N=52)
Placebo
+ Mood Stabilizer
(N=51)
Gastrointestinal system
Saliva increased
10%
0%
Diarrhea
8%
4%
Abdominal pain
6%
0%
Constipation
6%
4%
Mouth dry
6%
4%
Tooth ache
4%
0%
Tooth disorder
4%
0%
Central & peripheral nervous system
Dizziness
14%
2%
Parkinsonism
14%
4%
Akathisia
8%
0%
Dystonia
6%
4%
Psychiatric
Somnolence
25%
12%
Anxiety
6%
4%
Confusion
4%
0%
Respiratory system
Rhinitis
8%
4%
Pharyngitis
6%
4%
Coughing
4%
0%
Body as a whole - general
Asthenia
4%
2%
Urinary system
Urinary incontinence
6%
2%
Heart rate and rhythm
Tachycardia
4%
2%
Metabolic and nutritional
Weight increase
4%
2%
Skin and appendages
Rash
4%
2%
1 Events reported by at least 2% of patients treated with RISPERDAL® are included and are
rounded to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL®
that were less than the incidence reported by patients treated with placebo are not listed in the
table, but included the following: dyspepsia, nausea, vomiting, headache, tremor, insomnia,
chest pain, fatigue, pain, skeletal pain, hypertension, and vision abnormal.
Dose Dependency of Adverse Events
Extrapyramidal Symptoms
Data from two fixed-dose trials provided evidence of dose-relatedness for extrapyramidal
symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a parkinsonism
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score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2)
incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
Ris 2
Ris 6
Ris 10
Ris 16
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
13%
16%
20%
31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups
Ris 1
Ris 4
Ris 8
Ris 12
Ris 16
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
18%
18%
21%
Other Adverse Events
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse events: sleepiness, increased duration of sleep,
accommodation disturbances, orthostatic dizziness, palpitations, weight gain, erectile
dysfunction,
ejaculatory
dysfunction,
orgastic
dysfunction,
asthenia/lassitude/increased
fatigability, and increased pigmentation.
Vital Sign Changes
RISPERDAL®
is
associated
with
orthostatic
hypotension
and
tachycardia
(see PRECAUTIONS).
Weight Changes
The proportions of RISPERDAL® and placebo-treated patients meeting a weight gain criterion
of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials,
revealing a statistically significantly greater incidence of weight gain for RISPERDAL® (18%)
compared to placebo (9%).
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33
Laboratory Changes
A between-group comparison for 6- to 8-week placebo-controlled trials revealed no statistically
significant RISPERDAL®/placebo differences in the proportions of patients experiencing
potentially important changes in routine serum chemistry, hematology, or urinalysis parameters.
Similarly, there were no RISPERDAL®/placebo differences in the incidence of discontinuations
for changes in serum chemistry, hematology, or urinalysis. However, RISPERDAL®
administration was associated with increases in serum prolactin (see PRECAUTIONS).
ECG Changes
Between-group comparisons for pooled placebo-controlled trials revealed no statistically
significant differences between risperidone and placebo in mean changes from baseline in ECG
parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL® doses
were pooled from randomized controlled trials in several indications, there was a mean increase
in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term
schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher
mean increase in heart rate compared to placebo (4-6 beats per minute).
Adverse Events and Other Safety Measures in Pediatric Patients With Autistic
Disorder
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n=156), two patients (one treated with RISPERDAL® and one treated with
placebo) discontinued treatment due to an adverse event.
In addition to spontaneous reporting, in one of the studies, adverse events were also elicited from
a checklist for detecting selected events, a method that is more sensitive than spontaneous
reporting.
The most common adverse events with RISPERDAL® that occurred at an incidence equal to or
greater than 5% and at a rate of at least twice that of placebo are shown in Table 4.
Table 4
Incidence of Treatment-Emergent Adverse Events in Two 8-Week, Placebo-Controlled
Trials in Pediatric Patients with Autistic Disorder
Body System
Preferred Term
RISPERDAL®
(n=76)
Placebo
(n=80)
Psychiatric
Somnolence
67%
23%
Appetite increased
49%
19%
Confusion
5%
0%
Gastrointestinal
Saliva increased
22%
6%
Constipation
21%
8%
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34
Dry mouth
13%
6%
Body as a whole - general
Fatigue
42%
13%
Central & peripheral
nervous system
Tremor
12%
1%
Dystonia
12%
6%
Dizziness
9%
3%
Automatism
7%
1%
Dyskinesia
7%
0%
Parkinsonism
8%
0%
Respiratory
Upper respiratory tract
infection
34%
15%
Metabolic and nutritional
Weight increase
5%
0%
Heart rate and rhythm
Tachycardia
7%
0%
Weight increase was reported more frequently with RISPERDAL® than with placebo. The
average weight increase over 8 weeks was 2.6 kg in patients treated with RISPERDAL®
compared with 0.9 kg in patients treated with placebo. (See also PRECAUTIONS – Pediatric
Use – Weight Gain.)
There was a higher incidence of adverse events reflecting extrapyramidal symptoms (EPS) in the
RISPERDAL® group (27.6%) compared with the placebo group (10.0%). In addition, between-
group comparison of the severity of EPS were assessed objectively by the following rating
instruments: the Simpson-Angus Rating Scale (SARS) and the Abnormal Involuntary Movement
Scale (AIMS) in one study, and the Extrapyramidal Symptom Rating Scale (ESRS) in the other
study. The mean changes between baseline and endpoint in the total ESRS score were –0.3 in the
RISPERDAL® group and –0.4 in the placebo group. The median change from baseline to
endpoint was 0 in both treatment groups for each EPS rating scale.
Somnolence was the most frequent adverse event, and was reported at a higher incidence in the
RISPERDAL® group compared with the placebo group. The vast majority of cases (96%) were
either mild or moderate in severity. These events were most often of early onset with peak
incidence occurring during the first 2 weeks of treatment, and median duration was 16 days.
Patients experiencing persistent somnolence may benefit from a change in dosing regimen (see
DOSAGE AND ADMINISTRATION – Irritability Associated with Autistic Disorder –
Pediatrics [Children and Adolescents]).
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Other Events Observed During the Premarketing Evaluation of RISPERDAL®
During its premarketing assessment, multiple doses of RISPERDAL® were administered to 2607
adult patients with schizophrenia and 1923 pediatric patients in Phase 2 and 3 studies. The
conditions and duration of exposure to RISPERDAL® varied greatly, and included (in
overlapping categories) open-label and double-blind studies, uncontrolled and controlled studies,
inpatient and outpatient studies, fixed-dose and titration studies, and short-term or longer-term
exposure. In most studies, untoward events associated with this exposure were obtained by
spontaneous report and recorded by clinical investigators using terminology of their own
choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of
individuals experiencing adverse events without first grouping similar types of untoward events
into a smaller number of standardized event categories. In two large studies, adverse events were
also elicited utilizing the UKU (direct questioning) side effect rating scale, and these events were
not further categorized using standard terminology. (Note: These events are marked with an
asterisk in the listings that follow.)
In the listings that follow, spontaneously reported adverse events were classified using World
Health Organization (WHO) preferred terms. The frequencies presented, therefore, represent the
proportion of the 2607 adult or 1923 pediatric patients exposed to multiple doses of
RISPERDAL® who experienced an event of the type cited on at least one occasion while
receiving RISPERDAL®. All reported events are included, except those already listed in Table 1,
those events for which a drug cause was remote, and those event terms which were so general as
to be uninformative. It is important to emphasize that, although the events reported occurred
during treatment with RISPERDAL®, they were not necessarily caused by it. Serious adverse
reactions experienced by the pediatric population were similar to those seen in the adult
population (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS).
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring in at least
1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials
appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients;
rare events are those occurring in fewer than 1/1000 patients.
Psychiatric Disorders
Frequent: increased dream activity∗, diminished sexual desire∗, nervousness. Infrequent:
impaired concentration, depression, apathy, catatonic reaction, euphoria, increased libido,
amnesia. Rare: emotional lability, nightmares, delirium, withdrawal syndrome, yawning.
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Central and Peripheral Nervous System Disorders
Frequent: increased sleep duration∗. Infrequent: dysarthria, vertigo, stupor, paraesthesia,
confusion. Rare: aphasia, cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps,
torticollis, hypotonia, coma, migraine, hyperreflexia, choreoathetosis.
Gastrointestinal Disorders
Frequent: anorexia, reduced salivation∗. Infrequent: flatulence, diarrhea, increased appetite,
stomatitis, melena, dysphagia, hemorrhoids, gastritis. Rare: fecal incontinence, eructation,
gastroesophageal reflux, gastroenteritis, esophagitis, tongue discoloration, cholelithiasis, tongue
edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis.
Body as a Whole/General Disorders
Frequent: fatigue. Infrequent: edema, rigors, malaise, influenza-like symptoms. Rare: pallor,
enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing.
Respiratory System Disorders
Infrequent: hyperventilation, bronchospasm, pneumonia, stridor. Rare: asthma, increased
sputum, aspiration.
Skin and Appendage Disorders
Frequent: increased pigmentation∗, photosensitivity∗ Infrequent: increased sweating, acne,
decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation. Rare: bullous eruption,
skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis,
genital pruritus, urticaria.
Cardiovascular Disorders
Infrequent: palpitation, hypertension, hypotension, AV block, myocardial infarction. Rare:
ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversions,
ventricular extrasystoles, ST depression, myocarditis.
Vision Disorders
Infrequent: abnormal accommodation, xerophthalmia. Rare: diplopia, eye pain, blepharitis,
photopsia, photophobia, abnormal lacrimation.
Metabolic and Nutritional Disorders
Infrequent: hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight
decrease, diabetes mellitus. Rare: decreased serum iron, cachexia, dehydration, hypokalemia,
hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia.
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Urinary System Disorders
Frequent: polyuria/polydipsia∗. Infrequent: urinary incontinence, hematuria, dysuria. Rare:
urinary retention, cystitis, renal insufficiency.
Musculo-Skeletal System Disorders
Infrequent: myalgia. Rare: arthrosis, synostosis, bursitis, arthritis, skeletal pain.
Reproductive Disorders, Female
Frequent: menorrhagia∗, orgastic dysfunction∗, dry vagina∗ Infrequent: nonpuerperal lactation,
amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain,
intermenstrual bleeding, vaginal hemorrhage.
Liver and Biliary System Disorders
Infrequent: increased SGOT, increased SGPT. Rare: hepatic failure, cholestatic hepatitis,
cholecystitis, cholelithiasis, hepatitis, hepatocellular damage.
Platelet, Bleeding, and Clotting Disorders
Infrequent: epistaxis, purpura. Rare: hemorrhage, superficial phlebitis, thrombophlebitis,
thrombocytopenia.
Hearing and Vestibular Disorders
Rare: tinnitus, hyperacusis, decreased hearing.
Red Blood Cell Disorders
Infrequent: anemia, hypochromic anemia. Rare: normocytic anemia.
Reproductive Disorders, Male
Frequent: erectile dysfunction∗ Infrequent: ejaculation failure.
White Cell and Resistance Disorders
Infrequent: granulocytopenia. Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet
anomaly.
Endocrine Disorders
Rare: gynecomastia, male breast pain, antidiuretic hormone disorder.
Special Senses
Rare: bitter taste.
∗ Incidence based on elicited reports.
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Postintroduction Reports
Adverse events reported since market introduction which were temporally (but not necessarily
causally) related to RISPERDAL® therapy, include the following: anaphylactic reaction,
angioedema, apnea, atrial fibrillation, cerebrovascular disorder, including cerebrovascular
accident, diabetes mellitus aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal
obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated, pituitary adenomas,
pulmonary embolism, and precocious puberty. There have been rare reports of sudden death
and/or cardiopulmonary arrest in patients receiving RISPERDAL®. A causal relationship with
RISPERDAL® has not been established. It is important to note that sudden and unexpected death
may occur in psychotic patients whether they remain untreated or whether they are treated with
other antipsychotic drugs.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
RISPERDAL® (risperidone) is not a controlled substance.
Physical and Psychological Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for
any drug-seeking behavior, these observations were not systematic and it is not possible to
predict on the basis of this limited experience the extent to which a CNS-active drug will be
misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated
carefully for a history of drug abuse, and such patients should be observed closely for signs of
RISPERDAL® misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking
behavior).
OVERDOSAGE
Human Experience
Premarketing experience included eight reports of acute RISPERDAL® (risperidone) overdosage
with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
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Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse events reported
since market introduction which were temporally (but not necessarily causally) related to
RISPERDAL® overdose, include torsade de pointes, prolonged QT interval, convulsions,
cardiopulmonary arrest, and rare fatality associated with multiple drug overdose.
Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
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DOSAGE AND ADMINISTRATION
Schizophrenia
Usual Initial Dose
RISPERDAL® (risperidone) can be administered on either a BID or a QD schedule. In early
clinical trials, RISPERDAL® was generally administered at 1 mg BID initially, with increases in
increments of 1 mg BID on the second and third day, as tolerated, to a target dose of 3 mg BID
by the third day. Subsequent controlled trials have indicated that total daily risperidone doses of
up to 8 mg on a QD regimen are also safe and effective. However, regardless of which regimen
is employed, in some patients a slower titration may be medically appropriate. Further dosage
adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady
state for the active metabolite would not be achieved for approximately 1 week in the typical
patient. When dosage adjustments are necessary, small dose increments/decrements of 1-2 mg
are recommended.
Efficacy in schizophrenia was demonstrated in a dose range of 4 to 16 mg/day in the clinical
trials supporting effectiveness of RISPERDAL®; however, maximal effect was generally seen in
a range of 4 to 8 mg/day. Doses above 6 mg/day for BID dosing were not demonstrated to be
more efficacious than lower doses, were associated with more extrapyramidal symptoms and
other adverse effects, and are not generally recommended. In a single study supporting QD
dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses
above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While there is no body of evidence available to answer the question of how long the
schizophrenic patient treated with RISPERDAL® should remain on it, the effectiveness of
RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial
in patients who had been clinically stable for at least 4 weeks and were then followed for a
period of 1 to 2 years. In this trial, RISPERDAL® was administered on a QD schedule, at 1 mg
QD initially, with increases to 2 mg QD on the second day, and to a target dose of 4 mg QD on
the third day (see CLINICAL PHARMACOLOGY – Clinical Trials). Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment with an
appropriate dose.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that when restarting patients who have had an interval off RISPERDAL®, the initial titration
schedule should be followed.
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Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or concerning concomitant administration
with other antipsychotics. While immediate discontinuation of the previous antipsychotic
treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may
be most appropriate for others. In all cases, the period of overlapping antipsychotic
administration should be minimized. When switching schizophrenic patients from depot
antipsychotics, if medically appropriate, initiate RISPERDAL® therapy in place of the next
scheduled injection. The need for continuing existing EPS medication should be re-evaluated
periodically.
Pediatric Use
The safety and effectiveness of RISPERDAL® in pediatric patients with schizophrenia have not
been established.
Bipolar Mania
Usual Dose
Risperidone should be administered on a once daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day (see CLINICAL PHARMACOLOGY – Clinical Trials).
RISPERDAL® doses higher than 6 mg per day were not studied.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
risperidone. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of risperidone
in such longer-term treatment (i.e., beyond 3 weeks).
Pediatric Use
The safety and effectiveness of RISPERDAL® in pediatric patients with bipolar mania have not
been established.
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Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weighed less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, see CLINICAL PHARMACOLOGY – Clinical Trials) received doses of RISPERDAL®
between 0.5 mg and 2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the
pivotal trials, when the therapeutic effect reached plateau, was 1.0 mg in patients < 20 kg, 2.5 mg
in patients ≥ 20 kg, or 3.0 mg in patients > 45 kg. No dosing data are available for children who
weigh less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
Dosage in Special Populations
The recommended initial dose is 0.5 mg BID in patients who are elderly or debilitated, patients
with severe renal or hepatic impairment, and patients either predisposed to hypotension or for
whom hypotension would pose a risk. Dosage increases in these patients should be in increments
of no more than 0.5 mg BID. Increases to dosages above 1.5 mg BID should generally occur at
intervals of at least 1 week. In some patients, slower titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
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increases in the free fraction of risperidone, possibly resulting in an enhanced effect (see
CLINICAL PHARMACOLOGY). Patients with a predisposition to hypotensive reactions or for
whom such reactions would pose a particular risk likewise need to be titrated cautiously and
carefully monitored (see PRECAUTIONS). If a once-a-day dosing regimen in the elderly or
debilitated patient is being considered, it is recommended that the patient be titrated on a twice-a-
day regimen for 2-3 days at the target dose. Subsequent switches to a once-a-day dosing regimen
can be done thereafter.
Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with risperidone would be expected to cause decreases in the plasma
concentrations of active moiety (the sum of risperidone and 9-hydroxyrisperidone), which could
lead to decreased efficacy of risperidone treatment. The dose of risperidone needs to be titrated
accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers (see CLINICAL PHARMACOLOGY and
PRECAUTIONS).
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-
hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is
co-administered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-
resistant pouch containing a blister with 1 tablet each.
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The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M-
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
HOW SUPPLIED
RISPERDAL® (risperidone) tablets are imprinted "JANSSEN", and either “Ris” and the strength
“0.25”, “0.5”, or "R" and the strength "1", "2", "3", or "4".
0.25 mg dark yellow tablet: bottles of 60 NDC 50458-301-04, bottles of 500 NDC 50458-301-
50, hospital unit dose packs of 100 NDC 50458-301-01.
0.5 mg red-brown tablet: bottles of 60 NDC 50458-302-06, bottles of 500 NDC 50458-302-50,
hospital unit dose packs of 100 NDC 50458-302-01.
1 mg white tablet: bottles of 60 NDC 50458-300-06, blister pack of 100 NDC 50458-300-01,
bottles of 500 NDC 50458-300-50.
2 mg orange tablet: bottles of 60 NDC 50458-320-06, blister pack of 100 NDC 50458-320-01,
bottles of 500 NDC 50458-320-50.
3 mg yellow tablet: bottles of 60 NDC 50458-330-06, blister pack of 100 NDC 50458-330-01,
bottles of 500 NDC 50458-330-50.
4 mg green tablet: bottles of 60 NDC 50458-350-06, blister pack of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) 1 mg/mL oral solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
Tests indicate that RISPERDAL® (risperidone) oral solution is compatible in the following
beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or
tea, however.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
45
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, and “R4”, respectively. RISPERDAL® M-TAB® Orally
Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of 4 (2 X 2) tablets.
Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant pouch containing a
blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC 50458-395-28,
long-term care packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages per box, NDC 50458-315-28, long-
term care packaging of 30 tablets NDC 50458-315-30.
2 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
Keep out of reach of children.
RISPERDAL® 1 mg/mL oral solution should be stored at controlled room temperature 15°-25°C
(59°-77°F). Protect from light and freezing.
Keep out of reach of children.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
[INSERT NEW COMPONENT CODE]
Revised October 2006
©Janssen 2003
RISPERDAL® tablets are manufactured by:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-272 / S-036, 20-588 / S-024, 21-444 / S-008: Final Agreed-Upon Labeling
46
JOLLC, Gurabo, Puerto Rico or
Janssen-Cilag, SpA, Latina, Italy
RISPERDAL® oral solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico
RISPERDAL® tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and oral solution
are distributed by:
Janssen, L.P.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:17.338094
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021444s008s015,020588s024s028s029,020272s036s041lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
12,394
|
For Pediatric Use
LUPRON® INJECTION
(leuprolide acetate)
Rx only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing
hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The
chemical name is 5- oxo -L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl
N-ethyl-L-prolinamide acetate (salt) with the following structural formula: Structural Formula
LUPRON INJECTION is a sterile, aqueous solution intended for daily subcutaneous injection.
It is available in a 2.8 mL multiple dose vial containing leuprolide acetate (5 mg/mL), sodium chloride,
USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water
for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid,
NF.
CLINICAL PHARMACOLOGY
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given
continuously and in therapeutic doses. Animal and human studies indicate that following an initial
stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of
ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
Pharmacokinetics
A pharmacokinetic study of leuprolide acetate in children has not been performed.
Absorption
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In adults, bioavailability by subcutaneous administration is comparable to that by intravenous
administration.
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration
to healthy adult male volunteers was 27 L. In vitro binding to human plasma proteins ranged from
43% to 49%.
Metabolism
In healthy adult male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that
the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3
hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller
inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide
(Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached
maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug
concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of
mean leuprolide concentrations.
Excretion
Following administration of LUPRON DEPOT 3.75 mg to three adult patients, less than 5% of the
dose was recovered as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients has not been
determined.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide
acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase
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and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to
occur.
CLINICAL STUDIES
In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to
prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females
respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and
development. Natural maturation occurs when gonadotropins return to pubertal levels following
discontinuation of leuprolide acetate.
The following physiologic effects have been noted with the chronic administration of leuprolide
acetate in this patient population.
1. Skeletal Growth. A measurable increase in body length can be noted since the epiphyseal
plates will not close prematurely.
2. Organ Growth. Reproductive organs will return to a prepubertal state.
3. Menses. Menses, if present, will cease.
INDICATIONS AND USAGE
LUPRON INJECTION is indicated in the treatment of children with central precocious puberty.
Children should be selected using the following criteria:
1. Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual
characteristics earlier than 8 years in females and 9 years in males.
2. Clinical diagnosis should be confirmed prior to initiation of therapy:
• Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The
sensitivity and methodology of this assay must be understood.
• Bone age advanced 1 year beyond the chronological age.
3. Baseline evaluation should also include:
• Height and weight measurements.
• Sex steroid levels.
• Adrenal steroid level to exclude congenital adrenal hyperplasia.
• Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting
tumor.
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•
Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor.
•
Computerized tomography of the head to rule out intracranial tumor.
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON
INJECTION. Reports of anaphylactic reactions to GnRH agonist analogs have been reported
in the medical literature.1,2
2. LUPRON is contraindicated in women who are or may become pregnant while receiving the
drug. LUPRON may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate
throughout gestation. There was increased fetal mortality and decreased fetal weights in rats
and rabbits. (See PRECAUTIONS, Pregnancy, Teratogenic Effects section.) The effects on
fetal mortality are expected consequences of the alterations in hormonal levels brought about
by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is
administered during pregnancy. If this drug is administered during pregnancy or if the patient
becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of
the potential hazard to the fetus.
WARNINGS
During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the
natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be
observed (see CLINICAL PHARMACOLOGY section).
Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the
pubertal process. The consequences of poor control include the return of pubertal signs such as
menses, breast development, and testicular growth. The long-term consequences of inadequate
control of gonadal steroid secretion are unknown, but may include a further compromise of adult
stature.
PRECAUTIONS
Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of LUPRON INJECTION,
may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the
injection site.
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Information for Parents
Prior to starting therapy with LUPRON INJECTION, the parent or guardian must be aware of the
importance of continuous therapy. Adherence to daily drug administration schedules must be
accepted if therapy is to be successful. Irregular dosing could restart the maturation process.
• During the first 2 months of therapy, a female may experience menses or spotting. If bleeding
continues beyond the second month, notify the physician.
• Any irritation at the injection site should be reported to the physician immediately. If the child
has experienced an allergic reaction to other drugs like LUPRON, this drug should not be
used.
• Report any unusual signs or symptoms to the physician, like continued pubertal changes,
substantial mood swings or behavioral changes.
Laboratory Tests
Response to leuprolide acetate should be monitored 1-2 months after the start of therapy with a
GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be
done every 6-12 months.
Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see
WARNINGS section). Once a therapeutic dose has been established, gonadotropin and sex steroid
levels will decline to prepubertal levels.
Drug Interactions
See CLINICAL PHARMACOLOGY, Pharmacokinetics section.
Drug/Laboratory Test Interactions
Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-
gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is
discontinued.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of
benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug
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was administered subcutaneously at high daily doses of 0.6 to 4 mg/kg (>100 times the clinical doses
of 7.5 to 15 mg/month based on body surface area). There was a significant but not dose-related
increase of pancreatic islet-cell adenomas in females and of testes interstitial cell adenomas in males
(highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary
abnormalities were observed at daily dose as high as 60 mg/kg (>5000 times the clinical doses based
on body surface area). Adult patients have been treated with leuprolide acetate for up to three years
with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without
demonstrable pituitary abnormalities.
Although no clinical studies have been completed in children to assess the full reversibility of fertility
suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and
other GnRH analogs have shown functional recovery. However, following a study with leuprolide
acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery
period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the
controls. Also, no histologic changes were observed in the female rats following the same protocol. In
both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the
parents on the reproductive performance of the F1 generation was not tested. The clinical
significance of these findings is unknown.
Pregnancy
Teratogenic Effects
Pregnancy Category X
(see CONTRAINDICATIONS section)
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg
(1/1200 to 1/12 the human pediatric dose) to rabbits, LUPRON produced a dose-related increase in
major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal
malformations. There was increased fetal mortality and decreased fetal weights with the two higher
doses of LUPRON in rabbits and with the highest dose in rats.
Nursing Mothers
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It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by
nursing mothers.
Geriatric Use
See labeling for LUPRON INJECTION for the pharmacokinetics, efficacy and safety of LUPRON in
this population.
ADVERSE REACTIONS
Clinical Trials:
Potential exacerbation of signs and symptoms during the first few weeks of treatment (see
PRECAUTIONS section) is a concern in patients with rapidly advancing central precocious puberty.
In two studies of children with central precocious puberty, in 2% or more of the patients receiving the
drug, the following adverse reactions were reported to have a possible or probable relationship to
drug as ascribed by the treating physician. Reactions considered not drug related are excluded.
Number of Patients
N = 395 (Percent)
Body as a Whole
General Pain
7
(2)
Integumentary System
Acne/Seborrhea
7
(2)
Injection Site Reactions Including Abscess
21
(5)
Rash Including Erythema Multiforme
8
(2)
Urogenital System
Vaginitis/Bleeding/ Discharge
7
(2)
In those same studies, the following adverse reactions were reported in less than 2% of the patients.
Body as a Whole - Body Odor, Fever, Headache, Infection; Cardiovascular System - Syncope,
Vasodilation; Digestive System - Dysphagia, Gingivitis, Nausea/Vomiting; Endocrine System
Accelerated Sexual Maturity; Metabolic and Nutritional Disorders - Peripheral Edema, Weight Gain;
Nervous System - Nervousness, Personality Disorder, Somnolence, Emotional Lability; Respiratory
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System - Epistaxis; Integumentary System - Alopecia, Skin Striae; Urogenital System - Cervix
Disorder, Gynecomastia/Breast Disorders, Urinary Incontinence.
Postmarketing
During postmarketing surveillance, which includes other dosage forms and other patient populations,
the following adverse events were reported.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of
about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders,
gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Cardiovascular System – Hypotension, Pulmonary embolism; Gastrointestinal System – Hepatic
dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth;
Central/Peripheral Nervous System – Peripheral neuropathy, Spinal fracture/paralysis, Hearing
disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal
System – Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders; Urogenital
System – Prostate pain.
Changes in Bone Density: Decreased bone density has been reported in the medical literature in men
who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial,
25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at
least six months, underwent bone density studies as a result of pain. The leuprolide-treated group
had lower bone density scores than the nontreated control group. The effects on bone density in
children are unknown.
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical
syndrome secondary to infarction of the pituitary gland) have been reported after the administration of
gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was
diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and
some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache,
vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular
collapse. Immediate medical attention has been required.
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See other LUPRON INJECTION and LUPRON DEPOT package inserts for adverse events reported
in other patient populations.
OVERDOSAGE
In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose,
expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at
the injection site. There is no evidence at present that there is a clinical counterpart of this
phenomenon. In early clinical trials using leuprolide acetate in adult patients, doses as high as 20
mg/day for up to two years caused no adverse effects differing from those observed with the 1
mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON INJECTION can be administered by a patient/parent or health care professional.
The dose of LUPRON INJECTION must be individualized for each child. The dose is based on a
mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio.
After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH
stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone
age for advancement should be monitored every 6-12 months. The dose should be titrated upward
until no progression of the condition is noted either clinically and/or by laboratory parameters.
The first dose found to result in adequate downregulation can probably be maintained for the duration
of therapy in most children. However, there are insufficient data to guide dosage adjustment as
patients move into higher weight categories after beginning therapy at very young ages and low
dosages. It is recommended that adequate downregulation be verified in such patients whose weight
has increased significantly while on therapy.
As with other drugs administered by injection, the injection site should be varied periodically.
Discontinuation of LUPRON INJECTION should be considered before age 11 for females and age 12
for males.
The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If
total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose
will be considered the maintenance dose.
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Usage Illustration
Follow the pictorial directions on the reverse side of this package insert for administration.
NOTE: As with other parenteral products, inspect the solution for discoloration and particulate matter
before each use.
HOW SUPPLIED
LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial.
The vial is packaged as follows:
• 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC
0074-3612-30.
• Six-vial carton, NDC 0074-3612-34.
• Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use.
• Use the syringes supplied with LUPRON INJECTION.
U.S. Patent Nos. 4,005,063; 4,005,194.
REFERENCES
1. Taylor, JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Australia 1994 Oct;
161(3): 455.
2. Letterie GS, et al. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol
1991 Nov; 78: 943–946.
Manufactured for
Abbott Laboratories
North Chicago, IL 60064, U.S.A.
® – Registered
(No. 3612)
ADMINISTERING THE INJECTION
Read this booklet before injecting the medication. Read the complete instructions for injection.
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Abbott Laboratories
North Chicago, IL 60064, U.S.A.
(No. 3612)
May, 2009
© 2008 Abbott Laboratories
Provided as an educational service by
Abbott Laboratories
Abbott Laboratories
North Chicago, IL 60064, U.S.A.
ADMINISTERING THE INJECTION
1.
Wash hands thoroughly. Usage Illustration
2.
Check the liquid in the container. It should look clear. DO NOT USE if it is not clear or if it has
particles in it. If using a new bottle, flip off the plastic cover to expose the grey rubber stopper.
Use an alcohol swab to cleanse the metal ring and rubber stopper on medication bottle every
day, just before you use it. Usage Illustration
3.
Remove outer wrapping from one syringe. Usage Illustration
4.
Pull the syringe plunger back until its tip is at the proper mark.
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5.
Uncover needle. Do not touch the needle. Usage Illustration
6.
Place the bottle on a clean, flat surface and push the needle through the center of the rubber
stopper on the bottle. Push the plunger all the way in to inject air into the bottle. Usage Illustration
7.
Keep the needle in the bottle.
Lift the bottle and turn it straight upside down.
Check to see that the needle tip is in the liquid. Usage Illustration
8.
With the needle tip in the liquid, slowly pull back the plunger until syringe fills to the proper
mark.
If any bubbles appear in the syringe, remove them by pushing the plunger up slowly.
With the needle tip still in the liquid, pull the plunger until it is once more at the proper mark. Usage Illustration
9.
Choose a different injection site each day.
Cleanse the injection site with a new alcohol swab.
Hold the skin the way you were instructed.
Slide the needle quickly all the way through the skin, into the subcutaneous tissue, at a 90°
angle. Usage Illustration
10.
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Push the plunger to inject the medication.
Withdraw the needle at the same angle it was inserted (90°).
Wipe the skin with an alcohol swab. Usage Illustration
11.
Dispose of the syringe and alcohol swabs as you were instructed.
Remember: use the disposable syringe only once.
Abbott Laboratories
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Lupron Depot - Ped (leuprolide acetate for depot suspension) Injection, Powder, Lyophilized, For
Suspension
[Abbott Laboratories]
Rx only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing
hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The
chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N
ethyl-L-prolinamide acetate (salt) with the following structural formula: Structural Formula
LUPRON DEPOT-PED is available in a prefilled dual-chamber syringe containing sterile lyophilized
microspheres which, when mixed with diluent, become a suspension intended as a single
intramuscular injection.
The front chamber of LUPRON DEPOT-PED 7.5 mg, 11.25 mg, and 15 mg prefilled dual-chamber
syringe contains leuprolide acetate (7.5/11.25/15 mg), purified gelatin (1.3/1.95/2.6 mg), DL-lactic and
glycolic acids copolymer (66.2/99.3/132.4 mg), and D-mannitol (13.2/19.8/26.4 mg). The second
chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate
80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
During the manufacture of LUPRON DEPOT-PED, acetic acid is lost, leaving the peptide.
CLINICAL PHARMACOLOGY
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given
continuously and in therapeutic doses. Human studies indicate that following an initial stimulation of
gonadotropins, chronic stimulation with leuprolide acetate results in suppression or "downregulation"
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of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These
effects are reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
Pharmacokinetics
Absorption
Following a single LUPRON DEPOT 7.5 mg injection to adult patients, mean peak leuprolide plasma
concentration was almost 20 ng/mL at 4 hours and then declined to 0.36 ng/mL at 4 weeks. However,
intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was
employed in the study. Nondetectable leuprolide plasma concentrations have been observed during
chronic LUPRON DEPOT 7.5 mg administration, but testosterone levels appear to be maintained at
castrate levels.
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration
to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to
49%.
Metabolism
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the
mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours
based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller
inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide
(Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached
maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug
concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of
mean leuprolide concentrations.
Excretion
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was
recovered as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients have not been
determined.
CLINICAL STUDIES
In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to
prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females
respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and
development. Natural maturation occurs when gonadotropins return to pubertal levels following
discontinuation of leuprolide acetate.
The following physiologic effects have been noted with the chronic administration of leuprolide
acetate in this patient population.
1. Skeletal Growth. A measurable increase in body length can be noted since the epiphyseal
plates will not close prematurely.
2. Organ Growth. Reproductive organs will return to a prepubertal state.
3. Menses. Menses, if present, will cease.
In a study of 22 children with central precocious puberty, doses of LUPRON DEPOT were given
every 4 weeks and plasma levels were determined according to weight categories as summarized
below:
Patient Weight
Group Weight
Dose (mg)
Trough Plasma Leuprolide Level
Range (kg)
Average (kg)
Mean ±SD (ng/mL)*
20.2 - 27.0
22.7
7.5
0.77±0.033
28.4 - 36.8
32.5
11.25
1.25±1.06
39.3 - 57.5
44.2
15.0
1.59±0.65
* Group average values determined at Week 4 immediately prior to leuprolide injection. Drug levels at 12
and 24 weeks were similar to respective 4 week levels.
Page 3
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INDICATIONS AND USAGE
LUPRON DEPOT-PED is indicated in the treatment of children with central precocious puberty.
Children should be selected using the following criteria:
1. Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual
characteristics earlier than 8 years in females and 9 years in males.
2. Clinical diagnosis should be confirmed prior to initiation of therapy:
• Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The
sensitivity and methodology of this assay must be understood.
• Bone age advanced one year beyond the chronological age.
3. Baseline evaluation should also include:
• Height and weight measurements.
• Sex steroid levels.
• Adrenal steroid level to exclude congenital adrenal hyperplasia.
• Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin-secreting
tumor.
• Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor.
• Computerized tomography of the head to rule out intracranial tumor.
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT.
Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical
literature.1,2
2. LUPRON DEPOT-PED is contraindicated in women who are or may become pregnant while
receiving the drug. When administered on day 6 of pregnancy at test dosages of 0.00024,
0.0024, and 0.024 mg/kg (1/1200 to 1/12 of the human pediatric dose) to rabbits, LUPRON
DEPOT produced a dose-related increase in major fetal abnormalities. Similar studies in rats
failed to demonstrate an increase in fetal malformations. There was increased fetal mortality
and decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and with
the highest dose in rats. The effects on fetal mortality are logical consequences of the
alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that
spontaneous abortion may occur if the drug is administered during pregnancy.
Page 4
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WARNINGS
During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the
natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be
observed. (See CLINICAL PHARMACOLOGY section.)
Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the
pubertal process. The consequences of poor control include the return of pubertal signs such as
menses, breast development, and testicular growth. The long-term consequences of inadequate
control of gonadal steroid secretion are unknown, but may include a further compromise of adult
stature.
PRECAUTIONS
Laboratory Tests
Response to LUPRON DEPOT-PED should be monitored 1-2 months after the start of therapy with a
GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be
done every 6-12 months.
Sex steroids may increase or rise above prepubertal levels if the dose is inadequate. (See
WARNINGS section.) Once a therapeutic dose has been established, gonadotropin and sex steroid
levels will decline to prepubertal levels.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted. However, because
leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450
enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug
interactions would not be expected to occur.
Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT 3.75 mg in women results in suppression of the pituitary-gonadal
system. Normal function is usually restored within three months after treatment is discontinued.
Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during
treatment and for up to three months after discontinuation of LUPRON DEPOT may be misleading.
Page 5
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Information for Parents
Prior to starting therapy with LUPRON DEPOT-PED, the parent or guardian must be aware of the
importance of continuous therapy. Adherence to 4 week drug administration schedules must be
accepted if therapy is to be successful.
• During the first 2 months of therapy, a female may experience menses or spotting. If bleeding
continues beyond the second month, notify the physician.
• Any irritation at the injection site should be reported to the physician immediately.
• Report any unusual signs or symptoms to the physician.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of
benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug
was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not
dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell
adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced
tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Adult
patients have been treated with leuprolide acetate for up to three years with doses as high as 10
mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary
abnormalities.
Although no clinical studies have been completed in children to assess the full reversibility of fertility
suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and
other GnRH analogs have shown functional recovery. However, following a study with leuprolide
acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery
period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the
controls. Also, no histologic changes were observed in the female rats following the same protocol. In
both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the
parents on the reproductive performance of the F1 generation was not tested. The clinical
significance of these findings is unknown.
Pregnancy
Teratogenic Effects
Page 6
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Pregnancy Category X
(See CONTRAINDICATIONS section.)
Nursing Mothers
It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by
nursing mothers.
Geriatric Use
See also the labeling for LUPRON DEPOT 7.5 mg which is indicated for the palliative treatment of
advanced prostate cancer. For LUPRON DEPOT-PED 11.25 mg and LUPRON DEPOT-PED 15 mg,
no clinical information has been established for persons aged 65 and over.
ADVERSE REACTIONS
Clinical Trials
Potential exacerbation of signs and symptoms during the first few weeks of treatment (See
PRECAUTIONS section.) is a concern in patients with rapidly advancing central precocious puberty.
In two studies of children with central precocious puberty, in 2% or more of the patients receiving the
drug, the following adverse reactions were reported to have a possible or probable relationship to
drug as ascribed by the treating physician. Reactions which are not considered drug-related are
excluded.
Number of Patients
N = 395
(%)
Body as a Whole
General Pain
7
(2)
Integumentary System
Acne/Seborrhea
7
(2)
Injection Site Reactions Including Abscess
21
(5)
Rash Including Erythema Multiforme
8
(2)
Urogenital System
Vaginitis/Bleeding/Discharge
7
(2)
Page 7
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In those same studies, the following adverse reactions were reported in less than 2% of the patients.
Body as a Whole - Body Odor, Fever, Headache, Infection; Cardiovascular System - Syncope,
Vasodilation; Digestive System - Dysphagia, Gingivitis, Nausea/Vomiting; Endocrine System -
Accelerated Sexual Maturity; Metabolic and Nutritional Disorders - Peripheral Edema, Weight Gain;
Nervous System - Emotional Lability, Nervousness, Personality Disorder, Somnolence; Respiratory
System - Epistaxis; Integumentary System - Alopecia, Skin Striae; Urogenital System - Cervix
Disorder, Gynecomastia/Breast Disorders, Urinary Incontinence.
Postmarketing
During postmarketing surveillance, which includes other dosage forms, the following adverse events
were reported.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash,
urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Cardiovascular System - Hypotension; Hemic and Lymphatic System - Decreased WBC;
Central/Peripheral Nervous System - Peripheral neuropathy, Spinal fracture/paralysis;
Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System - Prostate pain.
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical
syndrome secondary to infarction of the pituitary gland) have been reported after the administration of
gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was
diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and
some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache,
vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular
collapse. Immediate medical attention has been required.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in
different patient populations.
OVERDOSAGE
In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose,
expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at
Page 8
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the injection site. There is no evidence at present that there is a clinical counterpart of this
phenomenon. In early clinical trials using leuprolide acetate in adult patients, doses as high as 20
mg/day for up to two years caused no adverse effects differing from those observed with the 1
mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT-PED must be administered under the supervision of a physician.
The dose of LUPRON DEPOT-PED must be individualized for each child. The dose is based on a
mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio.
For each dosage form, after 1-2 months of initiating therapy or changing doses, the child must be
monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation.
Measurements of bone age for advancement should be monitored every 6-12 months. The dose
should be titrated upward until no progression of the condition is noted either clinically and/or by
laboratory parameters.
The first dose found to result in adequate downregulation can probably be maintained for the duration
of therapy in most children. However, there are insufficient data to guide dosage adjustment as
patients move into higher weight categories after beginning therapy at very young ages and low
dosages. It is recommended that adequate downregulation be verified in such patients whose weight
has increased significantly while on therapy.
Discontinuation of LUPRON DEPOT-PED should be considered before age 11 for females and age
12 for males.
The recommended starting dose is 0.3 mg/kg/4 weeks (minimum 7.5 mg) administered as a single
intramuscular injection. The starting dose will be dictated by the child's weight.
≤ 25 kg
7.5 mg
> 25-37.5 kg
11.25 mg
> 37.5 kg
15 mg
If total downregulation is not achieved, the dose should be titrated upward in increments of 3.75 mg
every 4 weeks. This dose will be considered the maintenance dose.
Page 9
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The lyophilized microspheres are to be reconstituted and administered as a single intramuscular
injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the
following instructions:
• The lyophilized microspheres are to be reconstituted and administered as a single
intramuscular injection.
• Since LUPRON DEPOT-PED does not contain a preservative, the suspension should be
discarded if not used immediately.
1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE
USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is
considered normal. The diluent should appear clear.
2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins
to turn.
3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the
plunger until the first stopper is at the blue line in the middle of the barrel.
4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to form a
uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or
caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of
the powder has not gone into suspension.
5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without
twisting.
6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is
accidentally penetrated. If present, blood can be seen through the transparent LuproLoc™
safety device. If blood is present remove the needle immediately. Do not inject the medication.
7. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The
suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be
mixed and used immediately.
Page 10
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AFTER INJECTION
8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by pushing the arrow
forward with the thumb or finger until the device is fully extended and a CLICK is heard or felt.
Since the product does not contain a preservative, the suspension should be discarded if not used
immediately.
As with other drugs administered by injection, the injection site should be varied periodically.
HOW SUPPLIED
LUPRON DEPOT-PED is packaged as follows:
Kit with prefilled dual-chamber syringe
7.5 mg
NDC 0074-2108-03
Kit with prefilled dual-chamber syringe
11.25 mg
NDC 0074-2282-03
Kit with prefilled dual-chamber syringe
15 mg
NDC 0074-2440-03
Each syringe contains sterile lyophilized microspheres of leuprolide acetate incorporated in a
biodegradable lactic acid/glycolic acid copolymer. When mixed with 1 milliliter of accompanying
diluent, LUPRON DEPOT-PED is administered as a single intramuscular injection.
Each kit contains:
•
one prefilled dual-chamber syringe containing 1½ inch needle with LuproLoc™ safety device
•
one plunger
•
two alcohol swabs
•
instructions for how to mix and administer
•
an information pamphlet for patients
•
a complete prescribing information enclosure
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room
Temperature]
REFERENCES
1. Taylor, JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Australia 1994 Oct;
161(3): 455.
Page 11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2. Letterie GS, et al. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol
1991 Nov; 78: 943–946.
U.S. Patent Nos. 4,652,441; 4,677,191; 4,728,721; 4,849,228; 4,917,893; 5,330,767; 5,476,663;
5,823,997; 5,980,488; and 6,036,976. Other patents pending.
Manufactured for
Abbott Laboratories
North Chicago, IL 60064
by Takeda Pharmaceutical Company Limited
Osaka, Japan 540-8645
™ -Trademark
® -Registered Trademark
(Nos. 2108, 2282, 2440)
Revised: May, 2009
© 2008, Abbott Laboratories
Abbott Laboratories
Page 12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:17.388048
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020263s033lbl.pdf', 'application_number': 20263, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
12,399
|
1
JANSSEN
PHARMACEUTICA
PRODUCTS, L.P.
RISPERDAL
(RISPERIDONE)
TABLETS/ORAL SOLUTION
RISPERDAL M-TAB
(RISPERIDONE)
ORALLY DISINTEGRATING TABLETS
Increased Mortality in Elderly Patients with Dementia –Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical
antipsychotic drugs are at an increased risk of death compared to placebo.
Analyses of seventeen placebo controlled trials (modal duration of 10 weeks) in
these patients revealed a risk of death in the drug-treated patients of between
1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical
10 week controlled trial, the rate of death in drug-treated patients was about
4.5%, compared to a rate of about 2.6% in the placebo group. Although the
causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
in nature. RISPERDAL (risperidone) is not approved for the treatment of
patients with Dementia-Related Psychosis.
DESCRIPTION
RISPERDAL (risperidone) is a psychotropic agent belonging to the chemical class
of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-
benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-
a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight
is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water,
freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.
This label may not be the latest approved by FDA.
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2
RISPERDAL tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown),
1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. Inactive
ingredients are colloidal silicon dioxide, hypromellose, lactose, magnesium stearate,
microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
Tablets of 0.25, 0.5, 2, 3, and 4 mg also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide;
the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and
4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No.
2 Aluminum Lake.
RISPERDAL is also available as a 1 mg/mL oral solution. The inactive ingredients
for this solution are tartaric acid, benzoic acid, sodium hydroxide, and purified water.
RISPERDAL M-TAB Orally Disintegrating Tablets are available in 0.5 mg, 1 mg,
and 2 mg strengths and are light coral in color.
RISPERDAL M-TAB Orally Disintegrating Tablets contain the following inactive
ingredients: Amberlite resin, gelatin, mannitol, glycine, simethicone, carbomer,
sodium hydroxide, aspartame, red ferric oxide, and peppermint oil.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of RISPERDAL (risperidone), as with other drugs used to
treat schizophrenia, is unknown. However, it has been proposed that the drug's
therapeutic activity in schizophrenia is mediated through a combination of dopamine
Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. Antagonism at
receptors other than D2 and 5HT2 may explain some of the other effects of
RISPERDAL.
RISPERDAL is a selective monoaminergic antagonist with high affinity (Ki of
0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and
α2 adrenergic, and H1 histaminergic receptors. RISPERDAL acts as an antagonist at
other receptors, but with lower potency. RISPERDAL has low to moderate affinity
(Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak
affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma
site, and no affinity (when tested at concentrations >10-5 M) for cholinergic
muscarinic or β1 and β2 adrenergic receptors.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is
70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is
94% (CV=10%) when compared to a solution.
Pharmacokinetic studies showed that RISPERDAL M-TAB Orally Disintegrating
Tablets and RISPERDAL Oral Solution are bioequivalent to RISPERDAL Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of
1 to 16 mg daily (0.5 to 8 mg BID). Following oral administration of solution or
tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour.
Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive
metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of
risperidone are reached in 1 day in extensive metabolizers and would be expected to
reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations
of 9-hydroxyrisperidone are reached in 5-6 days (measured in extensive
metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus,
risperidone can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma,
risperidone is bound to albumin and a1-acid glycoprotein. The plasma protein binding
of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is
77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma
binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL),
warfarin (10 mcg/mL), and carbamazepine (10mcg/mL) caused only a slight increase
in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL,
changes of unknown clinical significance.
Metabolism
Risperidone is extensively metabolized in the liver. The main metabolic pathway is
through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme,
CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main
metabolite,
9-hydroxyrisperidone,
has
similar
pharmacological
activity
as
risperidone. Consequently, the clinical effect of the drug (e.g., the active moiety)
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
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4
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for
metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs.
CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a
very low percentage of Asians, have little or no activity and are “poor metabolizers”)
and to inhibition by a variety of substrates and some non-substrates, notably
quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into
9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly. Although extensive metabolizers have lower risperidone and higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
the active moiety, after single and multiple doses, are similar in extensive and poor
metabolizers.
Risperidone
could
be
subject
to
two
kinds
of
drug-drug
interactions
(see PRECAUTIONS – Drug Interactions). First, inhibitors of CYP 2D6 interfere
with conversion of risperidone to 9-hydroxyrisperidone. This occurs with quinidine,
giving essentially all recipients a risperidone pharmacokinetic profile typical of poor
metabolizers. The therapeutic benefits and adverse effects of risperidone in patients
receiving quinidine have not been evaluated, but observations in a modest number
(n@70) of poor metabolizers given risperidone do not suggest important differences
between poor and extensive metabolizers. Second, co-administration of known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may
cause a decrease in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone. It would also be possible for risperidone to interfere with
metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding
of risperidone to the enzyme suggests this is unlikely.
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone
titrated to 6 mg/day for 3 weeks, followed by concurrent administration
of carbamazepine for an additional 3 weeks. During co-administration, the plasma
concentrations of risperidone and its pharmacologically active metabolite,
9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations
of carbamazepine did not appear to be affected. Co-administration of other known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may
cause similar decreases in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone
treatment (see PRECAUTIONS – Drug Interactions and DOSAGE AND
ADMINISTRATION – Co-Administration of RISPERDAL with Certain Other
Medications).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the
plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine
did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered
the concentration of 9-hydroxyrisperidone an average of 13% (see PRECAUTIONS
-Drug Interactions and DOSAGE AND ADMINISTRATION – Co-Administration
of RISPERDAL with Certain Other Medications).
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13) (see PRECAUTIONS – Drug
Interactions).
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three
divided doses) compared to placebo (n=21). However, there was a 20% increase in
valproate peak plasma concentration (Cmax) after concomitant administration
of risperidone (see PRECAUTIONS – Drug Interactions).
There
were
no
significant
interactions
between
risperidone
(1 mg QD)
and erythromycin (500 mg QID) (see PRECAUTIONS – Drug Interactions).
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser
extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose
of 14C-risperidone administered as solution to three healthy male volunteers, total
recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in
the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive
metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life
of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers
and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of the active
moiety, after single and multiple doses, were similar in extensive and poor
metabolizers, with an overall mean elimination half-life of about 20 hours.
Special Populations
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone
and its active metabolite decreased by 60% compared to young healthy subjects.
RISPERDAL doses should be reduced in patients with renal disease
(see PRECAUTIONS 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
6
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were
comparable to those in young healthy subjects, the mean free fraction of risperidone
in plasma was increased by about 35% because of the diminished concentration
of both albumin and a1-acid glycoprotein. RISPERDAL doses should be reduced in
patients
with
liver
disease
(see
PRECAUTIONS
and
DOSAGE
AND
ADMINISTRATION).
Elderly
In
healthy
elderly
subjects,
renal
clearance
of
both
risperidone
and
9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged
compared to young healthy subjects. Dosing should be modified accordingly in the
elderly patients (see DOSAGE AND ADMINISTRATION).
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender
effects, but a population pharmacokinetic analysis did not identify important
differences in the disposition of risperidone due to gender (whether corrected for
body weight or not) or race.
CLINICAL TRIALS
Schizophrenia
Short-Term Efficacy
The efficacy of RISPERDAL in the treatment of schizophrenia was established in
four short-term (4- to 8-week) controlled trials of psychotic inpatients who met
DSM-III-R criteria for schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these
studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item
inventory of general psychopathology traditionally used to evaluate the effects of
drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual
disorganization, hallucinatory behavior, suspiciousness, and unusual thought content)
is considered a particularly useful subset for assessing actively psychotic
schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In
addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for
Assessing Negative Symptoms (SANS) were employed.
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The results of the trials follow:
(1)
In
a
6-week,
placebo-controlled
trial
(n=160)
involving
titration
of RISPERDAL in doses up to 10 mg/day (BID schedule), RISPERDAL was
generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster,
and marginally superior to placebo on the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses
of RISPERDAL (2, 6, 10, and 16 mg/day, on a BID schedule), all 4 RISPERDAL
groups were generally superior to placebo on the BPRS total score, BPRS psychosis
cluster, and CGI severity score; the 3 highest RISPERDAL dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was
no suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses
of RISPERDAL (1, 4, 8, 12, and 16 mg/day, on a BID schedule), the four highest
RISPERDAL dose groups were generally superior to the 1 mg RISPERDAL dose
group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
of the dose groups were superior to the 1 mg group on the PANSS negative subscale.
The most consistently positive responses were seen for the 4 mg dose group.
(4)
In a 4-week, placebo-controlled dose comparison trial (n=246) involving
2 fixed doses of RISPERDAL (4 and 8 mg/day on a QD schedule), both
RISPERDAL dose groups were generally superior to placebo on several PANSS
measures, including a response measure (>20% reduction in PANSS total score),
PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The
results were generally stronger for the 8 mg than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria
for schizophrenia and who had been clinically stable for at least 4 weeks on an
antipsychotic medication were randomized to RISPERDAL (2-8 mg/day) or to an
active comparator, for 1 to 2 years of observation for relapse. Patients receiving
RISPERDAL experienced a significantly longer time to relapse over this time
period compared to those receiving the active comparator.
Bipolar Mania
Monotherapy
The efficacy of RISPERDAL in the treatment of acute manic or mixed episodes was
established in 2 short-term (3-week) placebo-controlled trials in patients who met the
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DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials
included patients with or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was
the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale
traditionally used to assess the degree of manic symptomatology (irritability,
disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity,
sexual interest, language/thought disorder, thought content, appearance, and insight)
in a range from 0 (no manic features) to 60 (maximum score). The primary outcome
in these trials was change from baseline in the Y-MRS total score. The results of the
trials follow:
(1)
In one 3-week placebo-controlled trial (n=246), limited to patients with manic
episodes, which involved a dose range of RISPERDAL 1-6 mg/day, once
daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), RISPERDAL
was superior to placebo in the reduction of Y-MRS total score.
(2)
In another 3-week placebo-controlled trial (n=286), which involved a dose
range of 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was
5.6 mg/day), RISPERDAL was superior to placebo in the reduction
of Y-MRS total score.
Combination Therapy
The efficacy of risperidone with concomitant lithium or valproate in the treatment
of acute manic or mixed episodes was established in one controlled trial in patients
who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with
or without psychotic features and with or without a rapid-cycling course.
(1)
In this 3-week placebo-controlled combination trial, 148 in- or outpatients on
lithium or valproate therapy with inadequately controlled manic or mixed
symptoms were randomized to receive RISPERDAL, placebo, or an active
comparator, in combination with their original therapy. RISPERDAL, in
a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal
dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic
range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of Y-MRS total
score.
(2)
In a second 3-week placebo-controlled combination trial, 142 in- or
outpatients on lithium, valproate, or carbamazepine therapy with inadequately
controlled manic or mixed symptoms were randomized to receive
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RISPERDAL or placebo, in combination with their original therapy.
RISPERDAL, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium,
valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L
for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4-12 mcg/mL for
carbamazepine, respectively) was not superior to lithium, valproate, or
carbamazepine alone in the reduction of Y-MRS total score. A possible
explanation for the failure of this trial was induction of risperidone and
9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic
levels of risperidone and 9-hydroxyrisperidone.
INDICATIONS AND USAGE
Schizophrenia
RISPERDAL (risperidone) is indicated for the treatment of schizophrenia.
The efficacy of RISPERDAL in schizophrenia was established in short-term
(6- to 8-weeks)
controlled
trials
of
schizophrenic
inpatients
(see CLINICAL PHARMACOLOGY).
The efficacy of RISPERDAL in delaying relapse was demonstrated in schizophrenic
patients who had been clinically stable for at least 4 weeks before initiation of
treatment with RISPERDAL or an active comparator and who were then observed
for relapse during a period of 1 to 2 years (see CLINICAL PHARMACOLOGY
-Clinical Trials). Nevertheless, the physician who elects to use RISPERDAL for
extended periods should periodically re-evaluate the long-term usefulness of the drug
for the individual patient (see DOSAGE AND ADMINISTRATION).
Bipolar Mania
Monotherapy
RISPERDAL is indicated for the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder.
The efficacy of RISPERDAL was established in two placebo-controlled trials
(3-week) with patients meeting DSM-IV criteria for Bipolar I Disorder who currently
displayed an acute manic or mixed episode with or without psychotic features
(see CLINICAL PHARMACOLOGY).
Combination Therapy
The combination of RISPERDAL with lithium or valproate is indicated for the
short-term treatment of acute manic or mixed episodes associated with Bipolar
I Disorder.
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The efficacy of RISPERDAL in combination with lithium or valproate was
established in one placebo-controlled (3-week) trial with patients meeting DSM-IV
criteria for Bipolar I Disorder who currently displayed an acute manic or mixed
episode with or without psychotic features (see CLINICAL PHARMACOLOGY).
The effectiveness of RISPERDAL for longer-term use, that is, for more than
3 weeks of treatment of an acute episode, and for prophylactic use in mania, has not
been systematically evaluated in controlled clinical trials. Therefore, physicians who
elect to use RISPERDAL for extended periods should periodically re-evaluate the
long-term risks and benefits of the drug for the individual patient (see DOSAGE
AND ADMINISTRATION).
CONTRAINDICATIONS
RISPERDAL (risperidone) is contraindicated in patients with a known
hypersensitivity to the product.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical
antipsychotic drugs are at an increased risk of death compared to placebo.
RISPERDAL(risperidone) is not approved for the treatment of dementia-
related psychosis (see Boxed Warning).
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and
evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,
diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated
creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at
a diagnosis, it is important to identify cases in which the clinical presentation includes
both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity,
heat stroke, drug fever, and primary central nervous system pathology.
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The management of NMS should include: (1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive
symptomatic treatment and medical monitoring; and (3) treatment of any concomitant
serious medical problems for which specific treatments are available. There is no
general agreement about specific pharmacological treatment regimens for
uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The patient
should be carefully monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may
develop in patients treated with antipsychotic drugs. Although the prevalence of the
syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception
of antipsychotic treatment, which patients are likely to develop the syndrome.
Whether antipsychotic drug products differ in their potential to cause tardive
dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total
cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively
brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the
signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptomatic suppression has upon the long-term course
of the syndrome is unknown.
Given these considerations, RISPERDAL (risperidone) should be prescribed in a
manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic
antipsychotic treatment should generally be reserved for patients who suffer from a
chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom
alternative, equally effective, but potentially less harmful treatments are not available
or appropriate. In patients who do require chronic treatment, the smallest dose and the
shortest duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
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If signs and symptoms of tardive dyskinesia appear in a patient treated on
RISPERDAL, drug discontinuation should be considered. However, some patients
may require treatment with RISPERDAL despite the presence of the syndrome.
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients
With Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including
fatalities, were reported in patients (mean age 85 years; range 73-97) in trials
of risperidone
in
elderly
patients
with
dementia-related
psychosis.
In
placebo-controlled
trials,
there
was
a
significantly
higher
incidence
of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL is not approved for the treatment
of patients with dementia-related psychosis. (See also Boxed WARNING,
WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related
Psychosis.)
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, has been reported in patients treated with atypical
antipsychotics including RISPERDAL. Assessment of the relationship between
atypical antipsychotic use and glucose abnormalities is complicated by the possibility
of an increased background risk of diabetes mellitus in patients with schizophrenia
and the increasing incidence of diabetes mellitus in the general population. Given
these confounders, the relationship between atypical antipsychotic use and
hyperglycemia-related adverse events is not completely understood. However,
epidemiological
studies
suggest
an
increased
risk
of
treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical
antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in
patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control.
Patients with risk factors for diabetes mellitus (e.g., obesity, family history
of diabetes) who are starting treatment with atypical antipsychotics should undergo
fasting blood glucose testing at the beginning of treatment and periodically during
treatment. Any patient treated with atypical antipsychotics should be monitored for
symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and
weakness. Patients who develop symptoms of hyperglycemia during treatment with
atypical antipsychotics should undergo fasting blood glucose testing. In some cases,
hyperglycemia has resolved when the atypical antipsychotic was discontinued;
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however, some patients required continuation of anti-diabetic treatment despite
discontinuation of the suspect drug.
PRECAUTIONS
General
Orthostatic Hypotension
RISPERDAL (risperidone) may induce orthostatic hypotension associated with
dizziness, tachycardia, and in some patients, syncope, especially during the initial
dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties.
Syncope was reported in 0.2% (6/2607) of RISPERDAL-treated patients in Phase
2 and 3 studies. The risk of orthostatic hypotension and syncope may be minimized
by limiting the initial dose to 2 mg total (either QD or 1 mg BID) in normal adults
and 0.5 mg BID in the elderly and patients with renal or hepatic impairment
(see DOSAGE AND ADMINISTRATION). Monitoring of orthostatic vital signs
should be considered in patients for whom this is of concern. A dose reduction should
be considered if hypotension occurs. RISPERDAL should be used with particular
caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular
disease, and conditions which would predispose patients to hypotension, e.g.,
dehydration and hypovolemia. Clinically significant hypotension has been observed
with concomitant use of RISPERDAL and antihypertensive medication.
Seizures
During
premarketing
testing,
seizures
occurred
in
0.3%
(9/2607)
of
RISPERDAL-treated patients, two in association with hyponatremia. RISPERDAL
should be used cautiously in patients with a history of seizures.
Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug
use. Aspiration pneumonia is a common cause of morbidity and mortality in patients
with advanced Alzheimer’s dementia. RISPERDAL and other antipsychotic drugs
should be used cautiously in patients at risk for aspiration pneumonia. (See also
Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients with
Dementia-Related Psychosis.)
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates
prolactin levels and the elevation persists during chronic administration. Tissue
culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of
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these drugs is contemplated in a patient with previously detected breast cancer.
Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported with prolactin-elevating compounds, the clinical
significance of elevated serum prolactin levels is unknown for most patients. As is
common with compounds which increase prolactin release, an increase in pituitary
gland, mammary gland, and pancreatic islet cell hyperplasia and/or neoplasia was
observed in the risperidone carcinogenicity studies conducted in mice and rats (see
PRECAUTIONS – Carcinogenesis, Mutagenesis, Impairment of Fertility). However,
neither clinical studies nor epidemiologic studies conducted to date have shown an
association between chronic administration of this class of drugs and tumorigenesis in
humans; the available evidence is considered too limited to be conclusive at this time.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL
treatment, especially when ascertained by direct questioning of patients. This adverse
event is dose-related, and in a study utilizing a checklist to detect adverse events,
41% of the high-dose patients (RISPERDAL 16 mg/day) reported somnolence
compared to 16% of placebo patients. Direct questioning is more sensitive for
detecting adverse events than spontaneous reporting, by which 8% of RISPERDAL
16 mg/day patients and 1% of placebo patients reported somnolence as an adverse
event. Since RISPERDAL has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that RISPERDAL therapy does not
affect them adversely.
Priapism
Rare cases of priapism have been reported. While the relationship of the events to
RISPERDAL use has not been established, other drugs with alpha-adrenergic
blocking effects have been reported to induce priapism, and it is possible that
RISPERDAL may share this capacity. Severe priapism may require surgical
intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving
RISPERDAL in a large, open premarketing
experience (approximately
1300 patients). She experienced jaundice, fever, and bruising, but eventually
recovered after receiving plasmapheresis. The relationship to RISPERDAL therapy
is unknown.
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Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans,
and may mask signs and symptoms of overdosage with certain drugs or of conditions
such as intestinal obstruction, Reye’s syndrome, and brain tumor.
Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents.
Both hyperthermia and hypothermia have been reported in association with oral
RISPERDAL use. Caution is advised when prescribing for patients who will be
exposed to temperature extremes.
Suicide
The possibility of a suicide attempt is inherent in schizophrenia, and close supervision
of high-risk patients should accompany drug therapy. Prescriptions for RISPERDAL
should be written for the smallest quantity of tablets, consistent with good patient
management, in order to reduce the risk of overdose.
Use in Patients With Concomitant Illness
Clinical experience with RISPERDAL in patients with certain concomitant systemic
illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies
who receive antipsychotics, including RISPERDAL, may be at increased risk of
Neuroleptic Malignant Syndrome as well as having an increased sensitivity to
antipsychotic medications. Manifestation of this increased sensitivity can include
confusion, obtundation, postural instability with frequent falls, in addition to
extrapyramidal symptoms.
Caution is advisable in using RISPERDAL in patients with diseases or conditions
that could affect metabolism or hemodynamic responses. RISPERDAL has not been
evaluated or used to any appreciable extent in patients with a recent history of
myocardial infarction or unstable heart disease. Patients with these diagnoses were
excluded from clinical studies during the product's premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in
patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2),
and an increase in the free fraction of risperidone is seen in patients with severe
hepatic impairment. A lower starting dose should be used in such patients
(see DOSAGE AND ADMINISTRATION).
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they
prescribe RISPERDAL:
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Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the
period of initial dose titration.
Interference With Cognitive and Motor Performance
Since RISPERDAL has the potential to impair judgment, thinking, or motor skills,
patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that RISPERDAL therapy does not
affect them adversely.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend
to become pregnant during therapy.
Nursing
Patients should be advised not to breast-feed an infant if they are taking
RISPERDAL.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to
take, any prescription or over-the-counter drugs, since there is a potential for
interactions.
Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL.
Phenylketonurics
Phenylalanine is a component of aspartame. Each 2 mg RISPERDAL M-TAB
Orally Disintegrating Tablet contains 0.56 mg phenylalanine; each 1 mg
RISPERDAL
M-TAB
Orally
Disintegrating
Tablet
contains
0.28 mg
phenylalanine; and each 0.5 mg RISPERDAL M-TAB Orally Disintegrating
Tablet contains 0.14 mg phenylalanine.
Laboratory Tests
No specific laboratory tests are recommended.
Drug Interactions
The interactions of RISPERDAL and other drugs have not been systematically
evaluated. Given the primary CNS effects of risperidone, caution should be used
when RISPERDAL is taken in combination with other centrally acting drugs and
alcohol.
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Because of its potential for inducing hypotension, RISPERDAL may enhance the
hypotensive effects of other therapeutic agents with this potential.
RISPERDAL may antagonize the effects of levodopa and dopamine agonists.
Amytriptyline does not affect the pharmacokinetics of risperidone or the active
antipsychotic fraction. Cimetidine and ranitidine increased the bioavailability of
risperidone, but only marginally increased the plasma concentration of the active
antipsychotic fraction.
Chronic administration of clozapine with risperidone may decrease the clearance of
risperidone.
Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone
titrated to 6 mg/day for 3 weeks, followed by concurrent administration
of carbamazepine for an additional 3 weeks. During co-administration, the plasma
concentrations of risperidone and its pharmacologically active metabolite,
9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations
of carbamazepine did not appear to be affected. The dose of risperidone may need to
be titrated accordingly for patients receiving carbamazepine, particularly during
initiation or discontinuation of carbamazepine therapy. Co-administration of other
known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with
risperidone may cause similar decreases in the combined plasma concentrations
of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy
of risperidone treatment.
Fluoxetine and Paroxetine
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the
plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine
did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered
the concentration of 9-hydroxyrisperidone an average of 13%. When either
concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should
re-evaluate the dosing of RISPERDAL. The effects of discontinuation
of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics
of risperidone and 9-hydroxyrisperidone have not been studied.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
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Valproate
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three
divided doses) compared to placebo (n=21). However, there was a 20% increase in
valproate peak plasma concentration (Cmax) after concomitant administration
of risperidone.
Digoxin
RISPERDAL (0.25 mg BID) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic
and other drugs (see CLINICAL PHARMACOLOGY). Drug interactions that reduce
the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma
concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone.
Analysis of clinical studies involving a modest number of poor metabolizers
(n@70) does not suggest that poor and extensive metabolizers have different rates of
adverse effects. No comparison of effectiveness in the two groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including
1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
There were no significant interactions between risperidone and erythromycin
(see CLINICAL PHARMACOLOGY).
Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of
CYP 2D6. Therefore, RISPERDAL is not expected to substantially inhibit the
clearance of drugs that are metabolized by this enzymatic pathway. In drug
interaction studies, risperidone did not significantly affect the pharmacokinetics of
donepezil and galantamine, which are metabolized by CYP 2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats.
Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for
18 months to mice and for 25 months to rats. These doses are equivalent to
2.4, 9.4, and 37.5 times the maximum recommended human dose (MRHD)
(16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or
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0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. A maximum tolerated dose
was not achieved in male mice. There were statistically significant increases in
pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland
adenocarcinomas. The following table summarizes the multiples of the human dose
on a mg/m2 (mg/kg) basis at which these tumors occurred.
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
None
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in
rodents. Serum prolactin levels were not measured during the risperidone
carcinogenicity studies; however, measurements during subchronic toxicity studies
showed that risperidone elevated serum prolactin levels 5-6 fold in mice and rats at
the same doses used in the carcinogenicity studies. An increase in mammary,
pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic
administration
of
other
antipsychotic
drugs
and
is
considered
to
be
prolactin-mediated.
The
relevance
for
human
risk
of
the
findings
of
prolactin-mediated endocrine tumors in rodents is unknown (see PRECAUTIONS,
General -Hyperprolactinemia).
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse
mutation test, mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in
vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or
the chromosomal aberration test in human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar
rats in three reproductive studies (two Segment I and a multigenerational study) at
doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a
mg/m2 basis. The effect appeared to be in females, since impaired mating behavior
was not noted in the Segment I study in which males only were treated. In a
subchronic study in Beagle dogs in which risperidone was administered at doses of
0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in
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serum testosterone at the same doses. Serum testosterone and sperm parameters
partially recovered, but remained decreased after treatment was discontinued.
No no-effect doses were noted in either rat or dog.
Pregnancy
Pregnancy Category C
The teratogenic potential of risperidone was studied in three Segment II studies in
Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum
recommended human dose [MRHD] on a mg/m2 basis) and in one Segment II study
in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the MRHD on a
mg/m2 basis). The incidence of malformations was not increased compared to control
in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m2 basis. In
three reproductive studies in rats (two Segment III and a multigenerational study),
there was an increase in pup deaths during the first 4 days of lactation at doses of
0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the
dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study,
there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the
MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the
fetus or pups, as evidenced by a decrease in the number of live pups and an increase
in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of
drug-treated dams were observed. In addition, there was an increase in deaths by Day
1 among pups of drug-treated dams, regardless of whether or not the pups were
cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups
born to control but reared by drug-treated dams. These effects were all noted at the
one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-
controlled studies in pregnant women. However, there was one report of a case of
agenesis of the corpus callosum in an infant exposed to risperidone in utero. The
causal relationship to RISPERDAL therapy is unknown.
RISPERDAL should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Labor and Delivery
The effect of RISPERDAL on labor and delivery in humans is unknown.
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Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk.
Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk.
Therefore, women receiving risperidone should not breast-feed.
Pediatric Use
Safety and effectiveness in children have not been established.
Geriatric Use
Clinical studies of RISPERDAL in the treatment of schizophrenia did not include
sufficient numbers of patients aged 65 and over to determine whether or not they
respond differently than younger patients. Other reported clinical experience has not
identified differences in responses between elderly and younger patients. In general, a
lower starting dose is recommended for an elderly patient, reflecting a decreased
pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy
(see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in
the elderly may be minimized by limiting the initial dose to 0.5 mg BID followed by
careful titration (see PRECAUTIONS). Monitoring of orthostatic vital signs should
be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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).
Concomitant use with Furosemide in Elderly Patients with Dementia-Related
Psychosis
In placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients
treated with risperidone alone (3.1%; mean age 84 years, range 70-96) or furosemide
alone (4.1%; mean age 80 years, range 67-90). The increase in mortality in patients
treated with furosemide plus risperidone was observed in two of the four clinical
trials.
No pathophysiological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death observed. Nevertheless, caution should be
exercised and the risks and benefits of this combination should be considered prior to
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the decision to use. There was no increased incidence of mortality among patients
taking other diuretics as concomitant medication with risperidone. Irrespective of
treatment, dehydration was an overall risk factor for mortality and should therefore be
carefully avoided in elderly patients with dementia-related psychosis. RISPERDAL
is not approved for the treatment of patients with dementia-related psychosis (See
also Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients
with Dementia-Related Psychosis.)
ADVERSE REACTIONS
The following findings are based on the short-term, placebo-controlled, North
American, premarketing trials for schizophrenia and acute bipolar mania. In patients
with Bipolar I Disorder, treatment-emergent adverse events are presented separately
for risperidone as monotherapy and as adjunctive therapy to mood stabilizers.
Certain portions of the discussion below relating to objective or numeric safety
parameters, namely dose-dependent adverse events, vital sign changes, weight gain,
laboratory changes, and ECG changes are derived from studies in patients with
schizophrenia. However, this information is also generally applicable to bipolar
mania.
Associated With Discontinuation of Treatment
Schizophrenia
Approximately 9% (244/2607) of RISPERDAL (risperidone)-treated patients in
Phase 2 and 3 studies discontinued treatment due to an adverse event, compared with
about 7% on placebo and 10% on active control drugs. The more common events
(³0.3%) associated with discontinuation and considered to be possibly or probably
drug-related included:
Adverse Event
RISPERDAL
Placebo
Extrapyramidal symptoms
2.1%
0%
Dizziness
0.7%
0%
Hyperkinesia
0.6%
0%
Somnolence
0.5%
0%
Nausea
0.3%
0%
Suicide
attempt
was
associated
with
discontinuation
in
1.2% of
RISPERDAL-treated patients compared to 0.6% of placebo patients, but, given the
almost 40-fold greater exposure time in RISPERDAL compared to placebo patients,
it is unlikely that suicide attempt is a RISPERDAL-related adverse event
(see PRECAUTIONS). Discontinuation for extrapyramidal symptoms was 0% in
placebo patients, but 3.8% in active-control patients in the Phase 2 and 3 trials.
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Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, approximately
8% (10/134) of RISPERDAL-treated patients discontinued treatment due to an
adverse event, compared with approximately 6% (7/125) of placebo-treated patients.
The adverse events associated with discontinuation and considered to be possibly,
probably, or very likely drug-related included paroniria, somnolence, dizziness,
extrapyramidal disorder, and muscle contractions involuntary. Each of these events
occurred in one RISPERDAL-treated patient (0.7%) and in no placebo-treated
patients (0%).
In the US placebo-controlled trial with risperidone as adjunctive therapy to mood
stabilizers, there was no overall difference in the incidence of discontinuation due to
adverse events (4% for RISPERDAL vs. 4% for placebo).
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
Schizophrenia
In
two
6-
to
8-week
placebo-controlled
trials,
spontaneously-reported,
treatment-emergent adverse events with an incidence of 5% or greater in at least one
of the RISPERDAL groups and at least twice that of placebo were anxiety,
somnolence, extrapyramidal symptoms, dizziness, constipation, nausea, dyspepsia,
rhinitis, rash, and tachycardia.
Adverse events were also elicited in one of these two trials (i.e., in the fixed-dose trial
comparing RISPERDAL at doses of 2, 6, 10, and 16 mg/day with placebo) utilizing
a checklist for detecting adverse events, a method that is more sensitive than
spontaneous reporting. By this method, the following additional common and
drug-related adverse events occurred at an incidence of at least 5% and twice the rate
of placebo: increased dream activity, increased duration of sleep, accommodation
disturbances, reduced salivation, micturition disturbances, diarrhea, weight gain,
menorrhagia, diminished sexual desire, erectile dysfunction, ejaculatory dysfunction,
and orgastic dysfunction.
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, the most
commonly observed adverse events associated with the use of RISPERDAL
(incidence of 5% or greater and at least twice that of placebo) were somnolence,
dystonia, akathisia, dyspepsia, nausea, parkinsonism, vision abnormal, and saliva
increased. In the US placebo-controlled trial with risperidone as adjunctive therapy to
mood stabilizers, the most commonly observed adverse events associated with the use
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of RISPERDAL were somnolence, dizziness, parkinsonism, saliva increased,
akathisia, abdominal pain, and urinary incontinence.
Adverse Events Occurring at an Incidence of 1% or More Among
RISPERDAL-Treated Patients - Schizophrenia
The table that follows enumerates adverse events that occurred at an incidence of
1% or more, and were more frequent among RISPERDAL-treated patients treated at
doses of <10 mg/day than among placebo-treated patients in the pooled results of two
6- to 8-week controlled trials. Patients received RISPERDAL doses of 2, 6, 10, or
16 mg/day in the dose comparison trial, or up to a maximum dose of 10 mg/day in the
titration study. This table shows the percentage of patients in each dose group
(<10 mg/day or 16 mg/day) who spontaneously reported at least one episode of an
event at some time during their treatment. Patients given doses of 2, 6, or 10 mg did
not differ materially in these rates. Reported adverse events were classified using the
World Health Organization preferred terms.
The prescriber should be aware that these figures cannot be used to predict the
incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those which prevailed in this clinical trial.
Similarly, the cited frequencies cannot be compared with figures obtained from other
clinical investigations involving different treatments, uses, and investigators. The
cited figures, however, do provide the prescribing physician with some basis for
estimating the relative contribution of drug and non-drug factors to the side effect
incidence rate in the population studied.
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Table 1.
Incidence of Treatment-Emergent Adverse Events
in 6- to 8-Week Controlled Clinical Trials1
RISPERDAL
Body System/
Preferred Term
<10mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(N=142)
Psychiatric
Insomnia
26%
23%
19%
Agitation
22%
26%
20%
Anxiety
12%
20%
9%
Somnolence
3%
8%
1%
Aggressive reaction
1%
3%
1%
Central & peripheral nervous system
Extrapyramidal symptoms2
17%
34%
16%
Headache
14%
12%
12%
Dizziness
4%
7%
1%
Gastrointestinal
Constipation
7%
13%
3%
Nausea
6%
4%
3%
Dyspepsia
5%
10%
4%
Vomiting
5%
7%
4%
Abdominal pain
4%
1%
0%
Saliva increased
2%
0%
1%
Toothache
2%
0%
0%
Respiratory system
Rhinitis
10%
8%
4%
Coughing
3%
3%
1%
Sinusitis
2%
1%
1%
Pharyngitis
2%
3%
0%
Dyspnea
1%
0%
0%
Body as a whole - general
Back pain
2%
0%
1%
Chest pain
2%
3%
1%
Fever
2%
3%
0%
Dermatological
Rash
2%
5%
1%
Dry skin
2%
4%
0%
Seborrhea
1%
0%
0%
Infections
Upper respiratory
3%
3%
1%
Visual
Abnormal vision
2%
1%
1%
Musculo-Skeletal
Arthralgia
2%
3%
0%
(continued)
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Table 1.
Incidence of Treatment-Emergent Adverse Events
in 6- to 8-Week Controlled Clinical Trials1
RISPERDAL
Body System/
Preferred Term
<10mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(N=142)
Cardiovascular
Tachycardia
3%
5%
0%
1 Events reported by at least 1% of patients treated with RISPERDAL <10 mg/day are included,
and are rounded to the nearest %. Comparative rates for RISPERDAL 16 mg/day and placebo
are provided as well. Events for which the RISPERDAL incidence (in both dose groups) was
equal to or less than placebo are not listed in the table, but included the following: nervousness,
injury, and fungal infection.
2 Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculogyric crisis, ataxia,
abnormal gait, involuntary muscle contractions, hyporeflexia, akathisia, and extrapyramidal
disorders. Although the incidence of 'extrapyramidal symptoms' does not appear to differ for the
'10 mg/day' group and placebo, the data for individual dose groups in fixed dose trials do suggest
a dose/response relationship (see ADVERSE REACTIONS – Dose Dependency of Adverse
Events).
Adverse Events Occurring at an Incidence of 2% or More Among
RISPERDAL-Treated Patients - Bipolar Mania
Tables 2 and 3 display adverse events that occurred at an incidence of 2% or more,
and were more frequent among patients treated with flexible doses of RISPERDAL
(1-6 mg daily as monotherapy and as adjunctive therapy to mood stabilizers,
respectively) than among patients treated with placebo. Reported adverse events were
classified using the World Health Organization preferred terms.
Table 2.
Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Monotherapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL
(N=134)
Placebo
(N=125)
Central & peripheral nervous system
Dystonia
18%
6%
Akathisia
16%
6%
Dizziness
11%
9%
Parkinsonism
6%
3%
Hypoaesthesia
2%
1%
Psychiatric
Somnolence
28%
7%
Agitation
8%
6%
Manic reaction
8%
6%
Anxiety
4%
2%
Concentration impaired
2%
1%
Gastrointestinal system
Dyspepsia
11%
6%
(continued)
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Table 2.
Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Monotherapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL
(N=134)
Placebo
(N=125)
Nausea
11%
2%
Saliva increased
5%
1%
Mouth dry
3%
2%
Body as a whole - general
Pain
5%
3%
Fatigue
4%
2%
Injury
2%
0%
Respiratory system
Sinusitis
4%
1%
Rhinitis
3%
2%
Coughing
2%
2%
Skin and appendages
Acne
2%
0%
Pruritus
2%
1%
Musculo-Skeletal
Myalgia
5%
2%
Skeletal pain
2%
1%
Metabolic and nutritional
Weight increase
2%
0%
Vision disorders
Vision abnormal
6%
2%
Cardiovascular, general
Hypertension
3%
1%
Hypotension
2%
0%
Heart rate and rhythm
Tachycardia
3%
2%
1Events reported by at least 2% of patients treated with RISPERDAL are included and are
rounded to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL
that were less than the incidence reported by patients treated with placebo are not listed in the
table, but included the following: headache, tremor, insomnia, constipation, back pain, upper
respiratory tract infection, pharyngitis, and arthralgia.
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Table 3.
Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Adjunctive Therapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL
+ Mood Stabilizer
(N=52)
Placebo
Mood Stabilizer
(N=51)
Gastrointestinal system
Saliva increased
10%
0%
Diarrhea
8%
4%
Abdominal pain
6%
0%
Constipation
6%
4%
Mouth dry
6%
4%
Tooth ache
4%
0%
Tooth disorder
4%
0%
Central & peripheral nervous system
Dizziness
14%
2%
Parkinsonism
14%
4%
Akathisia
8%
0%
Dystonia
6%
4%
Psychiatric
Somnolence
25%
12%
Anxiety
6%
4%
Confusion
4%
0%
Respiratory system
Rhinitis
8%
4%
Pharyngitis
6%
4%
Coughing
4%
0%
Body as a whole - general
Asthenia
4%
2%
Urinary system
Urinary incontinence
6%
2%
Heart rate and rhythm
Tachycardia
4%
2%
Metabolic and nutritional
Weight increase
4%
2%
Skin and appendages
Rash
4%
2%
1Events reported by at least 2% of patients treated with RISPERDAL are included and are
rounded to the nearest %. Events reported by at least 2% of patients treated with
RISPERDAL that were less than the incidence reported by patients treated with placebo are
not listed in the table, but included the following: dyspepsia, nausea, vomiting, headache,
tremor, insomnia, chest pain, fatigue, pain, skeletal pain, hypertension, and vision abnormal.
Dose Dependency of Adverse Events
Extrapyramidal Symptoms
Data from two fixed-dose trials provided evidence of dose-relatedness for
extrapyramidal symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week
trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including
(1) a parkinsonism score (mean change from baseline) from the Extrapyramidal
Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:
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Dose Groups
Placebo
Ris 2
Ris 6
Ris 10
Ris 16
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
13%
16%
20%
31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week
trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups
Ris 1
Ris 4
Ris 8
Ris 12
Ris 16
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
18%
18%
21%
Other Adverse Events
Adverse event data elicited by a checklist for side effects from a large study
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were
explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend
in these data revealed a positive trend (p<0.05) for the following adverse events:
sleepiness, increased duration of sleep, accommodation disturbances, orthostatic
dizziness, palpitations, weight gain, erectile dysfunction, ejaculatory dysfunction,
orgastic
dysfunction,
asthenia/lassitude/increased
fatigability,
and
increased
pigmentation.
Vital Sign Changes
RISPERDAL is associated with orthostatic hypotension and tachycardia
(see PRECAUTIONS).
Weight Changes
The proportions of RISPERDAL and placebo-treated patients meeting a weight gain
criterion of ³7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of
weight gain for RISPERDAL (18%) compared to placebo (9%).
Laboratory Changes
A between-group comparison for 6- to 8-week placebo-controlled trials revealed no
statistically significant RISPERDAL/placebo differences in the proportions
of patients experiencing potentially important changes in routine serum chemistry,
hematology,
or
urinalysis
parameters.
Similarly,
there
were
no
RISPERDAL/placebo differences in the incidence of discontinuations for changes in
serum chemistry, hematology, or urinalysis. However, RISPERDAL administration
was associated with increases in serum prolactin (see PRECAUTIONS).
ECG Changes
Between-group comparisons for pooled placebo-controlled trials revealed no
statistically significant differences between risperidone and placebo in mean changes
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from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart
rate. When all RISPERDAL doses were pooled from randomized controlled trials in
several indications, there was a mean increase in heart rate of 1 beat per minute
compared to no change for placebo patients. In short-term schizophrenia trials, higher
doses of risperidone (8-16 mg/day) were associated with a higher mean increase in
heart rate compared to placebo (4-6 beats per minute).
Other Events Observed During the Premarketing Evaluation of
RISPERDAL
During its premarketing assessment, multiple doses of RISPERDAL were
administered to 2607 patients in Phase 2 and 3 studies. The conditions and duration of
exposure to RISPERDAL varied greatly, and included (in overlapping categories)
open-label and double-blind studies, uncontrolled and controlled studies, inpatient
and outpatient studies, fixed-dose and titration studies, and short-term or longer-term
exposure. In most studies, untoward events associated with this exposure were
obtained by spontaneous report and recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a
meaningful estimate of the proportion of individuals experiencing adverse events
without first grouping similar types of untoward events into a smaller number of
standardized event categories. In two large studies, adverse events were also elicited
utilizing the UKU (direct questioning) side effect rating scale, and these events were
not further categorized using standard terminology. (Note: These events are marked
with an asterisk in the listings that follow.)
In the listings that follow, spontaneously reported adverse events were classified
using World Health Organization (WHO) preferred terms. The frequencies presented,
therefore, represent the proportion of the 2607 patients exposed to multiple doses of
RISPERDAL who experienced an event of the type cited on at least one occasion
while receiving RISPERDAL. All reported events are included, except those already
listed in Table 1, those events for which a drug cause was remote, and those event
terms which were so general as to be uninformative. It is important to emphasize that,
although the events reported occurred during treatment with RISPERDAL, they
were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are those
occurring in at least 1/100 patients (only those not already listed in the tabulated
results from placebo-controlled trials appear in this listing); infrequent adverse events
are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in
fewer than 1/1000 patients.
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Psychiatric Disorders
Frequent: increased dream activity∗, diminished sexual desire∗, nervousness.
Infrequent: impaired concentration, depression, apathy, catatonic reaction, euphoria,
increased libido, amnesia. Rare: emotional lability, nightmares, delirium, withdrawal
syndrome, yawning.
Central and Peripheral Nervous System Disorders
Frequent: increased sleep duration∗. Infrequent: dysarthria, vertigo, stupor,
paraesthesia, confusion. Rare: aphasia, cholinergic syndrome, hypoesthesia, tongue
paralysis, leg cramps, torticollis, hypotonia, coma, migraine, hyperreflexia,
choreoathetosis.
Gastrointestinal Disorders
Frequent: anorexia, reduced salivation∗. Infrequent: flatulence, diarrhea, increased
appetite, stomatitis, melena, dysphagia, hemorrhoids, gastritis. Rare: fecal
incontinence, eructation, gastroesophageal reflux, gastroenteritis, esophagitis, tongue
discoloration, cholelithiasis, tongue edema, diverticulitis, gingivitis, discolored feces,
GI hemorrhage, hematemesis.
Body as a Whole/General Disorders
Frequent: fatigue. Infrequent: edema, rigors, malaise, influenza-like symptoms. Rare:
pallor, enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing.
Respiratory System Disorders
Infrequent: hyperventilation, bronchospasm, pneumonia, stridor. Rare: asthma,
increased sputum, aspiration.
Skin and Appendage Disorders
Frequent: increased pigmentation∗, photosensitivity∗ Infrequent: increased sweating,
acne, decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation. Rare:
bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca,
dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria.
Cardiovascular Disorders
Infrequent: palpitation, hypertension, hypotension, AV block, myocardial infarction.
Rare: ventricular tachycardia, angina pectoris, premature atrial contractions, T wave
inversions, ventricular extrasystoles, ST depression, myocarditis.
Vision Disorders
Infrequent: abnormal accommodation, xerophthalmia. Rare: diplopia, eye pain,
blepharitis, photopsia, photophobia, abnormal lacrimation.
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32
Metabolic and Nutritional Disorders
Infrequent: hyponatremia, weight increase, creatine phosphokinase increase, thirst,
weight decrease, diabetes mellitus. Rare: decreased serum iron, cachexia,
dehydration,
hypokalemia,
hypoproteinemia,
hyperphosphatemia,
hypertriglyceridemia, hyperuricemia, hypoglycemia.
Urinary System Disorders
Frequent: polyuria/polydipsia∗. Infrequent: urinary incontinence, hematuria, dysuria.
Rare: urinary retention, cystitis, renal insufficiency.
Musculo-Skeletal System Disorders
Infrequent: myalgia. Rare: arthrosis, synostosis, bursitis, arthritis, skeletal pain.
Reproductive Disorders, Female
Frequent: menorrhagia∗, orgastic dysfunction∗, dry vagina∗ Infrequent: nonpuerperal
lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female
perineal pain, intermenstrual bleeding, vaginal hemorrhage.
Liver and Biliary System Disorders
Infrequent: increased SGOT, increased SGPT. Rare: hepatic failure, cholestatic
hepatitis, cholecystitis, cholelithiasis, hepatitis, hepatocellular damage.
Platelet, Bleeding, and Clotting Disorders
Infrequent:
epistaxis,
purpura.
Rare:
hemorrhage,
superficial
phlebitis,
thrombophlebitis, thrombocytopenia.
Hearing and Vestibular Disorders
Rare: tinnitus, hyperacusis, decreased hearing.
Red Blood Cell Disorders
Infrequent: anemia, hypochromic anemia. Rare: normocytic anemia.
Reproductive Disorders, Male
Frequent: erectile dysfunction∗ Infrequent: ejaculation failure.
White Cell and Resistance Disorders
Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly.
Endocrine Disorders
Rare: gynecomastia, male breast pain, antidiuretic hormone disorder.
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33
Special Senses
Rare: bitter taste.
∗ Incidence based on elicited reports.
Postintroduction Reports
Adverse events reported since market introduction which were temporally (but not
necessarily causally) related to RISPERDAL therapy, include the following:
anaphylactic reaction, angioedema, apnea, atrial fibrillation, cerebrovascular disorder,
including cerebrovascular accident, hyperglycemia, diabetes mellitus aggravated,
including diabetic ketoacidosis, intestinal obstruction, jaundice, mania, pancreatitis,
Parkinson's disease aggravated, pulmonary embolism. There have been rare reports of
sudden death and/or cardiopulmonary arrest in patients receiving RISPERDAL.
A causal relationship with RISPERDAL has not been established. It is important to
note that sudden and unexpected death may occur in psychotic patients whether they
remain untreated or whether they are treated with other antipsychotic drugs.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
RISPERDAL (risperidone) is not a controlled substance.
Physical and Psychological Dependence
RISPERDAL has not been systematically studied in animals or humans for its
potential for abuse, tolerance, or physical dependence. While the clinical trials did not
reveal any tendency for any drug-seeking behavior, these observations were not
systematic and it is not possible to predict on the basis of this limited experience the
extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug
abuse, and such patients should be observed closely for signs of RISPERDAL
misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking
behavior).
OVERDOSAGE
Human Experience
Premarketing experience included eight reports of acute RISPERDAL (risperidone)
overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In
general, reported signs and symptoms were those resulting from an exaggeration of
the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia
and hypotension, and extrapyramidal symptoms. One case, involving an estimated
overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT,
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34
and widened QRS. Another case, involving an estimated overdose of 36 mg, was
associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL overdosage, with
estimated doses of up to 360 mg. In general, the most frequently reported signs and
symptoms are those resulting from an exaggeration of the drug's known
pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and
extrapyramidal symptoms. Other adverse events reported since market introduction
which were temporally (but not necessarily causally) related to RISPERDAL
overdose, include torsade de pointes, prolonged QT interval, convulsions,
cardiopulmonary arrest, and rare fatality associated with multiple drug overdose.
Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate
oxygenation and ventilation. Gastric lavage (after intubation, if patient is
unconscious) and administration of activated charcoal together with a laxative should
be considered. Because of the rapid disintegration of RISPERDAL M-TABOrally
Disintegrating Tablets, pill fragments may not appear in gastric contents obtained
with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck
following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately and should include
continuous electrocardiographic monitoring to detect possible arrhythmias. If
antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine
carry a theoretical hazard of QT-prolonging effects that might be additive to those of
risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic
hypotension.
There is no specific antidote to RISPERDAL. Therefore, appropriate supportive
measures should be instituted. The possibility of multiple drug involvement should be
considered. Hypotension and circulatory collapse should be treated with appropriate
measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine
and dopamine should not be used, since beta stimulation may worsen hypotension in
the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal
symptoms, anticholinergic medication should be administered. Close medical
supervision and monitoring should continue until the patient recovers.
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DOSAGE AND ADMINISTRATION
Schizophrenia
Usual Initial Dose
RISPERDAL (risperidone) can be administered on either a BID or a QD schedule.
In early clinical trials, RISPERDAL was generally administered at 1 mg BID
initially, with increases in increments of 1 mg BID on the second and third day, as
tolerated, to a target dose of 3 mg BID by the third day. Subsequent controlled trials
have indicated that total daily risperidone doses of up to 8 mg on a QD regimen are
also safe and effective. However, regardless of which regimen is employed, in some
patients a slower titration may be medically appropriate. Further dosage adjustments,
if indicated, should generally occur at intervals of not less than 1 week, since steady
state for the active metabolite would not be achieved for approximately 1 week in the
typical
patient.
When
dosage
adjustments
are
necessary,
small
dose
increments/decrements of 1-2 mg are recommended.
Efficacy in schizophrenia was demonstrated in a dose range of 4 to 16 mg/day in the
clinical trials supporting effectiveness of RISPERDAL; however, maximal effect
was generally seen in a range of 4 to 8 mg/day. Doses above 6 mg/day for BID
dosing were not demonstrated to be more efficacious than lower doses, were
associated with more extrapyramidal symptoms and other adverse effects, and are not
generally recommended. In a single study supporting QD dosing, the efficacy results
were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg/day
has not been evaluated in clinical trials.
Maintenance Therapy
While there is no body of evidence available to answer the question of how long the
schizophrenic patient treated with RISPERDAL should remain on it, the
effectiveness of RISPERDAL 2 mg/day to 8 mg/day at delaying relapse was
demonstrated in a controlled trial in patients who had been clinically stable for at
least 4 weeks and were then followed for a period of 1 to 2 years. In this trial,
RISPERDAL was administered on a QD schedule, at 1 mg QD initially, with
increases to 2 mg QD on the second day, and to a target dose of 4 mg QD on the third
day (see CLINICAL PHARMACOLOGY – Clinical Trials). Nevertheless, patients
should be periodically reassessed to determine the need for maintenance treatment
with an appropriate dose.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is
recommended that when restarting patients who have had an interval
off RISPERDAL, the initial titration schedule should be followed.
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36
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching
schizophrenic patients from other antipsychotics to RISPERDAL, or concerning
concomitant
administration
with
other
antipsychotics.
While
immediate
discontinuation of the previous antipsychotic treatment may be acceptable for some
schizophrenic patients, more gradual discontinuation may be most appropriate for
others. In all cases, the period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, if
medically appropriate, initiate RISPERDAL therapy in place of the next scheduled
injection. The need for continuing existing EPS medication should be re-evaluated
periodically.
Bipolar Mania
Usual Dose
Risperidone should be administered on a once daily schedule, starting with 2 mg to
3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less
than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the
short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic
efficacy was demonstrated in a flexible dosage range of 1-6 mg per day
(see CLINICAL PHARMACOLOGY – Clinical Trials). RISPERDAL doses higher
than 6 mg per day were not studied.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in
the longer-term management of a patient who improves during treatment of an acute
manic episode with risperidone. While it is generally agreed that pharmacological
treatment beyond an acute response in mania is desirable, both for maintenance of the
initial response and for prevention of new manic episodes, there are no systematically
obtained data to support the use of risperidone in such longer-term treatment
(i.e., beyond 3 weeks).
Pediatric Use
Safety and effectiveness of RISPERDAL in pediatric patients with schizophrenia or
acute mania associated with Bipolar I Disorder have not been established.
Dosage in Special Populations
The recommended initial dose is 0.5 mg BID in patients who are elderly or
debilitated, patients with severe renal or hepatic impairment, and patients either
predisposed to hypotension or for whom hypotension would pose a risk. Dosage
increases in these patients should be in increments of no more than 0.5 mg BID.
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Increases to dosages above 1.5 mg BID should generally occur at intervals of at least
1 week. In some patients, slower titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less
ability to eliminate RISPERDAL than normal adults. Patients with impaired hepatic
function may have increases in the free fraction of risperidone, possibly resulting in
an enhanced effect (see CLINICAL PHARMACOLOGY). Patients with a
predisposition to hypotensive reactions or for whom such reactions would pose a
particular risk likewise need to be titrated cautiously and carefully monitored
(see PRECAUTIONS). If a once-a-day dosing regimen in the elderly or debilitated
patient is being considered, it is recommended that the patient be titrated on a
twice-a-day regimen for 2-3 days at the target dose. Subsequent switches to a
once-a-day dosing regimen can be done thereafter.
Co-Administration of RISPERDAL with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin,
rifampin, phenobarbital) with risperidone would be expected to cause decreases in the
plasma
concentrations
of
active
moiety
(the
sum
of
risperidone
and
9-hydroxyrisperidone), which could lead to decreased efficacy of risperidone
treatment. The dose of risperidone needs to be titrated accordingly for patients
receiving these enzyme inducers, especially during initiation or discontinuation of
therapy
with
these
inducers
(see
CLINICAL
PHARMACOLOGY
and
PRECAUTIONS).
Fluoxetine and paroxetine have been shown to increase the plasma concentration of
risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration
of 9-hydroxyrisperidone an average of 13%. The dose of risperidone needs to be
titrated accordingly when fluoxetine or paroxetine is co-administered (see CLINICAL
PHARMACOLOGY and PRECAUTIONS).
Directions for Use of RISPERDAL M-TAB Orally Disintegrating Tablets
RISPERDAL M-TAB Orally Disintegrating Tablets are supplied in blister packs of
4 tablet units each.
Tablet Accessing
Do not open the blister until ready to administer. For single tablet removal, separate
one of the four blister units by tearing apart at the perforations. Bend the corner
where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through
the foil because this could damage the tablet.
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38
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the
entire RISPERDAL M-TAB Orally Disintegrating Tablet on the tongue. The
RISPERDAL M-TAB Orally Disintegrating Tablet should be consumed
immediately, as the tablet cannot be stored once removed from the blister unit.
RISPERDAL M-TAB Orally Disintegrating Tablets disintegrate in the mouth
within seconds and can be swallowed subsequently with or without liquid. Patients
should not attempt to split or to chew the tablet.
HOW SUPPLIED
RISPERDAL (risperidone) tablets are imprinted "JANSSEN", and either “Ris” and
the strength “0.25”, “0.5”, or "R" and the strength "1", "2", "3", or "4".
0.25 mg dark yellow tablet: bottles of 60 NDC 50458-301-04, bottles of 500 NDC
50458-301-50, hospital unit dose packs of 100 NDC 50458-301-01.
0.5 mg red-brown tablet: bottles of 60 NDC 50458-302-06, bottles of 500 NDC
50458-302-50, hospital unit dose packs of 100 NDC 50458-302-01.
1 mg white tablet: bottles of 60 NDC 50458-300-06, blister pack of 100 NDC
50458-300-01, bottles of 500 NDC 50458-300-50.
2 mg orange tablet: bottles of 60 NDC 50458-320-06, blister pack of 100 NDC
50458-320-01, bottles of 500 NDC 50458-320-50.
3 mg yellow tablet: bottles of 60 NDC 50458-330-06, blister pack of 100 NDC
50458-330-01, bottles of 500 NDC 50458-330-50.
4 mg green tablet: bottles of 60 NDC 50458-350-06, blister pack of 100 NDC
50458-350-01.
RISPERDAL (risperidone) 1 mg/mL oral solution (NDC 50458-305-03) is supplied
in 30 mL bottles with a calibrated (in milligrams and milliliters) pipette. The
minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is
3 mL.
Tests indicate that RISPERDAL (risperidone) oral solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT
compatible with either cola or tea, however.
RISPERDAL M-TAB (risperidone) Orally Disintegrating Tablets are etched on
one side with “R0.5”, “R1”, and “R2”, respectively, and are packaged in blister packs
of 4 (2 X 2) tablets.
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39
0.5 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC
50458-395-28, long-term care packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages per box, NDC
50458-315-28, long-term care packaging of 30 tablets NDC 50458-315-30.
2 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC
50458-325-28.
Storage and Handling
RISPERDAL tablets should be stored at controlled room temperature
15o-25oC (59o-77oF). Protect from light and moisture.
Keep out of reach of children.
RISPERDAL 1 mg/mL oral solution should be stored at controlled room
temperature 15o-25oC (59o-77oF). Protect from light and freezing.
Keep out of reach of children.
RISPERDAL M-TAB Orally Disintegrating Tablets should be stored at controlled
room temperature 15o-25oC (59o-77oF).
Keep out of reach of children.
7503228
US Patent 4,804,663
Revised February 2005
©Janssen 2003
RISPERDAL tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico or
Janssen-Cilag, SpA, Latina, Italy
RISPERDAL oral solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL M-TAB Orally Disintegrating Tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico
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40
RISPERDAL tablets, RISPERDAL M-TAB Orally Disintegrating Tablets, and
oral solution are distributed by:
Janssen Pharmaceutica Products, L.P.
Titusville, NJ 08560
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1
JANSSEN
PHARMACEUTICA
PRODUCTS, L.P.
RISPERDAL CONSTA
(risperidone)
LONG-ACTING INJECTION
Increased Mortality in Elderly Patients with Dementia –Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical
antipsychotic drugs are at an increased risk of death compared to placebo.
Analyses of seventeen placebo controlled trials (modal duration of 10 weeks) in
these patients revealed a risk of death in the drug-treated patients of between
1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical
10 week controlled trial, the rate of death in drug-treated patients was about
4.5%, compared to a rate of about 2.6% in the placebo group. Although the
causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
in nature. RISPERDAL CONSTA(risperidone) is not approved for the
treatment of patients with Dementia-Related Psychosis.
DESCRIPTION
RISPERDAL® (risperidone) is a psychotropic agent belonging to the chemical class
of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-
benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-
a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is
410.49. The structural formula is:
Risperidone is practically insoluble in water, freely soluble in methylene chloride,
and soluble in methanol and 0.1 N HCl.
RISPERDAL CONSTA (risperidone) Long-Acting Injection is a combination of
extended release microspheres for injection and diluent for parenteral use.
The extended release microspheres formulation is a white to off-white, free-flowing
powder that is available in dosage strengths of 25, 37.5, or 50 mg risperidone per vial.
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Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide (PLG) at a
concentration of 381 mg risperidone per gram of microspheres.
The diluent for parenteral use is a clear, colorless solution. Composition of the diluent
includes polysorbate 20, sodium carboxymethyl cellulose, disodium hydrogen
phosphate dihydrate, citric acid anhydrous, sodium chloride, sodium hydroxide, and
water for injection. The microspheres are suspended in the diluent prior to injection.
RISPERDAL CONSTA is provided as a dose pack, consisting of a vial containing
the microspheres, a pre-filled syringe containing the diluent, a SmartSite
Needle-Free Vial Access Device, and one Needle-Pro 20 G TW safety needle.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of RISPERDAL (risperidone), as with other drugs used to
treat schizophrenia, is unknown. However, it has been proposed that the drug's
therapeutic activity in schizophrenia is mediated through a combination of dopamine
Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. Antagonism at
receptors other than D2 and 5HT2 may explain some of the other effects of
RISPERDAL.
RISPERDAL is a selective monoaminergic antagonist with high affinity (Ki of
0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2
adrenergic, and H1 histaminergic receptors. RISPERDAL acts as an antagonist at
other receptors, but with lower potency. RISPERDAL has low to moderate affinity
(Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak
affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma
site, and no affinity (when tested at concentrations >10-5 M) for cholinergic
muscarinic or β1 and β2 adrenergic receptors.
Pharmacokinetics
Absorption
After a single intramuscular (gluteal) injection of RISPERDAL CONSTA
(risperidone), there is a small initial release of the drug (<about 1% of the dose),
followed by a lag time of 3 weeks. The main release of the drug starts from 3 weeks
onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the
intramuscular (IM) injection. Therefore, oral antipsychotic supplementation should be
given during the first 3 weeks of treatment with RISPERDAL CONSTA to
maintain therapeutic levels until the main release of risperidone from the injection site
has begun (see DOSAGE AND ADMINISTRATION).
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3
The combination of the release profile and the dosage regimen (IM injections every
2 weeks)
of
RISPERDAL
CONSTA
results
in
sustained
therapeutic
concentrations. Steady-state plasma concentrations are reached after 4 injections and
are maintained for 4 to 6 weeks after the last injection. Plasma concentrations of
risperidone, 9-hydroxyrisperidone (the major metabolite), and risperidone plus
9-hydroxyrisperidone are linear over the dosing range of 25 mg to 50 mg.
Distribution
Once absorbed, risperidone is rapidly distributed. The volume of distribution is
1-2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The
plasma protein binding of risperidone is approximately 90%, and that of its major
metabolite,
9-hydroxyrisperidone,
is
77%.
Neither
risperidone
nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High
therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL),
and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of
risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of
unknown clinical significance.
Metabolism
Risperidone is extensively metabolized in the liver. The main metabolic pathway is
through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP
2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite,
9-hydroxyrisperidone, has similar pharmacological activity as risperidone.
Consequently, the clinical effect of the drug (i.e., the active moiety) results from the
combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for
metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs.
CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a
very low percentage of Asians, have little or no activity and are “poor metabolizers”)
and to inhibition by a variety of substrates and some non-substrates, notably
quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into
9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly. Although extensive metabolizers have lower risperidone and higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
the active moiety, after single and multiple doses, are similar in extensive and poor
metabolizers.
The interactions of RISPERDAL CONSTA and other drugs have not been
systematically evaluated in human subjects. Risperidone could be subject to two
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4
kinds of drug-drug interactions (see PRECAUTIONS - Drug Interactions). First,
inhibitors
of
CYP
2D6
interfere
with
conversion
of
risperidone
to
9-hydroxyrisperidone. This occurs with quinidine, giving essentially all recipients a
risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic
benefits and adverse effects of risperidone in patients receiving quinidine have not
been evaluated, but observations in a modest number (n≅70) of poor metabolizers
given risperidone do not suggest important differences between poor and extensive
metabolizers. Second, co-administration of carbamazepine and other known enzyme
inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone cause a
decrease
in
the
combined
plasma
concentrations
of
risperidone
and
9-hydroxyrisperidone (see PRECAUTIONS - Drug Interactions). It would also be
possible for risperidone to interfere with metabolism of other drugs metabolized by
CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is
unlikely.
In a drug interaction study in schizophrenic patients, 11 subjects received oral
risperidone titrated to 6 mg/day for 3 weeks, followed by concurrent administration of
carbamazepine for an additional 3 weeks. During co-administration, the plasma
concentrations of risperidone and its pharmacologically active metabolite,
9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of
carbamazepine did not appear to be affected. Co-administration of other known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may
cause similar decreases in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone
treatment (see PRECAUTIONS – Drug Interactions and DOSAGE AND
ADMINISTRATION – Co-Administration of RISPERDAL® CONSTA with Certain
Other Medications).
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the
plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine
did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered
the concentration of 9-hydroxyrisperidone an average of 13% (see PRECAUTIONS –
Drug Interactions and DOSAGE AND ADMINISTRATION – Co-Administration of
RISPERDAL® CONSTAwith Certain Other Medications).
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13) (see PRECAUTIONS – Drug
Interactions).
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5
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three
divided doses) compared to placebo (n=21). However, there was a 20% increase in
valproate peak plasma concentration (Cmax) after concomitant administration of
risperidone (see PRECAUTIONS – Drug Interactions).
There were no significant interactions between oral risperidone (1 mg QD) and
erythromycin (500 mg QID) (see PRECAUTIONS – Drug Interactions).
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser
extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose
of 14C-risperidone administered as solution to three healthy male volunteers, total
recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in
the feces.
The apparent half-life of risperidone plus 9-hydroxyrisperidone following
RISPERDAL CONSTA administration is 3 to 6 days, and is associated with a
monoexponential decline in plasma concentrations. This half-life of 3-6 days is
related to the erosion of the microspheres and subsequent absorption of risperidone.
The clearance of risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h
and 5.0 L/h in extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP
2D6 metabolizers, respectively. No accumulation of risperidone was observed during
long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg or
50 mg RISPERDAL CONSTA. The elimination phase is complete approximately
7 to 8 weeks after the last injection.
Special Populations
Renal Impairment
In patients with moderate to severe renal disease treated with oral RISPERDAL,
clearance of the sum of risperidone and its active metabolite decreased by
60% compared with young healthy subjects. Although patients with renal impairment
were not studied with RISPERDAL CONSTA, it is recommended that patients
with renal impairment be carefully titrated on oral RISPERDAL before treatment
with RISPERDAL CONSTA is initiated (see PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
Hepatic Impairment
While the pharmacokinetics of oral RISPERDAL in subjects with liver disease were
comparable to those in young healthy subjects, the mean free fraction of risperidone
in plasma was increased by about 35% because of the diminished concentration of
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6
both albumin and α1-acid glycoprotein. Although patients with hepatic impairment
were not studied with RISPERDAL CONSTA, it is recommended that patients
with hepatic impairment be carefully titrated on oral RISPERDAL before treatment
with RISPERDAL CONSTA is initiated (see PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
Elderly
In
an
open-label
trial,
steady-state
concentrations
of
risperidone
plus
9-hydroxyrisperidone in otherwise healthy elderly patients (≥65 years old) treated
with RISPERDAL CONSTA for up to 12 months fell within the range of values
observed in otherwise healthy nonelderly patients. Dosing recommendations are the
same for otherwise healthy elderly patients and nonelderly patients (see DOSAGE
AND ADMINISTRATION).
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender
effects, but a population pharmacokinetic analysis did not identify important
differences in the disposition of risperidone due to gender (whether or not corrected
for body weight) or race.
CLINICAL TRIALS
The effectiveness of RISPERDAL CONSTA (risperidone) in the treatment of
schizophrenia was established, in part, on the basis of extrapolation from the
established effectiveness of the oral formulation of risperidone. In addition, the
effectiveness of RISPERDAL CONSTA in the treatment of schizophrenia was
established in a 12-week, placebo-controlled trial in adult psychotic inpatients and
outpatients who met the DSM-IV criteria for schizophrenia.
Efficacy data were obtained from 400 patients with schizophrenia who were
randomized to receive injections of 25, 50, or 75 mg RISPERDAL CONSTA or
placebo every 2 weeks. During a 1-week run-in period, patients were discontinued
from other antipsychotics and were titrated to a dose of 4 mg oral RISPERDAL.
Patients who received RISPERDAL CONSTA were given doses of oral
RISPERDAL (2 mg for patients in the 25-mg group, 4 mg for patients in the 50-mg
group, and 6 mg for patients in the 75-mg group) for the 3 weeks after the first
injection to provide therapeutic plasma concentrations until the main release phase of
risperidone from the injection site had begun. Patients who received placebo
injections were given placebo tablets.
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Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a
validated, multi-item inventory, composed of five subscales to evaluate positive
symptoms,
negative
symptoms,
disorganized
thoughts,
uncontrolled
hostility/excitement, and anxiety/depression.
The primary efficacy variable in this trial was change from baseline to endpoint in the
total PANSS score. The mean total PANSS score at baseline for schizophrenic
patients in this study was 81.5.
Total PANSS scores showed significant improvement in the change from baseline to
endpoint in schizophrenic patients treated with each dose of RISPERDAL
CONSTA (25 mg, 50 mg, or 75 mg) compared with patients treated with placebo.
While there were no statistically significant differences between the treatment effects
for the three dose groups, the effect size for the 75 mg dose group was actually
numerically less than that observed for the 50 mg dose group.
Subgroup analyses did not indicate any differences in treatment outcome as a function
of age, race, or gender.
INDICATIONS AND USAGE
RISPERDAL CONSTA (risperidone) is indicated for the treatment of
schizophrenia.
The efficacy of RISPERDAL CONSTA is based in part on a 12-week,
placebo-controlled trial in schizophrenic inpatients or outpatients, along with
extrapolation from the established efficacy of oral RISPERDAL in this population.
The effectiveness of RISPERDAL CONSTA in longer-term use, that is, more than
12 weeks, has not been systematically evaluated in controlled trials. However, oral
risperidone has been shown to be effective in delaying time to relapse in longer-term
use. Patients should be periodically reassessed to determine the need for continued
treatment (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
RISPERDAL CONSTA (risperidone) is contraindicated in patients with a known
hypersensitivity to the product or any of its components.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical
antipsychotic drugs are at an increased risk of death compared to placebo.
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RISPERDALCONSTA(risperidone) is not approved for the treatment of
dementia-related psychosis (see Boxed Warning).
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and
evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,
diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine
phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at
a diagnosis, it is important to identify cases in which the clinical presentation includes
both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity,
heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive
symptomatic treatment and medical monitoring; and (3) treatment of any concomitant
serious medical problems for which specific treatments are available. There is no
general agreement about specific pharmacological treatment regimens for
uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The patient
should be carefully monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop
in patients treated with antipsychotic drugs. Although the prevalence of the syndrome
appears to be highest among the elderly, especially elderly women, it is impossible to
rely upon prevalence estimates to predict, at the inception of antipsychotic treatment,
which patients are likely to develop the syndrome. Whether antipsychotic drug products
differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total cumulative
dose of antipsychotic drugs administered to the patient increase. However, the syndrome
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9
can develop, although much less commonly, after relatively brief treatment periods at
low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the
signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptomatic suppression has upon the long-term course of
the syndrome is unknown.
Given these considerations, RISPERDAL CONSTA should be prescribed in a
manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic
antipsychotic treatment should generally be reserved for patients who suffer from a
chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom
alternative, equally effective, but potentially less harmful treatments are not available
or appropriate. In patients who do require chronic treatment, the smallest dose and the
shortest duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with
RISPERDAL CONSTA, drug discontinuation should be considered. However,
some patients may require treatment with RISPERDAL CONSTA despite the
presence of the syndrome.
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients
with Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including
fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of oral
risperidone in elderly patients with dementia-related psychosis. In placebo-controlled
trials, there was a significantly higher incidence of cerebrovascular adverse events in
patients treated with oral risperidone compared to patients treated with placebo.
RISPERDAL CONSTA is not approved for the treatment of patients with
dementia-related psychosis. (See also Boxed WARNING, WARNINGS: Increased
Mortality in Elderly Patients with Dementia-Related Psychosis.)
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, has been reported in patients treated with atypical
antipsychotics including RISPERDAL. Assessment of the relationship between
atypical antipsychotic use and glucose abnormalities is complicated by the possibility
of an increased background risk of diabetes mellitus in patients with schizophrenia
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and the increasing incidence of diabetes mellitus in the general population. Given
these confounders, the relationship between atypical antipsychotic use and
hyperglycemia-related adverse events is not completely understood. However,
epidemiological
studies
suggest
an
increased
risk
of
treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical
antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in
patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control.
Patients with risk factors for diabetes mellitus (e.g., obesity, family history of
diabetes) who are starting treatment with atypical antipsychotics should undergo
fasting blood glucose testing at the beginning of treatment and periodically during
treatment. Any patient treated with atypical antipsychotics should be monitored for
symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and
weakness. Patients who develop symptoms of hyperglycemia during treatment with
atypical antipsychotics should undergo fasting blood glucose testing. In some cases,
hyperglycemia has resolved when the atypical antipsychotic was discontinued;
however, some patients required continuation of anti-diabetic treatment despite
discontinuation of the suspect drug.
PRECAUTIONS
General
Orthostatic Hypotension
RISPERDAL CONSTA (risperidone) may induce orthostatic hypotension
associated with dizziness, tachycardia, and in some patients, syncope, probably
reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in
0.8% (12/1499 patients) of patients treated with RISPERDAL CONSTA in
multiple-dose studies. Patients should be instructed in nonpharmacologic
interventions that help to reduce the occurrence of orthostatic hypotension
(e.g., sitting on the edge of the bed for several minutes before attempting to stand in
the morning and slowly rising from a seated position).
RISPERDAL CONSTA should be used with particular caution in (1) patients with
known cardiovascular disease (history of myocardial infarction or ischemia, heart
failure, or conduction abnormalities), cerebrovascular disease, and conditions which
would predispose patients to hypotension, e.g., dehydration and hypovolemia, and
(2) in the elderly and patients with renal or hepatic impairment. Monitoring of
orthostatic vital signs should be considered in all such patients, and a dose reduction
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should be considered if hypotension occurs. Clinically significant hypotension has been
observed with concomitant use of oral RISPERDAL and antihypertensive medication.
Seizures
During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients
treated with RISPERDAL CONSTA. Therefore, RISPERDAL CONSTA should
be used cautiously in patients with a history of seizures.
Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug
use. Aspiration pneumonia is a common cause of morbidity and mortality in patients
with advanced Alzheimer’s dementia. RISPERDAL CONSTA and other
antipsychotic drugs should be used cautiously in patients at risk for aspiration
pneumonia. (See also Boxed WARNING, WARNINGS: Increased Mortality in
Elderly Patients with Dementia-Related Psychosis.)
Osteodystrophy and Tumors in Animals
RISPERDAL CONSTA produced osteodystrophy in male and female rats in a
1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg
administered IM every 2 weeks.
RISPERDAL
CONSTA
produced
renal
tubular
tumors
(adenoma,
adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year
carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition,
RISPERDAL CONSTA produced an increase in a marker of cellular proliferation
in renal tissue in males in the 1-year toxicity study and in renal tumor-bearing males
in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks.
(Cellular proliferation was not measured at the low dose or in females in either
study.)
The effect dose for osteodystrophy and the tumor findings is 8 times the IM
maximum recommended human dose (MRHD) (50 mg) on a mg/m2 basis and is
associated with a plasma exposure (AUC) 2 times the expected plasma exposure
(AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to
the IM MRHD on a mg/m2 basis). Plasma exposure (AUC) at the no-effect dose was
one third the expected plasma exposure (AUC) at the IM MRHD.
Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of
orally administered risperidone. Osteodystrophy was not observed in dogs at doses
up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study.
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The renal tubular and adrenomedullary tumors in male rats and other tumor findings
are described in more detail under PRECAUTIONS, Carcinogenicity, Mutagenesis,
Impairment of Fertility.
The relevance of these findings to human risk is unknown.
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates
prolactin levels and the elevation persists during chronic administration. Tissue
culture experiments indicate that approximately one-third of human breast cancers are
prolactin-dependent in vitro, a factor of potential importance if the prescription of
these drugs is contemplated in a patient with previously detected breast cancer.
Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported with prolactin-elevating compounds, the clinical
significance of elevated serum prolactin levels is unknown for most patients.
As has been observed with other compounds that increase prolactin release, an
increase in the incidence of pituitary gland, mammary gland, and endocrine
pancreatic islet cell hyperplasias and/or neoplasias, was observed in rodent
carcinogenicity studies with RISPERDAL Tablets and RISPERDAL CONSTA
(see PRECAUTIONS – Carcinogenesis, Mutagenesis, Impairment of Fertility).
Neither clinical studies nor epidemiologic studies conducted to date have shown an
association between chronic administration of this class of drugs and tumorigenesis in
humans; the available evidence is considered too limited to be conclusive at this time.
Potential for Cognitive and Motor Impairment
Somnolence was reported by 5% of patients treated with RISPERDAL CONSTA
in multiple-dose trials. Since risperidone has the potential to impair judgment,
thinking, or motor skills, patients should be cautioned about operating hazardous
machinery, including automobiles, until they are reasonably certain that treatment
with RISPERDAL CONSTA does not affect them adversely.
Priapism
No cases of priapism have been reported in patients treated with RISPERDAL
CONSTA. However, rare cases of priapism have been reported in patients treated with
oral RISPERDAL. While the relationship of these events to oral RISPERDAL use
has not been established, other drugs with alpha-adrenergic blocking effects have been
reported to induce priapism, and it is possible that RISPERDAL may share this
capacity. Severe priapism may require surgical intervention.
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Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral
RISPERDAL® in a large, open premarketing experience (approximately 1300 patients).
She experienced jaundice, fever, and bruising, but eventually recovered after receiving
plasmapheresis. The relationship to RISPERDAL® therapy is unknown.
Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans,
and may mask signs and symptoms of overdosage with certain drugs or of conditions
such as intestinal obstruction, Reye’s syndrome, and brain tumor.
Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents.
Both hyperthermia and hypothermia have been reported in association with oral
RISPERDAL use. Caution is advised when prescribing RISPERDAL CONSTA for
patients who will be exposed to temperature extremes.
Suicide
The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of
high-risk patients should accompany drug therapy. RISPERDAL CONSTA is to be
administered by a health care professional (see DOSAGE and ADMINISTRATION);
therefore, suicide due to an overdose is unlikely.
Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL CONSTA in patients with certain
concomitant systemic illnesses is limited. Patients with Parkinson's Disease or
Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL
CONSTA, may be at increased risk of Neuroleptic Malignant Syndrome as well as
having an increased sensitivity to antipsychotic medications. Manifestation of this
increased sensitivity can include confusion, obtundation, postural instability with
frequent falls, in addition to extrapyramidal symptoms.
Caution is advisable when using RISPERDAL CONSTA in patients with diseases or
conditions that could affect metabolism or hemodynamic responses.RISPERDAL
CONSTA has not been evaluated or used to any appreciable extent in patients with a
recent history of myocardial infarction or unstable heart disease. Patients with these
diagnoses were excluded from clinical studies during the product’s premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in
patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) treated
with oral RISPERDAL; an increase in the free fraction of risperidone is also seen in
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14
patients with severe hepatic impairment. Patients with renal or hepatic impairment
should be carefully titrated on oral RISPERDAL before treatment with RISPERDAL
CONSTA is initiated (see DOSAGE AND ADMINISTRATION).
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they
prescribe RISPERDAL CONSTA.
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension and instructed in
nonpharmacologic interventions that help to reduce the occurrence of orthostatic
hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to
stand in the morning and slowly rising from a seated position).
Interference With Cognitive and Motor Performance
Because RISPERDAL CONSTA has the potential to impair judgment, thinking, or
motor skills, patients should be cautioned about operating hazardous machinery,
including automobiles, until they are reasonably certain that treatment with
RISPERDAL CONSTA does not affect them adversely.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy and for at least 12 weeks after the last injection of
RISPERDAL CONSTA.
Nursing
Patients should be advised not to breast-feed an infant during treatment and for at least
12 weeks after the last injection of RISPERDAL CONSTA.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take,
any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol during treatment with RISPERDAL
CONSTA.
Laboratory Tests
No specific laboratory tests are recommended.
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Drug Interactions
The interactions of RISPERDAL CONSTA and other drugs have not been
systematically evaluated. Given the primary CNS effects of risperidone, caution should
be used when RISPERDAL CONSTA is administered in combination with other
centrally-acting drugs or alcohol.
Because of its potential for inducing hypotension, RISPERDAL CONSTA may
enhance the hypotensive effects of other therapeutic agents with this potential.
RISPERDAL CONSTA may antagonize the effects of levodopa and dopamine
agonists.
Amytriptyline does not affect the pharmacokinetics of risperidone or the active
antipsychotic fraction. Cimetidine and ranitidine increased the bioavailability of
risperidone, but only marginally increased the plasma concentration of the active
antipsychotic fraction.
Chronic administration of clozapine with risperidone may decrease the clearance of
risperidone.
Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received oral
risperidone titrated to 6 mg/day for 3 weeks, followed by concurrent administration of
carbamazepine for an additional 3 weeks. During co-administration, the plasma
concentrations of risperidone and its pharmacologically active metabolite,
9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of
carbamazepine did not appear to be affected. Co-administration of other known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may
cause similar decreases in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone
treatment. At the initiation of therapy with carbamazepine or other known hepatic
enzyme inducers, patients should be closely monitored during the first 4-8 weeks,
since the dose of RISPERDAL CONSTA may need to be adjusted. A dose
increase, or additional oral RISPERDAL, may need to be considered. On
discontinuation of carbamazepine or other hepatic enzyme inducers, the dosage of
RISPERDAL CONSTA should be re-evaluated and, if necessary, decreased. Patients
may be placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks
before the planned discontinuation of carbamazepine therapy to adjust for the expected
increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients
treated with the lowest available dose (25 mg) of RISPERDAL CONSTA, it is
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16
recommended to continue treatment with the 25-mg dose unless clinical judgment
necessitates interruption of treatment with RISPERDAL CONSTA.
Fluoxetine and Paroxetine
Fluoxetine (20 mg QD) and paroxetine (20 mg QD), which inhibits CYP 2D6, have
been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and
3-9 fold respectively.Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone
an average of 13%. When either concomitant fluoxetine or paroxetine is initiated or
discontinued, the physician should re-evaluate the dosage of RISPERDAL
CONSTA. When initiation of fluoxetine or paroxetine is considered, patients may be
placed on a lower dose of RISPERDAL CONSTA between 2 to 4 weeks before the
planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in
plasma concentrations of risperidone. For patients treated with the lowest available
dose (25 mg), it is recommended to continue treatment with the 25-mg dose unless
clinical judgment necessitates interruption of treatment with RISPERDAL
CONSTA. The effects of discontinuation of concomitant fluoxetine or paroxetine
therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not
been studied.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
Valproate
Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided
doses) compared to placebo (n=21). However, there was a 20% increase in valproate
peak plasma concentration (Cmax) after concomitant administration of risperidone.
Digoxin
RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
Drugs that Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and
other drugs (see CLINICAL PHARMACOLOGY). Drug interactions that reduce the
metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma
concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone.
Analysis of clinical studies involving a modest number of poor metabolizers
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(n≅70 patients) does not suggest that poor and extensive metabolizers have different
rates of adverse effects. No comparison of effectiveness in the two groups has been
made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1,
1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
There were no significant interactions between risperidone and erythromycin (see
CLINICAL PHARMACOLOGY).
Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6.
Therefore, RISPERDAL CONSTA is not expected to substantially inhibit the
clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction
studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil
and galantamine, which are metabolized by CYP 2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis - Oral
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats.
Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for
18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and
37.5 times the oral maximum recommended human dose (MRHD) (16 mg/day) on a
mg/kg basis, or 0.2, 0.75, and 3 times the oral MRHD (mice) or 0.4, 1.5, and 6 times the
oral MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in
male mice. There was a significant increase in pituitary gland adenomas in female mice
at doses 0.75 and 3 times the oral MRHD on a mg/m2 basis. There was a significant
increase in endocrine pancreatic adenomas in male rats at doses 1.5 and 6 times the
oral MRHD on a mg/m2 basis. Mammary gland adenocarcinomas were significantly
increased in female mice at all doses tested (0.2, 0.75, and 3 times the oral MRHD on
a mg/m2 basis), in female rats at all doses tested (0.4, 1.5, and 6 times the oral MRHD
on a mg/m2 basis), and in male rats at a dose 6 times the oral MRHD on a mg/m2
basis.
Carcinogenesis - IM
RISPERDAL CONSTA was evaluated in a 24-month carcinogenicity study in
which SPF Wistar rats were treated every 2 weeks with IM injections of either
5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg)
on a mg/m2 basis. A control group received injections of 0.9% NaCl, and a vehicle
control group was injected with placebo microspheres. There was a significant
increase in pituitary gland adenomas, endocrine pancreas adenomas, and
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18
adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m2 basis. The
incidence of mammary gland adenocarcinomas was significantly increased in female
rats at both doses (1 and 8 times the IM MRHD on a mg/m2 basis). A significant
increase in renal tubular tumors (adenoma, adenocarcinomas) was observed in male
rats at 8 times the IM MRHD on a mg/m2 basis. Plasma exposures (AUC) in rats were
0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure
(AUC) at the IM MRHD.
Dopamine D2 receptor antagonists have been shown to chronically elevate prolactin
levels in rodents. Serum prolactin levels were not measured during the carcinogenicity
studies of oral risperidone; however, measurements taken during subchronic toxicity
studies showed that oral risperidone elevated serum prolactin levels 5- to 6-fold in mice
and rats at the same doses used in the oral carcinogenicity studies. Serum prolactin
levels increased in a dose-dependent manner up to 6- and 1.5-fold in male and female
rats, respectively, at the end of the 24-month treatment with RISPERDAL CONSTA
every 2 weeks. Increases in the incidence of pituitary gland, endocrine pancreas, and
mammary gland neoplasms have been found in rodents after chronic administration
of other antipsychotic drugs and may be prolactin-mediated.
The relevance for human risk of the findings of prolactin-mediated endocrine tumors in
rodents is unknown (see PRECAUTIONS - Hyperprolactinemia).
Mutagenesis
No evidence of mutagenic potential for oral risperidone was found in the in vitro Ames
reverse mutation test, in vitro mouse lymphoma assay, in vitro rat hepatocyte
DNA-repair assay, in vivo oral micronucleus test in mice, the sex-linked recessive lethal
test in Drosophila, or the in vitro chromosomal aberration test in human lymphocytes or
in Chinese hamster cells.
In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse
mutation test for RISPERDAL CONSTA.
Impairment of Fertility
Oral risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in
Wistar rats in three reproductive studies (two mating and fertility studies and a
multigenerational study) at doses 0.1 to 3 times the oral maximum recommended human
dose (MRHD) (16 mg/day) on a mg/m2 basis. The effect appeared to be in females,
since impaired mating behavior was not noted in the mating and fertility study in which
males only were treated. In a subchronic study in Beagle dogs in which oral risperidone
was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were
decreased at doses 0.6 to 10 times the oral MRHD on a mg/m2 basis. Dose-related
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decreases were also noted in serum testosterone at the same doses. Serum testosterone
and sperm values partially recovered, but remained decreased after treatment was
discontinued. No no-effect doses were noted in either rat or dog.
No mating and fertility studies were conducted with RISPERDAL CONSTA.
Pregnancy
Pregnancy Category C
The teratogenic potential of oral risperidone was studied in three embryofetal
development studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to
6 times the oral maximum recommended human dose [MRHD] on a mg/m2 basis) and
in one embryofetal development study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to
6 times the oral MRHD on a mg/m2 basis). The incidence of malformations was not
increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the oral
MRHD on a mg/m2 basis. In three reproductive studies in rats (two peri/post-natal
development studies and a multigenerational study), there was an increase in pup deaths
during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times the oral
MRHD on a mg/m2 basis. It is not known whether these deaths were due to a direct
effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one peri/post-natal
development study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or
1.5 times the oral MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats,
toxic effects on the fetus or pups, as evidenced by a decrease in the number of live
pups and an increase in the number of dead pups at birth (Day 0), and a decrease in
birth weight in pups of drug-treated dams were observed. In addition, there was an
increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether
or not the pups were cross-fostered. Risperidone also appeared to impair maternal
behavior in that pup body weight gain and survival (from Days 1 to 4 of lactation)
were reduced in pups born to control but reared by drug-treated dams. These effects
were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the oral
MRHD on a mg/m2 basis.
No studies were conducted with RISPERDAL CONSTA.
Placental transfer of risperidone occurs in rat pups. There are no adequate and
well-controlled studies in pregnant women. However, there was one report of a case of
agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal
relationship to oral RISPERDAL therapy is unknown.
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RISPERDAL CONSTA should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of RISPERDAL CONSTA on labor and delivery in humans is unknown.
Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk.
Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk.
Therefore, women should not breast-feed during treatment with RISPERDAL
CONSTA and for at least 12 weeks after the last injection.
Pediatric Use
RISPERDAL CONSTA has not been studied in children younger than 18 years old.
Geriatric Use
In an open-label study, 57 clinically stable, elderly patients (≥65 years old) with
schizophrenia or schizoaffective disorder received RISPERDAL CONSTA every
2 weeks for up to 12 months. In general, no differences in the tolerability of
RISPERDAL CONSTA were observed between otherwise healthy elderly and
nonelderly patients. Therefore, dosing recommendations for otherwise healthy elderly
patients are the same as for nonelderly patients. Because elderly patients exhibit a
greater tendency to orthostatic hypotension than nonelderly patients, elderly patients
should be instructed in nonpharmacologic interventions that help to reduce the
occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several
minutes before attempting to stand in the morning and slowly rising from a seated
position). In addition, monitoring of orthostatic vital signs should be considered in
elderly patients for whom orthostatic hypotension is of concern (see CLINICAL
PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Concomitant use with Furosemide in Elderly Patients with Dementia-Related
Psychosis
In placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
oral risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients
treated with oral risperidone alone (3.1%; mean age 84 years, range 70-96) or
furosemide alone (4.1%; mean age 80 years, range 67-90). The increase in mortality
in patients treated with furosemide plus oral risperidone was observed in two of the
four clinical trials.
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No pathophysiological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death observed. Nevertheless, caution should be
exercised and the risks and benefits of this combination should be considered prior to
the decision to use. There was no increased incidence of mortality among patients
taking other diuretics as concomitant medication with risperidone. Irrespective of
treatment, dehydration was an overall risk factor for mortality and should therefore be
carefully avoided in elderly patients with dementia-related psychosis. RISPERDAL
CONSTA is not approved for the treatment of patients with dementia-related
psychosis. (See also Boxed WARNING, WARNINGS: Increased Mortality in
Elderly Patients with Dementia-Related Psychosis.)
ADVERSE REACTIONS
Adverse findings were assessed by spontaneous reports of adverse events, laboratory
tests, vital signs, body weight, and ECGs. Adverse events were classified using the
World Health Organization preferred terms. Treatment-emergent adverse events were
defined as those events with an onset between the first dose and 49 days after the last
dose.
The prescriber should be aware that these figures cannot be used to predict the incidence
of side effects in the course of usual medical practice where patient characteristics and
other factors differ from those which prevailed in this clinical trial. Similarly, the cited
frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do
provide the prescribing physician with some basis for estimating the relative
contribution of drug and nondrug factors to the side effect incidence rate in the
population studied.
Associated with Discontinuation of Treatment
In the 12-week, placebo-controlled trial, the incidence of schizophrenic patients who
discontinued treatment due to an adverse event was lower with RISPERDAL
CONSTA (11%; 22/202 patients) than with placebo (13%; 13/98 patients).
Incidence in Controlled Trials
The incidence of adverse reactions in the placebo-controlled trial was based on
202 schizophrenic patients treated with 25 or 50 mg RISPERDAL CONSTA and
98 schizophrenic patients treated with placebo for up to 12 weeks.
Commonly Observed Adverse Events in Controlled Clinical Trials
Spontaneously reported, treatment-emergent adverse events with an incidence of 5%
or greater in at least one of the RISPERDAL CONSTA groups (25 mg or 50 mg)
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and at least twice that of placebo were: somnolence, akathisia, parkinsonism,
dyspepsia, constipation, dry mouth, fatigue, weight increase.
Adverse Events Occurring at an Incidence of 2% or More in Patients Treated
with RISPERDAL CONSTA:
Table 1 enumerates adverse events that occurred at an incidence of 2% or more, and
were at least as frequent among patients treated with 25 mg or 50 mg RISPERDAL
CONSTA as patients treated with placebo in the 12-week, placebo-controlled trial.
This table shows the percentage of patients in each dose group who spontaneously
reported at least one episode of an event at some time during double-blind treatment. All
patients were titrated to a dose of 4 mg oral RISPERDAL during a 1-week run-in
period. Patients who received RISPERDAL CONSTA were given doses of oral
RISPERDAL (2 mg for patients in the 25-mg group, and 4 mg for patients in the
50-mg group) during the 3 weeks after the first injection to provide therapeutic levels
until the main release phase of risperidone from the injection site had begun. Patients
who received placebo injections were given placebo tablets.
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Table 1.
Incidence (% of Patients) of Treatment-Emergent Adverse Events in a
12-Week, Placebo-Controlled Clinical Trial
RISPERDAL CONSTA
WHO Body System Disorder/
Preferred Term
25 mg
(N=99)
50 mg
(N=103)
Placebo
(N=98)
Psychiatric
Insomnia
16
13
14
Hallucination
7
6
5
Somnolence
5
6
3
Suicide attempt
1
4
3
Abnormal thinking
0
3
2
Abnormal dreaming
2
0
0
Central & peripheral nervous system
Headache
15
22
12
Dizziness
8
11
6
Akathisia
2
9
4
Parkinsonisma
4
10
3
Tremor
0
3
0
Hypoaesthesia
2
0
0
Gastrointestinal
Dyspepsia
7
7
2
Constipation
5
7
1
Mouth dry
0
7
1
Toothache
1
3
0
Saliva increased
6
2
1
Tooth disorder
4
2
0
Diarrhea
5
1
3
Body as a whole - general
Fatigue
3
7
0
Pain
10
3
4
Peripheral edema
2
3
1
Leg pain
4
1
1
Fever
2
1
0
Syncope
2
0
0
Respiratory system
Rhinitis
14
4
8
Coughing
5
2
4
Sinusitis
3
1
0
Upper respiratory tract infection
2
0
1
Metabolic & nutritional
Weight increase
5
4
2
Weight decrease
4
1
1
Cardiovascular
Hypertension
3
3
2
Hearing & vestibular
Ear disorder (NOS)
0
3
0
Vision
Vision abnormal
2
3
0
Skin & appendages
Acne
2
2
0
Skin dry
2
0
0
Musculo-Skeletal
Myalgia
4
2
1
a Includes adverse events of bradykinesia, extrapyramidal disorder, and hypokinesia.
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Dose Dependency of Adverse Events
Extrapyramidal Symptoms:
Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week,
placebo-controlled trial comparing three doses of RISPERDAL CONSTA (25 mg,
50 mg, and 75 mg) with placebo, including: (1) the incidence of spontaneous reports of
EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of
the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal
Symptom Rating Scale (ESRS).
As shown in Table 1, the overall incidence of EPS-related adverse events (akathisia,
dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL
CONSTA was comparable to that of patients treated with placebo; the incidence of
EPS-related adverse events was higher in patients treated with 50 mg RISPERDAL
CONSTA.
The median change from baseline to endpoint in total ESRS score showed no
worsening in patients treated with RISPERDAL CONSTA compared with patients
treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the
placebo group); and 0 (50-mg group).
Vital Sign Changes:
RISPERDAL is associated with orthostatic hypotension and tachycardia (see
PRECAUTIONS). In the placebo-controlled trial, orthostatic hypotension was
observed in 2% of patients treated with 25 mg or 50 mg RISPERDAL CONSTA
(see PRECAUTIONS).
Weight Changes:
In the 12-week, placebo-controlled trial, 9% of patients treated with RISPERDAL
CONSTA, compared with 6% of patients treated with placebo, experienced a weight
gain of >7% of body weight at endpoint.
Laboratory Changes:
The percentage of patients treated with RISPERDAL CONSTA who experienced
potentially important changes in routine serum chemistry, hematology, or urinalysis
parameters was similar to or less than that of placebo patients. Additionally, no patients
discontinued treatment due to changes in serum chemistry, hematology, or urinalysis
parameters.
ECG Changes:
The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg
RISPERDAL CONSTA and 98 schizophrenic patients treated with placebo in a
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12-week, double-blind, placebo-controlled trial were evaluated. Compared with placebo,
there were no statistically significant differences in QTc intervals (using Fridericia’s and
linear correction factors) during treatment with RISPERDAL CONSTA.
Between-group
comparisons
for
pooled
placebo-controlled
trials with
oral
RISPERDAL revealed no statistically significant differences between risperidone and
placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR
intervals, and heart rate. When all oral RISPERDAL® doses were pooled from
randomized controlled trials in several indications, there was a mean increase in heart
rate of 1 beat per minute compared to no change for placebo patients. In short-term
schizophrenia trials, higher doses of oral risperidone (8-16 mg/day) were associated with
a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
Pain Assessment and Local Injection Site Reactions:
The mean intensity of injection pain reported by patients using a visual analog scale
(0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first
to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8).
After the sixth injection (Week 10), investigator ratings indicated that 1% of patients
treated with 25 mg or 50 mg RISPERDAL CONSTA experienced redness,
swelling, or induration at the injection site.
Other Events Observed During the Premarketing Evaluation of
RISPERDAL CONSTA
During its premarketing assessment, RISPERDAL CONSTA was administered to
1499 patients in multiple-dose studies. The conditions and duration of exposure to
RISPERDAL CONSTA varied greatly, and included (in overlapping categories)
open-label and double-blind studies, uncontrolled and controlled studies, inpatient and
outpatient studies, fixed-dose and titration studies, and short-term and long-term
exposure studies. In all studies, untoward events associated with this exposure were
obtained by spontaneous report and were recorded by clinical investigators using
terminology of their own choosing. Consequently, it is not possible to provide a
meaningful estimate of the proportion of individuals experiencing adverse events
without first grouping similar types of untoward events into a smaller number of
standardized event categories.
In the listings that follow, spontaneously reported adverse events were classified using
World Health Organization (WHO) preferred terms. The frequencies presented,
therefore, represent the proportion of the 1499 patients exposed to multiple doses of
RISPERDAL CONSTA who experienced an event of the type cited on at least one
occasion while receiving RISPERDAL CONSTA. All reported events are included
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except those already listed in Table 1, those events for which a drug cause was remote,
those event terms which were so general as to be uninformative, and those events
reported only once which did not have a substantial probability of being acutely
life-threatening. It is important to emphasize that, although the reported events occurred
during treatment with RISPERDAL CONSTA, they were not necessarily caused by
it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are those
occurring in at least 1/100 patients (only those not already listed in the tabulated
results from the placebo-controlled trial appear in this listing); infrequent adverse
events are those occurring in 1/100 to 1/1000 patients; and rare events are those
occurring in fewer than 1/1000 patients.
Psychiatric Disorders
Frequent: anxiety, psychosis, depression, agitation, nervousness, paranoid reaction,
delusion, apathy. Infrequent: anorexia, impaired concentration, impotence, emotional
lability, manic reaction, decreased libido, increased appetite, amnesia, confusion,
euphoria, depersonalization, paroniria, delirium, psychotic depression.
Central and Peripheral Nervous System Disorders
Frequent: hypertonia, dystonia. Infrequent: dyskinesia, vertigo, leg cramps,
tardive dyskinesiaa, involuntary muscle contractions, paraesthesia, abnormal gait,
bradykinesia, convulsions, hypokinesia, ataxia, fecal incontinence, oculogyric crisis,
tetany, apraxia, dementia, migraine. Rare: neuroleptic malignant syndrome.
a
In the integrated database of multiple-dose studies (1499 patients with
schizophrenia or schizoaffective disorder), 9 patients (0.6%) treated with
RISPERDAL CONSTA (all dosages combined) experienced an adverse event
of tardive dyskinesia.
Body as a Whole/General Disorders
Frequent: back pain, chest pain, asthenia. Infrequent: malaise, choking.
Gastrointestinal Disorders
Frequent: nausea, vomiting, abdominal pain. Infrequent: gastritis, gastroesophageal
reflux, flatulence, hemorrhoids, melena, dysphagia, rectal hemorrhage, stomatitis,
colitis, gastric ulcer, gingivitis, irritable bowel syndrome, ulcerative stomatitis.
Respiratory System Disorders
Frequent: dyspnea. Infrequent: pneumonia, stridor, hemoptysis. Rare: pulmonary
edema.
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Skin and Appendage Disorders
Frequent: rash. Infrequent: eczema, pruritus, erythematous rash, dermatitis, alopecia,
seborrhea, photosensitivity reaction, increased sweating.
Metabolic and Nutritional Disorders
Infrequent: hyperuricemia, hyperglycemia, hyperlipemia, hypokalemia, glycosuria,
hypercholesterolemia, obesity, dehydration, diabetes mellitus, hyponatremia.
Musculo-Skeletal System Disorders
Frequent: arthralgia, skeletal pain. Infrequent: torticollis, arthrosis, muscle weakness,
tendinitis, arthritis, arthropathy.
Heart Rate and Rhythm Disorders
Frequent: tachycardia. Infrequent: bradycardia, AV block, palpitation, bundle branch
block. Rare: T-wave inversion.
Cardiovascular Disorders
Frequent: hypotension. Infrequent: postural hypotension.
Urinary System Disorders
Frequent: urinary incontinence. Infrequent: hematuria, micturition frequency, renal
pain, urinary retention.
Vision Disorders
Infrequent: conjunctivitis, eye pain, abnormal accommodation.
Reproductive Disorders, Female
Frequent: amenorrhea. Infrequent: nonpuerperal lactation, vaginitis, dysmenorrhea,
breast pain, leukorrhea.
Resistance Mechanism Disorders
Infrequent: abscess.
Liver and Biliary System Disorders
Frequent: increased hepatic enzymes. Infrequent: hepatomegaly, increased SGPT.
Rare: bilirubinemia, increased GGT, hepatitis, hepatocellular damage, jaundice, fatty
liver, increased SGOT.
Reproductive Disorders, Male
Infrequent: ejaculation failure.
Application Site Disorders
Frequent: injection site pain. Infrequent: injection site reaction.
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Hearing and Vestibular Disorders
Infrequent: earache, deafness, hearing decreased.
Red Blood Cell Disorders
Frequent: anemia.
White Cell and Resistance Disorders
Infrequent:
lymphadenopathy,
leucopenia,
cervical
lymphadenopathy.
Rare: granulocytopenia, leukocytosis, lymphopenia.
Endocrine Disorders
Infrequent: hyperprolactinemia, gynecomastia, hypothyroidism.
Platelet, Bleeding and Clotting Disorders
Infrequent:
purpura,
epistaxis.
Rare:
pulmonary
embolism,
hematoma,
thrombocytopenia.
Myo-, Endo-, and Pericardial and Valve Disorders
Infrequent: myocardial ischemia, angina pectoris, myocardial infarction.
Vascular (Extracardiac) Disorders
Infrequent: phlebitis. Rare: intermittent claudication, flushing, thrombophlebitis.
Postintroduction Reports
Adverse events reported since market introduction which were temporally (but not
necessarily causally) related to oral RISPERDAL therapy include the following:
anaphylactic reaction, angioedema, apnea, atrial fibrillation, cerebrovascular disorder,
including cerebrovascular accident, hyperglycemia, diabetes mellitus aggravated,
including diabetic ketoacidosis, intestinal obstruction, jaundice, mania, pancreatitis,
Parkinson’s disease aggravated, pulmonary embolism. There have been rare reports of
sudden death and/or cardiopulmonary arrest in patients receiving oral RISPERDAL. A
causal relationship with oral RISPERDAL has not been established. It is important to
note that sudden and unexpected death may occur in psychotic patients whether they
remain untreated or whether they are treated with other antipsychotic drugs.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
RISPERDAL CONSTA (risperidone) is not a controlled substance.
Physical and Psychological Dependence
RISPERDAL CONSTA has not been systematically studied in animals or humans
for its potential for abuse, tolerance, or physical dependence. Because RISPERDAL
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CONSTA is to be administered by health care professionals, the potential for misuse
or abuse by patients is low.
OVERDOSAGE
Human Experience
No cases of overdose were reported in premarketing studies with RISPERDAL
CONSTA (risperidone). Because RISPERDAL CONSTA is to be administered
by health care professionals, the potential for overdosage by patients is low.
In premarketing experience with oral RISPERDAL (risperidone), there were eight
reports of acute RISPERDAL overdosage, with estimated doses ranging from 20 to
300 mg and no fatalities. In general, reported signs and symptoms were those
resulting from an exaggeration of the drug’s known pharmacological effects,
i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated
with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case,
involving an estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience with oral RISPERDAL includes reports of acute
overdose, with estimated doses of up to 360 mg. In general, the most frequently
reported signs and symptoms are those resulting from an exaggeration of the drug’s
known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension,
and extrapyramidal symptoms. Other adverse events reported since market
introduction which were temporally (but not necessarily causally) related to oral
RISPERDAL overdose include torsades de pointes, prolonged QT interval,
convulsions, cardiopulmonary arrest, and rare fatality associated with multiple drug
overdose.
Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate
oxygenation and ventilation. Cardiovascular monitoring should commence
immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide,
procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that
might be additive to those of risperidone. Similarly, it is reasonable to expect that the
alpha-blocking properties of bretylium might be additive to those of risperidone,
resulting in problematic hypotension.
There is no specific antidote to oral RISPERDAL. Therefore, appropriate supportive
measures should be instituted. The possibility of multiple drug involvement should be
considered. Hypotension and circulatory collapse should be treated with appropriate
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measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine
and dopamine should not be used, since beta stimulation may worsen hypotension in
the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal
symptoms, anticholinergic medication should be administered. Close medical
supervision and monitoring should continue until the patient recovers.
DOSAGE AND ADMINISTRATION
For patients who have never taken oral RISPERDAL, it is recommended to establish
tolerability with oral RISPERDAL prior to initiating treatment with RISPERDAL
CONSTA (risperidone).
RISPERDAL CONSTA should be administered every 2 weeks by deep
intramuscular (IM) gluteal injection. Each injection should be administered by a
health care professional using the enclosed safety needle (see HOW SUPPLIED).
Injections should alternate between the two buttocks. Do not administer
intravenously.
The recommended dose is 25 mg IM every 2 weeks. Although dose response for
effectiveness has not been established for RISPERDAL CONSTA, some patients
not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The
maximum dose should not exceed 50 mg RISPERDAL CONSTA every 2 weeks.
No additional benefit was observed with dosages greater than 50 mg RISPERDAL
CONSTA; however, a higher incidence of adverse effects was observed.
Oral RISPERDAL (or another antipsychotic medication) should be given with the
first injection of RISPERDAL CONSTA and continued for 3 weeks (and then
discontinued) to ensure that adequate therapeutic plasma concentrations are
maintained prior to the main release phase of risperidone from the injection site (see
CLINICAL PHARMACOLOGY).
Upward dosage adjustment should not be made more frequently than every 4 weeks.
The clinical effects of this dose adjustment should not be anticipated earlier than
3 weeks after the first injection with the higher dose.
Do not combine two different dosage strengths of RISPERDAL CONSTAin a
single administration.
Pediatric Use
RISPERDAL CONSTA has not been studied in children younger than 18 years
old.
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Dosage in Special Populations
For elderly patients treated with RISPERDAL CONSTA, the recommended dosage
is 25 mg IM every 2 weeks. Oral RISPERDAL (or another antipsychotic medication)
should be given with the first injection of RISPERDAL CONSTA and should be
continued for 3 weeks to ensure that adequate therapeutic plasma concentrations are
maintained prior to the main release phase of risperidone from the injection site (see
CLINICAL PHARMACOLOGY).
Patients with renal or hepatic impairment should be treated with titrated doses of oral
RISPERDAL prior to initiating treatment with RISPERDAL CONSTA. The
recommended starting dose is 0.5 mg oral RISPERDAL b.i.d. during the first week,
which can be increased to 1 mg b.i.d. or 2 mg once daily during the second week. If a
dose of at least 2 mg oral RISPERDAL is well tolerated, an injection of 25 mg
RISPERDAL CONSTAcan be administered every 2 weeks. Oral supplementation
should be continued for 3 weeks after the first injection until the main release of
risperidone from the injection site has begun. In some patients, slower titration may
be medically appropriate.
Patients with renal impairment may have less ability to eliminate risperidone than
normal adults. Patients with impaired hepatic function may have an increase in the
free fraction of the risperidone, possibly resulting in an enhanced effect (see
CLINICAL PHARMACOLOGY). Elderly patients and patients with a predisposition
to hypotensive reactions or for whom such reactions would pose a particular risk
should be instructed in nonpharmacologic interventions that help to reduce the
occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several
minutes before attempting to stand in the morning and slowly rising from a seated
position). These patients should avoid sodium depletion or dehydration, and
circumstances that accentuate hypotension (alcohol intake, high ambient temperature,
etc.).
Monitoring
of
orthostatic
vital
signs
should
be
considered
(see
PRECAUTIONS).
Maintenance Therapy
Although no controlled studies have been conducted to answer the question of how
long patients should be treated with RISPERDAL CONSTA, oral risperidone has
been shown to be effective in delaying time to relapse in longer-term use. It is
recommended that responding patients be continued on treatment with RISPERDAL
CONSTA at the lowest dose needed. Patients should be periodically reassessed to
determine the need for continued treatment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Reinitiation of Treatment in Patients Previously Discontinued
There are no data to specifically address reinitiation of treatment. When restarting
patients who have had an interval off treatment with RISPERDAL CONSTA,
supplementation with oral RISPERDAL (or another antipsychotic medication)
should be administered.
Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching
schizophrenic patients from other antipsychotics to RISPERDAL CONSTA, or
concerning concomitant administration with other antipsychotics. Previous
antipsychotics should be continued for 3 weeks after the first injection of
RISPERDAL CONSTA to ensure that therapeutic concentrations are maintained
until the main release phase of risperidone from the injection site has begun (see
CLINICAL PHARMACOLOGY). For schizophrenic patients who have never taken
oral RISPERDAL, it is recommended to establish tolerability with oral
RISPERDAL prior to initiating treatment with RISPERDAL CONSTA. As
recommended with other antipsychotic medications, the need for continuing existing
EPS medication should be re-evaluated periodically.
Co-Administration of RISPERDAL CONSTA with Certain Other
Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin,
rifampin, phenobarbital) with risperidone would be expected to cause decreases in the
plasma
concentrations
of
active
moiety
(the
sum
of
risperidone
and
9-hydroxyrisperidone), which could lead to decreased efficacy of risperidone
treatment. The dose of risperidone needs to be titrated accordingly for patients
receiving these enzyme inducers, especially during initiation or discontinuation of
therapy
with
these
inducers
(see
CLINICAL
PHARMACOLOGY
and
PRECAUTIONS). At the initiation of therapy with carbamazepine or other known
hepatic enzyme inducers, patients should be closely monitored during the first
4-8 weeks, since the dose of RISPERDAL® CONSTA may need to be adjusted. A
dose increase, or additional oral RISPERDAL®, may need to be considered. On
discontinuation of carbamazepine or other hepatic enzyme inducers, the dosage of
RISPERDAL® CONSTA should be re-evaluated and, if necessary, decreased.
Patients may be placed on a lower dose of RISPERDAL® CONSTA between 2 to
4 weeks before the planned discontinuation of carbamazepine therapy to adjust for the
expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone.
For patients treated with the lowest available dose (25 mg) of RISPERDAL®
CONSTA, it is recommended to continue treatment with the 25-mg dose unless
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
clinical judgment necessitates interruption of treatment with RISPERDAL®
CONSTA.
Fluoxetine and paroxetine have been shown to increase the plasma concentration of
risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration
of 9-hydroxyrisperidone an average of 13%. The dose of risperidone needs to be
titrated accordingly when fluoxetine or paroxetine is co-administered. When either
concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should
re-evaluate the dosage of RISPERDAL® CONSTA. When initiation of fluoxetine or
paroxetine is considered, patients may be placed on a lower dose of RISPERDAL
CONSTA between 2 to 4 weeks before the planned start of fluoxetine or paroxetine
therapy to adjust for the expected increase in plasma concentrations of risperidone.
For patients treated with the lowest available dose (25 mg), it is recommended to
continue treatment with the 25-mg dose unless clinical judgment necessitates
interruption of treatment with RISPERDAL CONSTA. The effects of
discontinuation of concomitant fluoxetine or paroxetine therapy on the
pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Instructions for Use
RISPERDAL CONSTA must be suspended only in the diluent supplied in the dose
pack, and must be administered with the needle supplied in the dose pack. All
components are required for administration. Do not substitute any components of the
dose pack.
Remove the dose pack of RISPERDAL CONSTA from the refrigerator and allow
it to come to room temperature prior to reconstitution.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
1. Flip off the plastic colored cap from the vial.
2. Peel back the blister pouch and remove the SmartSite Needle-Free Vial Access
Device by holding the white luer cap. Do not touch the spike tip of the access
device at any time.
3. Press the spike tip of the SmartSite Access Device through the vial’s rubber
stopper until the device clicks into place.
4. Swab the syringe connection point (blue circle) of the SmartSite® Access Device
with preferred antiseptic prior to attaching the syringe to the SmartSite® Access
Device.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
5. Twist off the white cap from the pre-filled syringe and remove together with the
rubber tip cap inside.
6. Press the syringe tip into the blue circle of the SmartSite® Access Device and
Twist in a clockwise motion to ensure that the syringe is securely attached to the
white luer cap of the access device. Keep the syringe and SmartSite® Access
Device aligned, and hold the skirt of the access device during attachment to
prevent spinning.
7. Inject the entire contents of the syringe containing the diluent into the vial.
8. Shake the vial vigorously while holding the plunger rod down with the thumb for
a minimum of 10 seconds to ensure a homogeneous suspension. When properly
mixed, the suspension appears uniform, thick, and milky in color. The particles
will be visible in liquid, but no dry particles remain.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
9. Do not store the vial after reconstitution or the suspension may settle. If 2 minutes
pass before injection, reconstitute by shaking vigorously.
10. Invert the vial completely and slowly withdraw the suspension from the vial. Tear
section of the vial label at the perforation and apply detached label to syringe for
identification purposes.
11. Unscrew the syringe from the SmartSite® access device and discard both the vial
and access device appropriately.
12. Peel the blister pouch of the Needle-Pro device open halfway. Grasp sheath
using the plastic peel pouch.
13. Attach the luer connection of the Needle-Pro® device to the syringe with an easy
clockwise twisting motion. Seat the needle firmly on the Needle-Pro® device with
a push and clockwise twist.
14. If 2 minutes pass before injection, reconstitute by shaking vigorously.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
15. Pull sheath away from the needle. Do not twist sheath, as needle may be loosened
from Needle-Pro device. Tap the syringe gently to make any air bubbles rise to
the top. De-aerate syringe by moving plunger rod carefully forward, with needle
in an upward position. Inject entire contents intramuscularly (IM) into the
upper-outer quadrant of the gluteal area within 2 minutes to avoid settling. DO
NOT ADMINISTER INTRAVENOUSLY.
WARNING: To avoid a needle stick injury with a contaminated needle, do not:
• intentionally disengage the Needle-Pro device
• attempt to straighten the needle or engage Needle-Pro device if the needle is bent
or damaged
• mishandle the needle protection device that could lead to protrusion of the needle
from the needle protector sheath
16. After injection is complete, use only one hand and tabletop or other hard surface
to snap needle into the orange safety guard before discarding. Discard needle
appropriately.
Upon suspension in the diluent, it is recommended to use RISPERDAL CONSTA
immediately. RISPERDAL CONSTA must be used within 6 hours of suspension.
Resuspension of RISPERDAL CONSTA will be necessary prior to administration,
as settling will occur over time once the product is in suspension. Keeping the vial
upright, shake vigorously back and forth for as long as it takes to resuspend the
microspheres. Once in suspension, the product should not be exposed to temperatures
above 77°F (25°C).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
HOW SUPPLIED
RISPERDAL CONSTA (risperidone) is available in dosage strengths of 25, 37.5,
or 50 mg risperidone. It is provided as a dose pack, consisting of a vial containing the
risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for
RISPERDAL CONSTA, a SmartSite Needle-Free Vial Access Device, and one
Needle-Pro safety needle for intramuscular injection (20 G TW needle with needle
protection device).
25-mg vial/kit (NDC 50458-306-11): 25 mg of a white to off-white powder provided
in a vial with a pink flip-off cap (NDC 50458-306-01).
37.5-mg vial/kit (NDC 50458-307-11): 37.5 mg of a white to off-white powder
provided in a vial with a green flip-off cap (NDC 50458-307-01).
50-mg vial/kit (NDC 50458-308-11): 50 mg of a white to off-white powder provided
in a vial with a blue flip-off cap (NDC 50458-308-01).
Storage and Handling
The entire dose pack should be stored in the refrigerator (36°- 46°F; 2°- 8°C) and
protected from light.
If refrigeration is unavailable, RISPERDAL CONSTA can be stored at
temperatures not exceeding 77°F (25°C) for no more than 7 days prior to
administration. Do not expose unrefrigerated product to temperatures above 77°F
(25°C).
Keep out of reach of children.
7519503
US Patent 4,804,663
Revised February 2005
©Janssen 2003
Risperidone is manufactured by:
Janssen Pharmaceutical Ltd.
Wallingstown, Little Island, County Cork, Ireland
Microspheres are manufactured by:
Alkermes Controlled Therapeutics II
Wilmington, Ohio
Diluent is manufactured by:
Vetter Pharma Fertigung GmbH & Co. KG
Ravensburg, Germany
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
RISPERDAL CONSTAis distributed by:
Janssen Pharmaceutica Products, L.P.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:17.703354
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020272s042,020588s030,021444s016,021346s010lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 42}
|
12,401
|
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with atypical
antipsychotic drugs are at an increased risk of death compared to
placebo. RISPERDAL® is not approved for use in patients with dementia-
related psychosis. (5.1)
-------------------------RECENT MAJOR CHANGES-------------------------
Indications and Usage, Schizophrenia/Adolescents (1.1) 06/2007
Indications and Usage, Bipolar Mania/Pediatrics (1.2) 06/2007
Indications and Usage, Autistic Disorder (1.3)
10/2006
Dosage and Administration, Schizophrenia/Adolescents (2.1) 06/2007
Dosage and Administration, Bipolar Mania/Pediatrics (2.2) 06/2007
Dosage and Administration, Autistic Disorder (2.3)
10/2006
Warnings and Precautions, Hyperprolactinemia (5.6)
10/2006
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophrenia
- adults (2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophrenia
– adolescents
(2.1)
0.5mg
/day
0.5- 1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar mania
– adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar mania
in children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder (2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Potential for cognitive and motor impairment (5.8)
• Seizures (5.9)
• Dysphagia (5.10)
• Priapism (5.11)
• Disruption of body temperature regulation (5.12)
• Antiemetic Effect (5.13)
• Suicide (5.14)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.15)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.15)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, appetite increased, fatigue, rhinitis, upper respiratory tract
infection, vomiting, coughing, urinary incontinence, saliva increased,
constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea,
dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were somnolence, nausea, abdominal pain, dizziness,
vomiting, agitation, and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen, L.P.
at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower intial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 08/2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
1
INDICATIONS AND USAGE
1.1
Schizophrenia
1.2
Bipolar Mania
1.3
Irritability Associated with Autistic Disorder
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
2.2
Bipolar Mania
2.3
Irritability Associated with Autistic Disorder –
Pediatrics (Children and Adolescents)
2.4
Dosage in Special Populations
2.5
Co-Administration of RISPERDAL® with Certain
Other Medications
2.6
Administration of RISPERDAL
® Oral Solution
2.7
Directions for Use of RISPERDAL® M-TAB®
Orally Disintegrating Tablets
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Increased Mortality in Elderly Patients with
Dementia-Related Psychosis
5.2
Cerebrovascular Adverse Events, Including
Stroke, in Elderly Patients with Dementia-
Related Psychosis
5.3
Neuroleptic Malignant Syndrome (NMS)
5.4
Tardive Dyskinesia
5.5
Hyperglycemia and Diabetes Mellitus
5.6
Hyperprolactinemia
5.7
Orthostatic Hypotension
5.8
Potential for Cognitive and Motor Impairment
5.9
Seizures
5.10
Dysphagia
5.11
Priapism
5.12 Body Temperature Regulation
5.13
Antiemetic Effect
5.14
Suicide
5.15
Use in Patients with Concomitant Illness
5.16
Monitoring: Laboratory Tests
6
ADVERSE REACTIONS
6.1
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Schizophrenia
6.2
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
– Bipolar Mania
6.3
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Autistic Disorder
6.4
Other Adverse Reactions Observed During the
Premarketing Evaluation of RISPERDAL
®
6.5
Discontinuations Due to Adverse Reactions
6.6
Dose Dependency of Adverse Reactions in
Clinical Trials
6.7
Changes in Body Weight
6.8
Changes in ECG
6.9
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
7.2
Drugs with Hypotensive Effects
7.3
Levodopa and Dopamine Agonists
7.4
Amitriptyline
7.5
Cimetidine and Ranitidine
7.6
Clozapine
7.7
Lithium
7.8
Valproate
7.9
Digoxin
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
Isozymes
7.11
Carbamazepine and Other Enzyme Inducers
7.12
Drugs Metabolized by CYP 2D6
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10 OVERDOSAGE
10.1
Human Experience
10.2
Management of 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
Schizophrenia
14.2
Bipolar Mania - Monotherapy
14.3
Bipolar Mania – Combination Therapy
14.4
Irritability Associated with Autistic Disorder
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1
Orthostatic Hypotension
17.2
Interference with Cognitive and Motor
Performance
17.3
Pregnancy
17.4
Nursing
17.5
Concomitant Medication
17.6
Alcohol
17.7
Phenylketonurics
*Sections or subsections omitted from the full prescribing information are not
listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. Analyses of seventeen placebo
controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in
the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients.
Over the course of a typical 10 week controlled trial, the rate of death in drug-treated
patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. RISPERDAL®
(risperidone) is not approved for the treatment of patients with Dementia-Related
Psychosis. [See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of 1-2
mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower titration
may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see Clinical
Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not demonstrated to
be more efficacious than lower doses, were associated with more extrapyramidal symptoms and
other adverse effects, and are generally not recommended. In a single study supporting once-
daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of
doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years[see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5
mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day
have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
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response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)] received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
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2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.15)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.7)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.8)].
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
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2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating
Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL®
M-TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RIPSERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (light coral,
round), 3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side
with “R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
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9
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. RISPERDAL®(risperidone) is not
approved for the treatment of dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional
signs
may
include
elevated
creatinine
phosphokinase,
myoglobinuria
(rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
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specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
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Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma
or death, has been reported in patients treated with atypical antipsychotics including
RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and glucose
abnormalities is complicated by the possibility of an increased background risk of diabetes
mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the
general population. Given these confounders, the relationship between atypical antipsychotic use
and hyperglycemia-related adverse events is not completely understood. However,
epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related
adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for
hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not
available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has
resolved when the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported in patients receiving prolactin-elevating compounds.
Long standing hyperprolactinemia when associated with hypogonadism may lead to decreased
bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
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pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
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5.9 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.10 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.11 Priapism
Rare cases of priapism have been reported. While the relationship of the events to RISPERDAL®
use has not been established, other drugs with alpha-adrenergic blocking effects have been
reported to induce priapism, and it is possible that RISPERDAL® may share this capacity.
Severe priapism may require surgical intervention.
5.12 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.13 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.14 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.15 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
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antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.16 Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
6
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.8)]
• Seizures [see Warnings and Precautions (5.9)]
• Dysphagia [see Warnings and Precautions (5.10)]
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• Priapism [see Warnings and Precautions (5.11)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.12)]
• Antiemetic effect [see Warnings and Precautions (5.13)]
• Suicide [see Warnings and Precautions (5.14)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.15)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.15)]
The most common adverse reactions in clinical trials (≥ 10%) were somnolence, appetite
increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary
incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain,
anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were somnolence,
nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia [see Adverse Reactions
(6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using WHOART terminology.
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Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
Body System
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per
day
(N=198)
Placebo
(N=225)
Body as a whole - general disorders
Back pain
3
2
<1
Fatigue
3
1
0
Chest pain
3
1
2
Fever
2
1
1
Asthenia
1
1
<1
Syncope
<1
1
<1
Edema
<1
1
0
Cardiovascular disorders, general
Hypotension postural
2
<1
0
Hypotension
<1
1
0
Central and peripheral nervous
system disorders
Parkinsonism*
12
17
6
Dizziness
10
4
2
Dystonia*
5
5
2
Akathisia*
5
5
2
Dyskinesia
1
1
<1
Gastrointestinal system disorders
Dyspepsia
10
7
6
Nausea
9
4
4
Constipation
8
9
7
Abdominal pain
4
3
0
Mouth dry
4
<1
<1
Saliva increased
3
1
<1
Diarrhea
2
<1
1
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Hearing and vestibular disorders
Earache
1
1
0
Heart rate and rhythm disorders
Tachycardia
2
5
0
Arrhythmia
0
1
0
Metabolic and nutritional disorders
Weight increase
1
<1
0
Creatine phosphokinase increased
<1
2
<1
Musculoskeletal system disorders
Arthralgia
2
3
<1
Myalgia
1
0
0
Platelet, bleeding and clotting
disorders
Epistaxis
<1
2
0
Psychiatric disorders
Anxiety
16
12
11
Somnolence
14
5
4
Anorexia
2
0
<1
Red blood cell disorders
Anemia
<1
1
0
Reproductive disorders, male
Ejaculation failure
<1
1
0
Respiratory system disorders
Rhinitis
7
11
6
Coughing
3
3
3
Upper respiratory tract infection
2
3
<1
Dyspnea
2
2
0
Skin and appendages disorders
Rash
2
4
2
Seborrhea
<1
2
0
Urinary system disorders
Urinary tract infection
<1
3
0
Vision disorders
Vision abnormal
3
1
<1
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia. Dystonia
includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany,
laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
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18
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
Body System
Adverse Reaction
1-3 mg per day
(N=55)
4-6 mg per day
(N=51)
Placebo
(N=54)
Central and peripheral nervous
system disorders
Parkinsonism*
13
16
6
Tremor
11
10
6
Dystonia*
9
18
7
Dizziness
7
14
2
Akathisia*
7
10
6
Gastrointestinal system disorders
Saliva increased
0
10
2
Psychiatric disorders
Somnolence
24
12
4
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradykinesia. Dystonia includes dystonia,
hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and
torticollis. Akathisia includes hyperkinesia and akathisia.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
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19
Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients
with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy
Trials
Percentage of Patients Reporting
Event
Body System
Adverse Reaction
RISPERDAL®
1-6 mg per day
(N=448)
Placebo
(N=424)
Body as a whole - general disorders
Fatigue
2
<1
Fever
1
<1
Asthenia
1
<1
Edema
1
<1
Central and peripheral nervous
system disorders
Parkinsonism*
20
6
Dystonia*
11
3
Akathisia*
9
3
Tremor
6
4
Dizziness
5
5
Gastrointestinal system disorders
Nausea
5
2
Dyspepsia
4
2
Saliva increased
3
<1
Diarrhea
3
2
Mouth dry
1
1
Heart rate and rhythm disorders
Tachycardia
1
<1
Liver and biliary system disorders
SGOT increased
1
<1
Musculoskeletal disorders
Myalgia
2
2
Psychiatric disorders
Somnolence
12
4
Anxiety
2
2
Reproductive disorders, female
Lactation nonpuerperal
1
0
Respiratory disorders
Rhinitis
2
2
Skin and appendages disorders
Acne
1
0
Vision disorders
Vision abnormal
2
<1
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia.
Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia
includes hyperkinesia and akathisia.
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20
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with Bipolar
Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Percentage of Patients Reporting Event
Body System
RISPERDAL® +
Mood Stabilizer
Placebo +
Mood Stabilizer
Adverse Reaction
(N=127)
(n=126)
Body as a whole – general disorders
Chest pain
2
2
Fatigue
2
2
Central and peripheral nervous system
disorders
Parkinsonism*
9
4
Dizziness
8
2
Dystonia*
6
3
Akathisia*
6
0
Tremor
5
2
Gastrointestinal system disorders
Nausea
6
5
Diarrhea
6
4
Saliva increased
4
0
Abdominal pain
2
0
Heart rate and rhythm disorders
Palpitation
2
0
Metabolic and nutritional disorders
Weight increase
2
2
Psychiatric disorders
Somnolence
12
5
Anxiety
4
2
Respiratory disorders
Pharyngitis
5
2
Coughing
3
1
Skin and appendages disorders
Rash
2
2
Urinary system disorders
Urinary incontinence
2
1
Urinary tract infection
2
1
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Dystonia
includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany,
laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and
akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
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21
Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL ®
Body System
Adverse Reaction
0.5-2.5 mg per day
(N=50)
3-6 mg per day
(N=61)
Placebo
(N=58)
Body as a whole - general disorders
Fatigue
18
30
3
Central and peripheral nervous
system disorders
Dizziness
16
13
5
Dystonia*
8
13
2
Parkinsonism*
2
7
2
Akathisia*
0
7
2
Gastrointestinal system disorders
Abdominal pain
18
15
5
Dyspepsia
16
5
3
Nausea
16
13
7
Vomiting
12
10
7
Diarrhea
8
7
2
Heart rate and rhythm disorders
Tachycardia
0
5
2
Psychiatric disorders
Somnolence
42
56
19
Appetite increased
4
7
2
Anxiety
0
8
3
Reproductive disorders, female
Lactation nonpuerperal
2
5
0
Respiratory system disorders
Rhinitis
14
13
10
Dyspnea
2
5
0
Skin and appendages disorders
Rash
0
7
2
Urinary system disorders
Urinary incontinence
0
5
0
Vision disorders
Vision abnormal
4
7
0
* Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus,
tongue paralysis, and torticollis. Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradykinesia.
Akathisia includes hyperkinesia and akathisia.
6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
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Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients
Treated for Irritability Associated with Autistic Disorder in Double-Blind,
Placebo-Controlled Trials
Percentage of Patients Reporting Event
Body System
Adverse Reaction
RISPERDAL®
0.5-4.0 mg per day
(N=76)
Placebo
(N=80)
Body as a whole - general disorders
Fatigue
42
13
Fever
20
19
Central and peripheral nervous system
disorders
Dystonia*
12
6
Tremor
12
1
Dizziness
9
3
Parkinsonism*
8
0
Automatism
7
1
Dyskinesia
7
0
Gastrointestinal system disorders
Vomiting
25
21
Saliva increased
22
6
Constipation
21
8
Mouth dry
13
6
Nausea
8
8
Heart rate and rhythm disorders
Tachycardia
7
0
Metabolic and nutritional disorders
Weight increase
5
0
Psychiatric disorders
Somnolence
67
23
Appetite increased
49
19
Anxiety
16
15
Anorexia
8
8
Confusion
5
0
Respiratory system disorders
Rhinitis
36
23
Upper respiratory tract infection
34
15
Coughing
24
18
Skin and appendages disorders
Rash
11
8
Urinary system disorders
Urinary incontinence
22
20
* Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Parkinsonism
includes extrapyramidal disorder, hypokinesia, and bradycardia.
6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of
RISPERDAL®
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
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active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or austistic disorder,
and studies in elderly patients with dementia.
Body as a Whole, General Disorders: edema peripheral, pain, influenza-like symptoms, leg
pain, malaise, allergy, crying abnormal, allergic reaction, rigors, allergy aggravated,
anaphylactoid reaction, hypothermia
Central Nervous System Disorders: gait abnormal, speech disorder, coma, ataxia, dysphonia,
stupor, cramps legs, vertigo, hypoesthesia, tardive dyskinesia, neuroleptic malignant syndrome
Endocrine Disorders: hyperprolactinemia, gynecomastia
Gastrointestinal System Disorders: dysphagia, flatulence
Heart Rate and Rhythm Disorders: AV block, bundle branch block
Liver and Biliary Disorders: SGPT increased, hepatic enzymes increased
Metabolic and Nutritional Disorders: thirst, hyperglycemia, xerophthalmia, generalized
edema, diabetes mellitus aggravated, diabetic coma
Musculoskeletal Disorders: muscle weakness, rhabdomyolysis
Platelet, Bleeding, and Clotting Disorders: purpura
Psychiatric Disorders: insomnia, agitation, emotional lability, apathy, nervousness,
concentration impaired, impotence, decreased libido
Reproductive Disorders, Female: amenorrhea, menstrual disorder, leukorrhea
Reproductive Disorders, Male: ejaculation disorder, abnormal sexual function, priapism
Resistance Mechanism Disorders: otitis media, viral infection
Respiratory Disorders: respiratory disorder
Skin and Appendages Disorders: skin ulceration, skin discoloration, rash erythematous, skin
exfoliation, rash maculopapular, erythema multiforme
Urinary Disorders: micturition frequency
Vascular Disorders: cerebrovascular disorder
Vision Disorders: conjunctivitis
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White Cell Disorders: leucopenia, granulocytopenia
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7.
Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated
Adult Patients in Schizophrenia Trials
RISPERDAL®
Adverse Reaction
2-8 mg/day
(N=366)
>8-16 mg/day
(N=198)
Placebo
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Agitation
1.1%
1.0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0.5%
0%
Dystonia
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Hypotension postural
0.3%
0.5%
0%
Tachycardia
0.3%
0.5%
0%
Akathisia
0%
1.0%
0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-
treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were somnolence (2%), dizziness (2%), anorexia (1%), anxiety
(1%), ataxia (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
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Table 8.
Adverse Reactions Associated With Discontinuation in 2 or More
RISPERDAL®-Treated Adult Patients in Bipolar Mania Clinical Trials
Adverse Reaction
RISPERDAL®
1-6 mg/day
(N=448)
Placebo
(N=424)
Parkinsonism
0.4%
0%
Somnolence
0.2%
0%
Dizziness
0.2%
0%
Dystonia
0.2%
0%
SGOT increased
0.2%
0.2%
SGPT increased
0.2%
0.2%
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were somnolence (5%), nausea (3%), abdominal pain (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
RISPERDAL®
2 mg
RISPERDAL®
6 mg
RISPERDAL®
10 mg
RISPERDAL®
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
11%
15%
16%
20%
31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
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Dose Groups
RISPERDAL®
1 mg
RISPERDAL®
4 mg
RISPERDAL®
8 mg
RISPERDAL®
12 mg
RISPERDAL®
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS
Incidence
7%
11%
17%
18%
20%
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 – 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
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RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of RISPERDAL®;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: anaphylactic reaction, angioedema, atrial
fibrillation, diabetic ketoacidosis in patients with impaired glucose metabolism, intestinal
obstruction, jaundice, mania, QT prolongation, and sleep apnea.
Other adverse events reported since market introduction, which were temporally related to
RISPERDAL® but not necessarily causally related, include the following: pancreatitis, pituitary
adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
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9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
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RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin .
7.11 Carbamazepine and Other Enzyme Inducers
Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
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and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of RISPERDAL® during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials (see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial (see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
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Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than
1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or
bipolar mania who were of similar age and weight, and who received similar dosages of
RISPERDAL® as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In
103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after
8 months of RISPERDAL® treatment. The majority of that increase was observed within the first
6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for
weight, 55 and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
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group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated.
8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
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between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
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RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
intervaland convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
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intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (light coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL®
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M-TAB® Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite®
resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 3 mg and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL®.
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
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9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions . First, inhibitors of CYP
2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions
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(7.12)]. This occurs with quinidine, giving essentially all recipients a risperidone
pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse
effects of risperidone in patients receiving quinidine have not been evaluated, but observations in
a modest number (n≅70) of poor metabolizers given RISPERDAL® do not suggest important
differences between poor and extensive metabolizers. Second, co-administration of known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.7)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.15)].
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.15)].
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Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
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measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
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Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The
most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
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significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
This label may not be the latest approved by FDA.
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44
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
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45
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this
open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL®
of 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as
≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very
much improved’) during the 4-6 month open-label treatment phase for about 140 days, on
average, were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either “Ris
0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of
500 NDC 50458-301-50, hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500 NDC
50458-302-50, hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, hospital unit dose blister
packs of 100 NDC 50458-300-01, bottles of 500 NDC 50458-300-50.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, hospital unit dose blister
packs of 100 NDC 50458-320-01, bottles of 500 NDC 50458-320-50.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, hospital unit dose blister
packs of 100 NDC 50458-330-01, bottles of 500 NDC 50458-330-50.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06, hospital unit dose blister
packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL®
M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC
50458-395-28, long-term care blister packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC
50458-315-28, long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC
50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature
15°-25°C (59°-77°F). Protect from light and freezing.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.8)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.2)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
M-TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each
0.5 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Revised DRAFT 06/2007
©Janssen 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and Oral
Solution are distributed by:
Janssen, L.P.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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|
12,400
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1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with atypical
antipsychotic drugs are at an increased risk of death compared to
placebo. RISPERDAL® is not approved for use in patients with dementia-
related psychosis. (5.1)
-------------------------RECENT MAJOR CHANGES-------------------------
Indications and Usage, Schizophrenia/Adolescents (1.1) 06/2007
Indications and Usage, Bipolar Mania/Pediatrics (1.2) 06/2007
Indications and Usage, Autistic Disorder (1.3)
10/2006
Dosage and Administration, Schizophrenia/Adolescents (2.1) 06/2007
Dosage and Administration, Bipolar Mania/Pediatrics (2.2) 06/2007
Dosage and Administration, Autistic Disorder (2.3)
10/2006
Warnings and Precautions, Hyperprolactinemia (5.6)
10/2006
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophrenia
- adults (2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophrenia
– adolescents
(2.1)
0.5mg
/day
0.5- 1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar mania
– adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar mania
in children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder (2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Potential for cognitive and motor impairment (5.8)
• Seizures (5.9)
• Dysphagia (5.10)
• Priapism (5.11)
• Disruption of body temperature regulation (5.12)
• Antiemetic Effect (5.13)
• Suicide (5.14)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.15)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.15)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, appetite increased, fatigue, rhinitis, upper respiratory tract
infection, vomiting, coughing, urinary incontinence, saliva increased,
constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea,
dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were somnolence, nausea, abdominal pain, dizziness,
vomiting, agitation, and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen, L.P.
at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower intial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 08/2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
1
INDICATIONS AND USAGE
1.1
Schizophrenia
1.2
Bipolar Mania
1.3
Irritability Associated with Autistic Disorder
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
2.2
Bipolar Mania
2.3
Irritability Associated with Autistic Disorder –
Pediatrics (Children and Adolescents)
2.4
Dosage in Special Populations
2.5
Co-Administration of RISPERDAL® with Certain
Other Medications
2.6
Administration of RISPERDAL
® Oral Solution
2.7
Directions for Use of RISPERDAL® M-TAB®
Orally Disintegrating Tablets
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Increased Mortality in Elderly Patients with
Dementia-Related Psychosis
5.2
Cerebrovascular Adverse Events, Including
Stroke, in Elderly Patients with Dementia-
Related Psychosis
5.3
Neuroleptic Malignant Syndrome (NMS)
5.4
Tardive Dyskinesia
5.5
Hyperglycemia and Diabetes Mellitus
5.6
Hyperprolactinemia
5.7
Orthostatic Hypotension
5.8
Potential for Cognitive and Motor Impairment
5.9
Seizures
5.10
Dysphagia
5.11
Priapism
5.12 Body Temperature Regulation
5.13
Antiemetic Effect
5.14
Suicide
5.15
Use in Patients with Concomitant Illness
5.16
Monitoring: Laboratory Tests
6
ADVERSE REACTIONS
6.1
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Schizophrenia
6.2
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
– Bipolar Mania
6.3
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Autistic Disorder
6.4
Other Adverse Reactions Observed During the
Premarketing Evaluation of RISPERDAL
®
6.5
Discontinuations Due to Adverse Reactions
6.6
Dose Dependency of Adverse Reactions in
Clinical Trials
6.7
Changes in Body Weight
6.8
Changes in ECG
6.9
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
7.2
Drugs with Hypotensive Effects
7.3
Levodopa and Dopamine Agonists
7.4
Amitriptyline
7.5
Cimetidine and Ranitidine
7.6
Clozapine
7.7
Lithium
7.8
Valproate
7.9
Digoxin
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
Isozymes
7.11
Carbamazepine and Other Enzyme Inducers
7.12
Drugs Metabolized by CYP 2D6
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10 OVERDOSAGE
10.1
Human Experience
10.2
Management of 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
Schizophrenia
14.2
Bipolar Mania - Monotherapy
14.3
Bipolar Mania – Combination Therapy
14.4
Irritability Associated with Autistic Disorder
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1
Orthostatic Hypotension
17.2
Interference with Cognitive and Motor
Performance
17.3
Pregnancy
17.4
Nursing
17.5
Concomitant Medication
17.6
Alcohol
17.7
Phenylketonurics
*Sections or subsections omitted from the full prescribing information are not
listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. Analyses of seventeen placebo
controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in
the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients.
Over the course of a typical 10 week controlled trial, the rate of death in drug-treated
patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. RISPERDAL®
(risperidone) is not approved for the treatment of patients with Dementia-Related
Psychosis. [See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
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4
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of 1-2
mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower titration
may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see Clinical
Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not demonstrated to
be more efficacious than lower doses, were associated with more extrapyramidal symptoms and
other adverse effects, and are generally not recommended. In a single study supporting once-
daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of
doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years[see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
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Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5
mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day
have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
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6
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)] received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
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7
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.15)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.7)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.8)].
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
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2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating
Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL®
M-TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RIPSERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (light coral,
round), 3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side
with “R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
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4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
are at an increased risk of death compared to placebo. RISPERDAL®(risperidone) is not
approved for the treatment of dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional
signs
may
include
elevated
creatinine
phosphokinase,
myoglobinuria
(rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
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specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
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Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma
or death, has been reported in patients treated with atypical antipsychotics including
RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and glucose
abnormalities is complicated by the possibility of an increased background risk of diabetes
mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the
general population. Given these confounders, the relationship between atypical antipsychotic use
and hyperglycemia-related adverse events is not completely understood. However,
epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related
adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for
hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not
available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has
resolved when the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported in patients receiving prolactin-elevating compounds.
Long standing hyperprolactinemia when associated with hypogonadism may lead to decreased
bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
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12
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
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5.9 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.10 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.11 Priapism
Rare cases of priapism have been reported. While the relationship of the events to RISPERDAL®
use has not been established, other drugs with alpha-adrenergic blocking effects have been
reported to induce priapism, and it is possible that RISPERDAL® may share this capacity.
Severe priapism may require surgical intervention.
5.12 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.13 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.14 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.15 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
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14
antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.16 Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
6
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.8)]
• Seizures [see Warnings and Precautions (5.9)]
• Dysphagia [see Warnings and Precautions (5.10)]
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• Priapism [see Warnings and Precautions (5.11)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.12)]
• Antiemetic effect [see Warnings and Precautions (5.13)]
• Suicide [see Warnings and Precautions (5.14)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.15)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.15)]
The most common adverse reactions in clinical trials (≥ 10%) were somnolence, appetite
increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary
incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain,
anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were somnolence,
nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia [see Adverse Reactions
(6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using WHOART terminology.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
Body System
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per
day
(N=198)
Placebo
(N=225)
Body as a whole - general disorders
Back pain
3
2
<1
Fatigue
3
1
0
Chest pain
3
1
2
Fever
2
1
1
Asthenia
1
1
<1
Syncope
<1
1
<1
Edema
<1
1
0
Cardiovascular disorders, general
Hypotension postural
2
<1
0
Hypotension
<1
1
0
Central and peripheral nervous
system disorders
Parkinsonism*
12
17
6
Dizziness
10
4
2
Dystonia*
5
5
2
Akathisia*
5
5
2
Dyskinesia
1
1
<1
Gastrointestinal system disorders
Dyspepsia
10
7
6
Nausea
9
4
4
Constipation
8
9
7
Abdominal pain
4
3
0
Mouth dry
4
<1
<1
Saliva increased
3
1
<1
Diarrhea
2
<1
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Hearing and vestibular disorders
Earache
1
1
0
Heart rate and rhythm disorders
Tachycardia
2
5
0
Arrhythmia
0
1
0
Metabolic and nutritional disorders
Weight increase
1
<1
0
Creatine phosphokinase increased
<1
2
<1
Musculoskeletal system disorders
Arthralgia
2
3
<1
Myalgia
1
0
0
Platelet, bleeding and clotting
disorders
Epistaxis
<1
2
0
Psychiatric disorders
Anxiety
16
12
11
Somnolence
14
5
4
Anorexia
2
0
<1
Red blood cell disorders
Anemia
<1
1
0
Reproductive disorders, male
Ejaculation failure
<1
1
0
Respiratory system disorders
Rhinitis
7
11
6
Coughing
3
3
3
Upper respiratory tract infection
2
3
<1
Dyspnea
2
2
0
Skin and appendages disorders
Rash
2
4
2
Seborrhea
<1
2
0
Urinary system disorders
Urinary tract infection
<1
3
0
Vision disorders
Vision abnormal
3
1
<1
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia. Dystonia
includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany,
laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
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18
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
Body System
Adverse Reaction
1-3 mg per day
(N=55)
4-6 mg per day
(N=51)
Placebo
(N=54)
Central and peripheral nervous
system disorders
Parkinsonism*
13
16
6
Tremor
11
10
6
Dystonia*
9
18
7
Dizziness
7
14
2
Akathisia*
7
10
6
Gastrointestinal system disorders
Saliva increased
0
10
2
Psychiatric disorders
Somnolence
24
12
4
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradykinesia. Dystonia includes dystonia,
hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and
torticollis. Akathisia includes hyperkinesia and akathisia.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
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19
Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients
with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy
Trials
Percentage of Patients Reporting
Event
Body System
Adverse Reaction
RISPERDAL®
1-6 mg per day
(N=448)
Placebo
(N=424)
Body as a whole - general disorders
Fatigue
2
<1
Fever
1
<1
Asthenia
1
<1
Edema
1
<1
Central and peripheral nervous
system disorders
Parkinsonism*
20
6
Dystonia*
11
3
Akathisia*
9
3
Tremor
6
4
Dizziness
5
5
Gastrointestinal system disorders
Nausea
5
2
Dyspepsia
4
2
Saliva increased
3
<1
Diarrhea
3
2
Mouth dry
1
1
Heart rate and rhythm disorders
Tachycardia
1
<1
Liver and biliary system disorders
SGOT increased
1
<1
Musculoskeletal disorders
Myalgia
2
2
Psychiatric disorders
Somnolence
12
4
Anxiety
2
2
Reproductive disorders, female
Lactation nonpuerperal
1
0
Respiratory disorders
Rhinitis
2
2
Skin and appendages disorders
Acne
1
0
Vision disorders
Vision abnormal
2
<1
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia.
Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia
includes hyperkinesia and akathisia.
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20
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with Bipolar
Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Percentage of Patients Reporting Event
Body System
RISPERDAL® +
Mood Stabilizer
Placebo +
Mood Stabilizer
Adverse Reaction
(N=127)
(n=126)
Body as a whole – general disorders
Chest pain
2
2
Fatigue
2
2
Central and peripheral nervous system
disorders
Parkinsonism*
9
4
Dizziness
8
2
Dystonia*
6
3
Akathisia*
6
0
Tremor
5
2
Gastrointestinal system disorders
Nausea
6
5
Diarrhea
6
4
Saliva increased
4
0
Abdominal pain
2
0
Heart rate and rhythm disorders
Palpitation
2
0
Metabolic and nutritional disorders
Weight increase
2
2
Psychiatric disorders
Somnolence
12
5
Anxiety
4
2
Respiratory disorders
Pharyngitis
5
2
Coughing
3
1
Skin and appendages disorders
Rash
2
2
Urinary system disorders
Urinary incontinence
2
1
Urinary tract infection
2
1
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Dystonia
includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany,
laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and
akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
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21
Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL ®
Body System
Adverse Reaction
0.5-2.5 mg per day
(N=50)
3-6 mg per day
(N=61)
Placebo
(N=58)
Body as a whole - general disorders
Fatigue
18
30
3
Central and peripheral nervous
system disorders
Dizziness
16
13
5
Dystonia*
8
13
2
Parkinsonism*
2
7
2
Akathisia*
0
7
2
Gastrointestinal system disorders
Abdominal pain
18
15
5
Dyspepsia
16
5
3
Nausea
16
13
7
Vomiting
12
10
7
Diarrhea
8
7
2
Heart rate and rhythm disorders
Tachycardia
0
5
2
Psychiatric disorders
Somnolence
42
56
19
Appetite increased
4
7
2
Anxiety
0
8
3
Reproductive disorders, female
Lactation nonpuerperal
2
5
0
Respiratory system disorders
Rhinitis
14
13
10
Dyspnea
2
5
0
Skin and appendages disorders
Rash
0
7
2
Urinary system disorders
Urinary incontinence
0
5
0
Vision disorders
Vision abnormal
4
7
0
* Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus,
tongue paralysis, and torticollis. Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradykinesia.
Akathisia includes hyperkinesia and akathisia.
6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
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22
Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients
Treated for Irritability Associated with Autistic Disorder in Double-Blind,
Placebo-Controlled Trials
Percentage of Patients Reporting Event
Body System
Adverse Reaction
RISPERDAL®
0.5-4.0 mg per day
(N=76)
Placebo
(N=80)
Body as a whole - general disorders
Fatigue
42
13
Fever
20
19
Central and peripheral nervous system
disorders
Dystonia*
12
6
Tremor
12
1
Dizziness
9
3
Parkinsonism*
8
0
Automatism
7
1
Dyskinesia
7
0
Gastrointestinal system disorders
Vomiting
25
21
Saliva increased
22
6
Constipation
21
8
Mouth dry
13
6
Nausea
8
8
Heart rate and rhythm disorders
Tachycardia
7
0
Metabolic and nutritional disorders
Weight increase
5
0
Psychiatric disorders
Somnolence
67
23
Appetite increased
49
19
Anxiety
16
15
Anorexia
8
8
Confusion
5
0
Respiratory system disorders
Rhinitis
36
23
Upper respiratory tract infection
34
15
Coughing
24
18
Skin and appendages disorders
Rash
11
8
Urinary system disorders
Urinary incontinence
22
20
* Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Parkinsonism
includes extrapyramidal disorder, hypokinesia, and bradycardia.
6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of
RISPERDAL®
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
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23
active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or austistic disorder,
and studies in elderly patients with dementia.
Body as a Whole, General Disorders: edema peripheral, pain, influenza-like symptoms, leg
pain, malaise, allergy, crying abnormal, allergic reaction, rigors, allergy aggravated,
anaphylactoid reaction, hypothermia
Central Nervous System Disorders: gait abnormal, speech disorder, coma, ataxia, dysphonia,
stupor, cramps legs, vertigo, hypoesthesia, tardive dyskinesia, neuroleptic malignant syndrome
Endocrine Disorders: hyperprolactinemia, gynecomastia
Gastrointestinal System Disorders: dysphagia, flatulence
Heart Rate and Rhythm Disorders: AV block, bundle branch block
Liver and Biliary Disorders: SGPT increased, hepatic enzymes increased
Metabolic and Nutritional Disorders: thirst, hyperglycemia, xerophthalmia, generalized
edema, diabetes mellitus aggravated, diabetic coma
Musculoskeletal Disorders: muscle weakness, rhabdomyolysis
Platelet, Bleeding, and Clotting Disorders: purpura
Psychiatric Disorders: insomnia, agitation, emotional lability, apathy, nervousness,
concentration impaired, impotence, decreased libido
Reproductive Disorders, Female: amenorrhea, menstrual disorder, leukorrhea
Reproductive Disorders, Male: ejaculation disorder, abnormal sexual function, priapism
Resistance Mechanism Disorders: otitis media, viral infection
Respiratory Disorders: respiratory disorder
Skin and Appendages Disorders: skin ulceration, skin discoloration, rash erythematous, skin
exfoliation, rash maculopapular, erythema multiforme
Urinary Disorders: micturition frequency
Vascular Disorders: cerebrovascular disorder
Vision Disorders: conjunctivitis
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24
White Cell Disorders: leucopenia, granulocytopenia
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7.
Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated
Adult Patients in Schizophrenia Trials
RISPERDAL®
Adverse Reaction
2-8 mg/day
(N=366)
>8-16 mg/day
(N=198)
Placebo
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Agitation
1.1%
1.0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0.5%
0%
Dystonia
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Hypotension postural
0.3%
0.5%
0%
Tachycardia
0.3%
0.5%
0%
Akathisia
0%
1.0%
0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-
treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were somnolence (2%), dizziness (2%), anorexia (1%), anxiety
(1%), ataxia (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
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25
Table 8.
Adverse Reactions Associated With Discontinuation in 2 or More
RISPERDAL®-Treated Adult Patients in Bipolar Mania Clinical Trials
Adverse Reaction
RISPERDAL®
1-6 mg/day
(N=448)
Placebo
(N=424)
Parkinsonism
0.4%
0%
Somnolence
0.2%
0%
Dizziness
0.2%
0%
Dystonia
0.2%
0%
SGOT increased
0.2%
0.2%
SGPT increased
0.2%
0.2%
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were somnolence (5%), nausea (3%), abdominal pain (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
RISPERDAL®
2 mg
RISPERDAL®
6 mg
RISPERDAL®
10 mg
RISPERDAL®
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
11%
15%
16%
20%
31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
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26
Dose Groups
RISPERDAL®
1 mg
RISPERDAL®
4 mg
RISPERDAL®
8 mg
RISPERDAL®
12 mg
RISPERDAL®
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS
Incidence
7%
11%
17%
18%
20%
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 – 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
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27
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of RISPERDAL®;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: anaphylactic reaction, angioedema, atrial
fibrillation, diabetic ketoacidosis in patients with impaired glucose metabolism, intestinal
obstruction, jaundice, mania, QT prolongation, and sleep apnea.
Other adverse events reported since market introduction, which were temporally related to
RISPERDAL® but not necessarily causally related, include the following: pancreatitis, pituitary
adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
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28
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
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RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin .
7.11 Carbamazepine and Other Enzyme Inducers
Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
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and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of RISPERDAL® during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials (see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial (see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
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Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than
1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or
bipolar mania who were of similar age and weight, and who received similar dosages of
RISPERDAL® as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In
103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after
8 months of RISPERDAL® treatment. The majority of that increase was observed within the first
6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for
weight, 55 and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
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group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated.
8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
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between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
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RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
intervaland convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
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intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (light coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL®
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M-TAB® Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite®
resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 3 mg and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL®.
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
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9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions . First, inhibitors of CYP
2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions
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(7.12)]. This occurs with quinidine, giving essentially all recipients a risperidone
pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse
effects of risperidone in patients receiving quinidine have not been evaluated, but observations in
a modest number (n≅70) of poor metabolizers given RISPERDAL® do not suggest important
differences between poor and extensive metabolizers. Second, co-administration of known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.7)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.15)].
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.15)].
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Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
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measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
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41
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The
most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
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42
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
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43
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
This label may not be the latest approved by FDA.
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44
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
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45
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this
open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL®
of 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as
≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very
much improved’) during the 4-6 month open-label treatment phase for about 140 days, on
average, were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either “Ris
0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of
500 NDC 50458-301-50, hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500 NDC
50458-302-50, hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, hospital unit dose blister
packs of 100 NDC 50458-300-01, bottles of 500 NDC 50458-300-50.
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46
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, hospital unit dose blister
packs of 100 NDC 50458-320-01, bottles of 500 NDC 50458-320-50.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, hospital unit dose blister
packs of 100 NDC 50458-330-01, bottles of 500 NDC 50458-330-50.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06, hospital unit dose blister
packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL®
M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC
50458-395-28, long-term care blister packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC
50458-315-28, long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC
50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature
15°-25°C (59°-77°F). Protect from light and freezing.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
47
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.8)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.2)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
M-TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each
0.5 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Revised DRAFT 06/2007
©Janssen 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and Oral
Solution are distributed by:
Janssen, L.P.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:18.115475
|
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|
12,402
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. RISPERDAL® is
not approved for use in patients with dementia-related psychosis. (5.1)
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophreni
a- adults
(2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophreni
a –
adolescents
(2.1)
0.5mg
/day
0.5- 1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar
mania –
adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar
mania in
children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder
(2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with
antipsychotics, including RISPERDAL®. Patients with a history of a
clinically significant low white blood cell count (WBC) or a drug-
induced leukopenia/neutropenia should have their complete blood count
(CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign
of a clinically significant decline in WBC in the absence of other
causative factors. (5.8)
• Potential for cognitive and motor impairment (5.9)
• Seizures (5.10)
• Dysphagia (5.11)
• Priapism (5.12)
• Thrombotic Thrombocytopenic Purpura (TTP) (5.13)
• Disruption of body temperature regulation (5.14)
• Antiemetic Effect (5.15)
• Suicide (5.16)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.17)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.17)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism,
akathisia, vomiting, cough, constipation, nasopharyngitis, drooling,
rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety,
headache, nasal congestion, rhinitis, tremor, and rash. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were nausea, somnolence, sedation, vomiting, dizziness,
and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800-
JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower initial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 08/2010
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
1
INDICATIONS AND USAGE
1.1
Schizophrenia
1.2
Bipolar Mania
1.3
Irritability Associated with Autistic Disorder
2
DOSAGE AND ADMI ISTRATION
N
2.1
Schizophrenia
2.2
Bipolar Mania
2.3
Irritability Associated with Autistic Disorder –
Pediatrics (Children and Adolescents)
2.4
Dosage in Special Populations
2.5
Co-Administration of RISPERDAL® with Certain
Other Medications
2.6
Administration of RISPERDAL
® Oral Solution
2.7
Directions for Use of RISPERDAL
® M-
TAB
® Orally Disintegrating ablets
T
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WA
S AND PRECAUTIONS
RNING
5.1
Increased Mortality in Elderly Patients with
Dementia-Related Psychosis
5.2
Cerebrovascular Adverse Events, Including
Stroke, in Elderly Patients with Dementia-
Related Psychosis
5.3
Neuroleptic Malignant Syndrome (NMS)
5.4
Tardive Dyskinesia
5.5
Hyperglycemia and Diabetes Mellitus
5.6
Hyperprolactinemia
5.7
Orthostatic Hypotension
5.8
Leukopenia, Neutropenia, and Agranulocytosis
5.9
Potential for Cognitive and Motor Impairment
5.10
Seizures
5.11
Dysphagia
5.12
Priapism
5.13
Thrombotic Thrombocytopenic Purpura (TTP)
5.14
Body Temperatu
Regulation
re
5.15
Antiemetic Effect
5.16
Suicide
5.17
Use in Patients with Concomitant Illness
5.18
Monitoring: Labo
tory Tests
ra
6
AD ERSE REACTIONS
V
6.1
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Schizophrenia
6.2
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
– Bipolar Mania
6.3
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Autistic Disorder
6.4
Other Adverse Reactions Observed During the
Premarketing Evaluation of RISPERDAL
®
6.5
Discontinuations Due to Adverse Reactions
6.6
Dose Dependency of Adverse Reactions in
Clinical Trials
6.7
Changes in Body Weight
6.8
Changes in ECG
6.9
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
7.2
Drugs with Hypotensive Effects
7.3
Levodopa and Dopamine Agonists
7.4
Amitriptyline
7.5
Cimetidine and Ranitidine
7.6
Clozapine
7.7
Lithium
7.8
Valproate
7.9
Digoxin
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
Isozymes
7.11
Carbamazepine and Other Enzy
me Inducers
7.12
Drugs Metabolized by CYP D6
2
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delive y
r
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10 OVERDOSAGE
10.1
Human Experience
10.2
Management of Overdosage
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Actio
n
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NON LINICAL TOXICOLOGY
C
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14 CLINICAL STUDIES
14.1
Schizophrenia
14.2
Bipolar Mania - Monotherapy
14.3
Bipolar Mania – Combination Therapy
14.4
Irritability Associated with Autistic Disorder
16 HOW SUPPLIED/STORAGE AND HANDLING
Storage and Handling
17 PATIENT COUNSELING INFO MATION
R
17.1
Orthostatic Hypotension
17.2
Interference with Cognitive and Motor
Performance
17.3
Pregnancy
17.4
Nursing
17.5
Concomitant Medication
17.6
Alcohol
17.7
Phenylketonurics
*Sections or subsections omitted from the full prescribing information are not
listed
This label may not be the latest approved by FDA.
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3
FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which the findings
of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. RISPERDAL®
(risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
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4
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of
1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower
titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see
Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not
demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal
symptoms and other adverse effects, and are generally not recommended. In a single study
supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for
4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
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5
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above
2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
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6
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
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7
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.17)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.10)].
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M-
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
9
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square),
3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. RISPERDAL® (risperidone) is not approved for the treatment of
dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
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10
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
11
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics
including RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus
in the general population. Given these confounders, the relationship between atypical
antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL®, should be monitored regularly for worsening of
glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history
of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL®,
should undergo fasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL®,
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing. In some
cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL®,
was discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of RISPERDAL®.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
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12
impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
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For current labeling information, please visit https://www.fda.gov/drugsatfda
13
complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9)].
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a
large, open premarketing experience (approximately 1300 patients). She experienced jaundice,
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14
fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.16 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.17 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.18 Monitoring: Laboratory Tests
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15
No specific laboratory tests are recommended.
6
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
• Antiemetic effect [see Warnings and Precautions (5.15)]
• Suicide [see Warnings and Precautions (5.16)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.17)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.17)]
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16
The most common adverse reactions in clinical trials (≥ 10%) were somnolence, increased
appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation,
nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea,
anxiety, headache, nasal congestion, rhinitis, tremor, and rash.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea,
somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions (6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
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17
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per day
(N=198)
Placebo
(N=225)
Blood and Lymphatic System
Disorders
Anemia
<1
1
0
Cardiac Disorders
Tachycardia
1
3
0
Ear and Labyrinth Disorders
Ear pain
<1
1
0
Eye Disorders
Vision blurred
3
1
1
Gastrointestinal Disorders
Nausea
9
4
4
Constipation
8
9
6
Dyspepsia
8
6
5
Vomiting
7
5
7
Dry mouth
4
0
1
Abdominal discomfort
3
1
1
Salivary hypersecretion
2
1
<1
Diarrhea
2
1
1
Abdominal pain
1
1
0
Abdominal pain upper
1
1
0
Stomach discomfort
1
1
1
General Disorders
Fatigue
3
1
0
Chest pain
2
2
1
Asthenia
2
1
<1
Immune System Disorders
Hypersensitivity
<1
1
0
Infections and Infestations
Nasopharyngitis
3
4
3
Upper respiratory tract infection
2
3
1
Sinusitis
1
2
1
Urinary tract infection
1
3
0
Investigations
Weight increased
1
1
0
Blood creatine phosphokinase
increased
1
2
<1
Heart rate increased
<1
2
0
Metabolism and Nutrition Disorders
Decreased appetite
1
0
<1
Musculoskeletal and Connective
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18
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per day
(N=198)
Placebo
(N=225)
Tissue Disorders
Back pain
4
1
1
Arthralgia
2
3
<1
Pain in extremity
2
1
1
Joint stiffness
1
1
0
Nervous System Disorders
Parkinsonism*
14
17
8
Akathisia*
10
10
3
Dizziness
7
4
2
Somnolence
7
2
1
Dystonia*
3
4
2
Sedation
3
3
1
Tremor*
2
3
1
Dizziness postural
2
0
0
Dyskinesia*
1
2
2
Syncope
1
1
0
Psychiatric Disorders
Insomnia
32
25
27
Anxiety
16
11
11
Nervousness
1
1
<1
Renal and Urinary Disorders
Urinary incontinence
1
1
0
Reproductive System and Breast
Disorders
Ejaculation failure
<1
1
0
Respiratory, Thoracic and
Mediastinal Disorders
Nasal congestion
4
6
2
Dyspnea
1
2
0
Epistaxis
<1
2
0
Skin and Subcutaneous Tissue
Disorders
Rash
1
4
1
Dry skin
1
3
0
Dandruff
1
1
0
Seborrheic dermatitis
<1
1
0
Hyperkeratosis
0
1
1
Vascular Disorders
Orthostatic hypotension
2
1
0
Hypotension
1
1
0
* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism,
cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity,
and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia
includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture,
oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis.
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19
Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
Adverse Reaction
1-3 mg per day
(N=55)
4-6 mg per day
(N=51)
Placebo
(N=54)
Gastrointestinal Disorders
Salivary hypersecretion
0
10
2
Nervous System Disorders
Parkinsonism*
16
28
11
Sedation
13
8
2
Somnolence
11
4
2
Tremor
11
10
6
Akathisia*
9
10
4
Dizziness
7
14
2
Dystonia*
2
6
0
Psychiatric Disorders
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, muscle
rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and
restlessness. Dystonia includes dystonia and oculogyration.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
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20
Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult
Patients with Bipolar Mania in Double-Blind, Placebo-Controlled
Monotherapy Trials
Percentage of Patients Reporting Event
System/Organ Class
Adverse Reaction
RISPERDAL®
1-6 mg per day
(N=448)
Placebo
(N=424)
Cardiac Disorders
Tachycardia
1
<1
Eye Disorders
Vision blurred
2
1
Gastrointestinal Disorders
Nausea
5
2
Diarrhea
3
2
Salivary hypersecretion
3
1
Dyspepsia
2
2
Stomach discomfort
2
<1
General Disorders
Fatigue
2
1
Asthenia
1
1
Pyrexia
1
1
Infections and Infestations
Nasopharyngitis
1
1
Investigations
Aspartate aminotransferase increased
1
<1
Nervous System Disorders
Parkinsonism*
25
9
Akathisia*
9
3
Tremor*
6
3
Dizziness
6
5
Sedation
6
2
Somnolence
5
2
Dystonia*
5
1
Lethargy
2
1
Dyskinesia*
1
<1
Reproductive System and Breast
Disorders
Galactorrhea
1
0
Skin and Subcutaneous Tissue
Disorders
Acne
1
0
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal
stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel
rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and
parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration,
torticollis. Dyskinesia includes muscle twitching and dyskinesia.
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
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Percentage of Patients Reporting Event
System/Organ Class
RISPERDAL® + Mood
Stabilizer
Placebo +
Mood Stabilizer
Adverse Reaction
(N=127)
(N=126)
Cardiac Disorders
Palpitations
2
0
Gastrointestinal Disorders
Dyspepsia
9
8
Nausea
6
4
Diarrhea
6
4
Dry mouth
4
4
Vomiting
4
6
Constipation
3
3
Salivary hypersecretion
2
0
General Disorders
Chest pain
2
1
Fatigue
2
2
Infections and Infestations
Nasopharyngitis
2
3
Urinary tract infection
2
1
Investigations
Weight increased
2
2
Nervous System Disorders
Parkinsonism*
14
4
Headache
14
15
Akathisia*
8
0
Dizziness
7
2
Sedation
6
3
Tremor
6
2
Somnolence
3
1
Lethargy
2
1
Psychiatric Disorders
Insomnia
4
8
Anxiety
3
2
Respiratory, Thoracic and
Mediastinal Disorders
Pharyngolaryngeal pain
5
2
Cough
2
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia.
Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
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Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
RISPERDAL ®
System/Organ Class
Adverse Reaction
0.5-2.5 mg per
day
(N=50)
3-6 mg per
day
(N=61)
Placebo
(N=58)
Eye Disorders
Vision blurred
4
7
0
Gastrointestinal Disorders
Abdominal pain upper
16
13
5
Nausea
16
13
7
Vomiting
10
10
5
Diarrhea
8
7
2
Dyspepsia
10
3
2
Stomach discomfort
6
0
2
General Disorders
Fatigue
18
30
3
Metabolism and Nutrition Disorders
Increased appetite
4
7
2
Nervous System Disorders
Somnolence
22
30
12
Sedation
20
23
7
Dizziness
16
13
5
Parkinsonism*
6
12
3
Dystonia*
6
5
0
Akathisia*
0
8
2
Psychiatric Disorders
Anxiety
0
8
3
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain
10
3
5
Skin and Subcutaneous Tissue Disorders
Rash
0
7
2
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity.
Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
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6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric
Patients Treated for Irritability Associated with Autistic Disorder
in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
System/Organ Class
Adverse Reaction
RISPERDAL®
0.5-4.0 mg per day
(N=76)
Placebo
(N=80)
Cardiac Disorders
Tachycardia
5
0
Gastrointestinal Disorders
Vomiting
25
21
Constipation
21
8
Dry mouth
15
6
Salivary hypersecretion
9
0
Nausea
8
6
General Disorders
Fatigue
42
13
Feeling abnormal
5
0
Infections and Infestations
Nasopharyngitis
21
10
Rhinitis
13
10
Upper respiratory tract infection
8
3
Investigations
Weight increased
5
0
Metabolism and Nutrition Disorders
Increased appetite
47
19
Nervous System Disorders
Somnolence
49
18
Sedation
29
3
Drooling
16
5
Tremor
12
1
Parkinsonism*
11
1
Dizziness
9
3
Dyskinesia
7
3
Lethargy
5
3
Respiratory, Thoracic and
Mediastinal Disorders
Cough
24
18
Rhinorrhea
16
13
Nasal congestion
13
5
Skin and Subcutaneous Tissue
Disorders
Rash
11
8
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder,
muscle rigidity, cogwheel rigidity, and muscle tightness.
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24
6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of
Risperidone
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder,
and studies in elderly patients with dementia.
Blood and Lymphatic System Disorders: granulocytopenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree,
bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye
swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual
acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling,
cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting
edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort,
generalized edema, drug withdrawal syndrome, peripheral coldness
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis,
tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media,
onychomycosis,
acarodermatitis,
bronchopneumonia,
respiratory
tract
infection,
tracheobronchitis, otitis media chronic
Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase
increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count
decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body
temperature decreased, blood pressure decreased, transaminases increased
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25
Metabolism and Nutrition Disorders: polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest
pain, posture abormal, myalgia, neck pain, muscular weakness, rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria,
unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia,
transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss
of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder,
neuroleptic malignant syndrome, diabetic coma
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep
disorder, listless, libido decreased, anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea,
gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation,
ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus
congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion,
rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus,
skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular
Vascular Disorders: flushing
Additional Adverse Reactions Reported with RISPERDAL® CONSTA®
The following is a list of additional adverse reactions that have been reported during the
premarketing evaluation of RISPERDAL® CONSTA®, regardless of frequency of occurrence:
Blood and Lymphatic Disorders: neutropenia
Cardiac Disorders: bradycardia
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blepharospasm
Gastrointestinal Disorders: toothache, tongue spasm
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26
General Disorders and Administration Site Conditions: pain
Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis,
subcutaneous abscess
Injury and Poisoning: fall
Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme
increased
Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain
Nervous System Disorders: convulsion, paresthesia
Psychiatric Disorders: depression
Skin and Subcutaneous Tissue Disorders: eczema
Vascular Disorders: hypertension
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7.
Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated
Adult Patients in Schizophrenia Trials
RISPERDAL®
Adverse Reaction
2-8 mg/day
(N=366)
>8-16 mg/day
(N=198)
Placebo
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Vomiting
0.8%
0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0%
0%
Dystonia
0.5%
0%
0%
Agitation
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Orthostatic hypotension
0.3%
0.5%
0%
Akathisia
0.3%
2.0%
0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
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Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54)
placebo-treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy
(1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
Table 8.
Adverse Reactions Associated With Discontinuation in 2 or More
RISPERDAL®-Treated Adult Patients in Bipolar Mania Clinical
Trials
Adverse Reaction
RISPERDAL®
1-6 mg/day
(N=448)
Placebo
(N=424)
Parkinsonism
0.4%
0%
Lethargy
0.2%
0%
Dizziness
0.2%
0%
Alanine aminotransferase
increased
0.2%
0.2%
Aspartate aminotransferase
increased
0.2%
0.2%
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
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Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
RISPERDAL®
2 mg
RISPERDAL®
6 mg
RISPERDAL®
10 mg
RISPERDAL®
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
17%
21%
21%
35%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
Dose Groups
RISPERDAL®
1 mg
RISPERDAL®
4 mg
RISPERDAL
® 8 mg
RISPERDAL®
12 mg
RISPERDAL®
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
17%
18%
20%
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing
difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur
at low doses, they occur more frequently and with greater severity with high potency and at
higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is
observed in males and younger age groups.
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
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The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction,
angioedema, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis in patients with impaired
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glucose metabolism, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion,
intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea
syndrome, thrombocytopenia, urinary retention, and water intoxication.
Other adverse events reported since market introduction, which were temporally related to
risperidone but not necessarily causally related, include the following: pituitary adenoma,
pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
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7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers
Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
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patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
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callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of RISPERDAL® during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than 1200
pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar
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mania who were of similar age and weight, and who received similar dosages of RISPERDAL®
as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In 103
adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of
RISPERDAL® treatment. The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55
and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
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transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated.
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8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
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such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
interval and convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
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There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
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RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB®
Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin,
gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL®.
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
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40
daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
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41
Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)].
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile
typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
patients receiving quinidine have not been evaluated, but observations in a modest number
(n≅70) of poor metabolizers given RISPERDAL® do not suggest important differences between
poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g.,
carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.17)].
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Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.17)].
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
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Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
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14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
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(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
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significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
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Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
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Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this open-
label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of
1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as ≥
25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much
improved’) during the 4-6 month open-label treatment phase for about 140 days, on average,
were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
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defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either
“Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, bottles of 500 NDC
50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01.
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, bottles of 500 NDC
50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, bottles of 500 NDC
50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06 and hospital unit dose
blister packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M-
TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30.
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1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature 15°-
25°C (59°-77°F). Protect from light and freezing.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M-
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Revised August 2010
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and
RISPERDAL® Oral Solution are manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:18.166046
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020272S-055S-058S-061S-062lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
12,404
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. RISPERDAL® is
not approved for use in patients with dementia-related psychosis. (5.1)
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophreni
a- adults
(2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophreni
a –
adolescents
(2.1)
0.5mg
/day
0.5- 1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar
mania –
adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar
mania in
children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder
(2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with
antipsychotics, including RISPERDAL®. Patients with a history of a
clinically significant low white blood cell count (WBC) or a drug-
induced leukopenia/neutropenia should have their complete blood count
(CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign
of a clinically significant decline in WBC in the absence of other
causative factors. (5.8)
• Potential for cognitive and motor impairment (5.9)
• Seizures (5.10)
• Dysphagia (5.11)
• Priapism (5.12)
• Thrombotic Thrombocytopenic Purpura (TTP) (5.13)
• Disruption of body temperature regulation (5.14)
• Antiemetic Effect (5.15)
• Suicide (5.16)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.17)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.17)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism,
akathisia, vomiting, cough, constipation, nasopharyngitis, drooling,
rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety,
headache, nasal congestion, rhinitis, tremor, and rash. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were nausea, somnolence, sedation, vomiting, dizziness,
and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800-
JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower initial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 08/2010
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
1
INDICATIONS AND USAGE
1.1
Schizophrenia
1.2
Bipolar Mania
1.3
Irritability Associated with Autistic Disorder
2
DOSAGE AND ADMI ISTRATION
N
2.1
Schizophrenia
2.2
Bipolar Mania
2.3
Irritability Associated with Autistic Disorder –
Pediatrics (Children and Adolescents)
2.4
Dosage in Special Populations
2.5
Co-Administration of RISPERDAL® with Certain
Other Medications
2.6
Administration of RISPERDAL
® Oral Solution
2.7
Directions for Use of RISPERDAL
® M-
TAB
® Orally Disintegrating ablets
T
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WA
S AND PRECAUTIONS
RNING
5.1
Increased Mortality in Elderly Patients with
Dementia-Related Psychosis
5.2
Cerebrovascular Adverse Events, Including
Stroke, in Elderly Patients with Dementia-
Related Psychosis
5.3
Neuroleptic Malignant Syndrome (NMS)
5.4
Tardive Dyskinesia
5.5
Hyperglycemia and Diabetes Mellitus
5.6
Hyperprolactinemia
5.7
Orthostatic Hypotension
5.8
Leukopenia, Neutropenia, and Agranulocytosis
5.9
Potential for Cognitive and Motor Impairment
5.10
Seizures
5.11
Dysphagia
5.12
Priapism
5.13
Thrombotic Thrombocytopenic Purpura (TTP)
5.14
Body Temperatu
Regulation
re
5.15
Antiemetic Effect
5.16
Suicide
5.17
Use in Patients with Concomitant Illness
5.18
Monitoring: Labo
tory Tests
ra
6
AD ERSE REACTIONS
V
6.1
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Schizophrenia
6.2
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
– Bipolar Mania
6.3
Commonly-Observed Adverse Reactions in
Double-Blind, Placebo-Controlled Clinical Trials
- Autistic Disorder
6.4
Other Adverse Reactions Observed During the
Premarketing Evaluation of RISPERDAL
®
6.5
Discontinuations Due to Adverse Reactions
6.6
Dose Dependency of Adverse Reactions in
Clinical Trials
6.7
Changes in Body Weight
6.8
Changes in ECG
6.9
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
7.2
Drugs with Hypotensive Effects
7.3
Levodopa and Dopamine Agonists
7.4
Amitriptyline
7.5
Cimetidine and Ranitidine
7.6
Clozapine
7.7
Lithium
7.8
Valproate
7.9
Digoxin
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
Isozymes
7.11
Carbamazepine and Other Enzy
me Inducers
7.12
Drugs Metabolized by CYP D6
2
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delive y
r
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10 OVERDOSAGE
10.1
Human Experience
10.2
Management of Overdosage
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Actio
n
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NON LINICAL TOXICOLOGY
C
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14 CLINICAL STUDIES
14.1
Schizophrenia
14.2
Bipolar Mania - Monotherapy
14.3
Bipolar Mania – Combination Therapy
14.4
Irritability Associated with Autistic Disorder
16 HOW SUPPLIED/STORAGE AND HANDLING
Storage and Handling
17 PATIENT COUNSELING INFO MATION
R
17.1
Orthostatic Hypotension
17.2
Interference with Cognitive and Motor
Performance
17.3
Pregnancy
17.4
Nursing
17.5
Concomitant Medication
17.6
Alcohol
17.7
Phenylketonurics
*Sections or subsections omitted from the full prescribing information are not
listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which the findings
of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. RISPERDAL®
(risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of
1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower
titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see
Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not
demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal
symptoms and other adverse effects, and are generally not recommended. In a single study
supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for
4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above
2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.17)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.10)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M-
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
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9
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square),
3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. RISPERDAL® (risperidone) is not approved for the treatment of
dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
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10
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
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If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics
including RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus
in the general population. Given these confounders, the relationship between atypical
antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL®, should be monitored regularly for worsening of
glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history
of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL®,
should undergo fasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL®,
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing. In some
cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL®,
was discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of RISPERDAL®.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
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12
impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
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13
complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9)].
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a
large, open premarketing experience (approximately 1300 patients). She experienced jaundice,
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14
fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.16 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.17 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.18 Monitoring: Laboratory Tests
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15
No specific laboratory tests are recommended.
6
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
• Antiemetic effect [see Warnings and Precautions (5.15)]
• Suicide [see Warnings and Precautions (5.16)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.17)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.17)]
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16
The most common adverse reactions in clinical trials (≥ 10%) were somnolence, increased
appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation,
nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea,
anxiety, headache, nasal congestion, rhinitis, tremor, and rash.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea,
somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions (6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
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6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per day
(N=198)
Placebo
(N=225)
Blood and Lymphatic System
Disorders
Anemia
<1
1
0
Cardiac Disorders
Tachycardia
1
3
0
Ear and Labyrinth Disorders
Ear pain
<1
1
0
Eye Disorders
Vision blurred
3
1
1
Gastrointestinal Disorders
Nausea
9
4
4
Constipation
8
9
6
Dyspepsia
8
6
5
Vomiting
7
5
7
Dry mouth
4
0
1
Abdominal discomfort
3
1
1
Salivary hypersecretion
2
1
<1
Diarrhea
2
1
1
Abdominal pain
1
1
0
Abdominal pain upper
1
1
0
Stomach discomfort
1
1
1
General Disorders
Fatigue
3
1
0
Chest pain
2
2
1
Asthenia
2
1
<1
Immune System Disorders
Hypersensitivity
<1
1
0
Infections and Infestations
Nasopharyngitis
3
4
3
Upper respiratory tract infection
2
3
1
Sinusitis
1
2
1
Urinary tract infection
1
3
0
Investigations
Weight increased
1
1
0
Blood creatine phosphokinase
increased
1
2
<1
Heart rate increased
<1
2
0
Metabolism and Nutrition Disorders
Decreased appetite
1
0
<1
Musculoskeletal and Connective
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18
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per day
(N=198)
Placebo
(N=225)
Tissue Disorders
Back pain
4
1
1
Arthralgia
2
3
<1
Pain in extremity
2
1
1
Joint stiffness
1
1
0
Nervous System Disorders
Parkinsonism*
14
17
8
Akathisia*
10
10
3
Dizziness
7
4
2
Somnolence
7
2
1
Dystonia*
3
4
2
Sedation
3
3
1
Tremor*
2
3
1
Dizziness postural
2
0
0
Dyskinesia*
1
2
2
Syncope
1
1
0
Psychiatric Disorders
Insomnia
32
25
27
Anxiety
16
11
11
Nervousness
1
1
<1
Renal and Urinary Disorders
Urinary incontinence
1
1
0
Reproductive System and Breast
Disorders
Ejaculation failure
<1
1
0
Respiratory, Thoracic and
Mediastinal Disorders
Nasal congestion
4
6
2
Dyspnea
1
2
0
Epistaxis
<1
2
0
Skin and Subcutaneous Tissue
Disorders
Rash
1
4
1
Dry skin
1
3
0
Dandruff
1
1
0
Seborrheic dermatitis
<1
1
0
Hyperkeratosis
0
1
1
Vascular Disorders
Orthostatic hypotension
2
1
0
Hypotension
1
1
0
* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism,
cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity,
and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia
includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture,
oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis.
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19
Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
Adverse Reaction
1-3 mg per day
(N=55)
4-6 mg per day
(N=51)
Placebo
(N=54)
Gastrointestinal Disorders
Salivary hypersecretion
0
10
2
Nervous System Disorders
Parkinsonism*
16
28
11
Sedation
13
8
2
Somnolence
11
4
2
Tremor
11
10
6
Akathisia*
9
10
4
Dizziness
7
14
2
Dystonia*
2
6
0
Psychiatric Disorders
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, muscle
rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and
restlessness. Dystonia includes dystonia and oculogyration.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
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Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult
Patients with Bipolar Mania in Double-Blind, Placebo-Controlled
Monotherapy Trials
Percentage of Patients Reporting Event
System/Organ Class
Adverse Reaction
RISPERDAL®
1-6 mg per day
(N=448)
Placebo
(N=424)
Cardiac Disorders
Tachycardia
1
<1
Eye Disorders
Vision blurred
2
1
Gastrointestinal Disorders
Nausea
5
2
Diarrhea
3
2
Salivary hypersecretion
3
1
Dyspepsia
2
2
Stomach discomfort
2
<1
General Disorders
Fatigue
2
1
Asthenia
1
1
Pyrexia
1
1
Infections and Infestations
Nasopharyngitis
1
1
Investigations
Aspartate aminotransferase increased
1
<1
Nervous System Disorders
Parkinsonism*
25
9
Akathisia*
9
3
Tremor*
6
3
Dizziness
6
5
Sedation
6
2
Somnolence
5
2
Dystonia*
5
1
Lethargy
2
1
Dyskinesia*
1
<1
Reproductive System and Breast
Disorders
Galactorrhea
1
0
Skin and Subcutaneous Tissue
Disorders
Acne
1
0
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal
stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel
rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and
parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration,
torticollis. Dyskinesia includes muscle twitching and dyskinesia.
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
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Percentage of Patients Reporting Event
System/Organ Class
RISPERDAL® + Mood
Stabilizer
Placebo +
Mood Stabilizer
Adverse Reaction
(N=127)
(N=126)
Cardiac Disorders
Palpitations
2
0
Gastrointestinal Disorders
Dyspepsia
9
8
Nausea
6
4
Diarrhea
6
4
Dry mouth
4
4
Vomiting
4
6
Constipation
3
3
Salivary hypersecretion
2
0
General Disorders
Chest pain
2
1
Fatigue
2
2
Infections and Infestations
Nasopharyngitis
2
3
Urinary tract infection
2
1
Investigations
Weight increased
2
2
Nervous System Disorders
Parkinsonism*
14
4
Headache
14
15
Akathisia*
8
0
Dizziness
7
2
Sedation
6
3
Tremor
6
2
Somnolence
3
1
Lethargy
2
1
Psychiatric Disorders
Insomnia
4
8
Anxiety
3
2
Respiratory, Thoracic and
Mediastinal Disorders
Pharyngolaryngeal pain
5
2
Cough
2
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia.
Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
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Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
RISPERDAL ®
System/Organ Class
Adverse Reaction
0.5-2.5 mg per
day
(N=50)
3-6 mg per
day
(N=61)
Placebo
(N=58)
Eye Disorders
Vision blurred
4
7
0
Gastrointestinal Disorders
Abdominal pain upper
16
13
5
Nausea
16
13
7
Vomiting
10
10
5
Diarrhea
8
7
2
Dyspepsia
10
3
2
Stomach discomfort
6
0
2
General Disorders
Fatigue
18
30
3
Metabolism and Nutrition Disorders
Increased appetite
4
7
2
Nervous System Disorders
Somnolence
22
30
12
Sedation
20
23
7
Dizziness
16
13
5
Parkinsonism*
6
12
3
Dystonia*
6
5
0
Akathisia*
0
8
2
Psychiatric Disorders
Anxiety
0
8
3
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain
10
3
5
Skin and Subcutaneous Tissue Disorders
Rash
0
7
2
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity.
Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
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6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric
Patients Treated for Irritability Associated with Autistic Disorder
in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
System/Organ Class
Adverse Reaction
RISPERDAL®
0.5-4.0 mg per day
(N=76)
Placebo
(N=80)
Cardiac Disorders
Tachycardia
5
0
Gastrointestinal Disorders
Vomiting
25
21
Constipation
21
8
Dry mouth
15
6
Salivary hypersecretion
9
0
Nausea
8
6
General Disorders
Fatigue
42
13
Feeling abnormal
5
0
Infections and Infestations
Nasopharyngitis
21
10
Rhinitis
13
10
Upper respiratory tract infection
8
3
Investigations
Weight increased
5
0
Metabolism and Nutrition Disorders
Increased appetite
47
19
Nervous System Disorders
Somnolence
49
18
Sedation
29
3
Drooling
16
5
Tremor
12
1
Parkinsonism*
11
1
Dizziness
9
3
Dyskinesia
7
3
Lethargy
5
3
Respiratory, Thoracic and
Mediastinal Disorders
Cough
24
18
Rhinorrhea
16
13
Nasal congestion
13
5
Skin and Subcutaneous Tissue
Disorders
Rash
11
8
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder,
muscle rigidity, cogwheel rigidity, and muscle tightness.
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6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of
Risperidone
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder,
and studies in elderly patients with dementia.
Blood and Lymphatic System Disorders: granulocytopenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree,
bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye
swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual
acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling,
cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting
edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort,
generalized edema, drug withdrawal syndrome, peripheral coldness
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis,
tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media,
onychomycosis,
acarodermatitis,
bronchopneumonia,
respiratory
tract
infection,
tracheobronchitis, otitis media chronic
Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase
increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count
decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body
temperature decreased, blood pressure decreased, transaminases increased
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Metabolism and Nutrition Disorders: polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest
pain, posture abormal, myalgia, neck pain, muscular weakness, rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria,
unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia,
transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss
of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder,
neuroleptic malignant syndrome, diabetic coma
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep
disorder, listless, libido decreased, anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea,
gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation,
ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus
congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion,
rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus,
skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular
Vascular Disorders: flushing
Additional Adverse Reactions Reported with RISPERDAL® CONSTA®
The following is a list of additional adverse reactions that have been reported during the
premarketing evaluation of RISPERDAL® CONSTA®, regardless of frequency of occurrence:
Blood and Lymphatic Disorders: neutropenia
Cardiac Disorders: bradycardia
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blepharospasm
Gastrointestinal Disorders: toothache, tongue spasm
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General Disorders and Administration Site Conditions: pain
Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis,
subcutaneous abscess
Injury and Poisoning: fall
Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme
increased
Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain
Nervous System Disorders: convulsion, paresthesia
Psychiatric Disorders: depression
Skin and Subcutaneous Tissue Disorders: eczema
Vascular Disorders: hypertension
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7.
Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated
Adult Patients in Schizophrenia Trials
RISPERDAL®
Adverse Reaction
2-8 mg/day
(N=366)
>8-16 mg/day
(N=198)
Placebo
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Vomiting
0.8%
0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0%
0%
Dystonia
0.5%
0%
0%
Agitation
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Orthostatic hypotension
0.3%
0.5%
0%
Akathisia
0.3%
2.0%
0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
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Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54)
placebo-treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy
(1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
Table 8.
Adverse Reactions Associated With Discontinuation in 2 or More
RISPERDAL®-Treated Adult Patients in Bipolar Mania Clinical
Trials
Adverse Reaction
RISPERDAL®
1-6 mg/day
(N=448)
Placebo
(N=424)
Parkinsonism
0.4%
0%
Lethargy
0.2%
0%
Dizziness
0.2%
0%
Alanine aminotransferase
increased
0.2%
0.2%
Aspartate aminotransferase
increased
0.2%
0.2%
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
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Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
RISPERDAL®
2 mg
RISPERDAL®
6 mg
RISPERDAL®
10 mg
RISPERDAL®
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
17%
21%
21%
35%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
Dose Groups
RISPERDAL®
1 mg
RISPERDAL®
4 mg
RISPERDAL
® 8 mg
RISPERDAL®
12 mg
RISPERDAL®
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
17%
18%
20%
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing
difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur
at low doses, they occur more frequently and with greater severity with high potency and at
higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is
observed in males and younger age groups.
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
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The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction,
angioedema, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis in patients with impaired
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glucose metabolism, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion,
intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea
syndrome, thrombocytopenia, urinary retention, and water intoxication.
Other adverse events reported since market introduction, which were temporally related to
risperidone but not necessarily causally related, include the following: pituitary adenoma,
pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
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7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers
Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
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patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
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callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of RISPERDAL® during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than 1200
pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar
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mania who were of similar age and weight, and who received similar dosages of RISPERDAL®
as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In 103
adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of
RISPERDAL® treatment. The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55
and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
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transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated.
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8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
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such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
interval and convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
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There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
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RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB®
Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin,
gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL®.
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
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daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
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Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)].
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile
typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
patients receiving quinidine have not been evaluated, but observations in a modest number
(n≅70) of poor metabolizers given RISPERDAL® do not suggest important differences between
poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g.,
carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.17)].
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Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.17)].
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
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Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
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14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
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(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
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significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this open-
label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of
1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as ≥
25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much
improved’) during the 4-6 month open-label treatment phase for about 140 days, on average,
were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either
“Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, bottles of 500 NDC
50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01.
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, bottles of 500 NDC
50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, bottles of 500 NDC
50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06 and hospital unit dose
blister packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M-
TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature 15°-
25°C (59°-77°F). Protect from light and freezing.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M-
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Revised August 2010
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and
RISPERDAL® Oral Solution are manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:18.601807
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020272S-055S-058S-061S-062lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 58}
|
12,403
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. RISPERDAL® is
not approved for use in patients with dementia-related psychosis. (5.1)
-------------------------RECENT MAJOR CHANGES------------------------
Boxed Warning
08/2008
Warnings and Precautions (5.1)
08/2008
Warnings and Precautions, Leucopenia, Neutropenia, and Agranulocytosis
(5.8)
09/2009
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophreni
a- adults
(2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophreni
a –
adolescents
(2.1)
0.5mg
/day
0.5- 1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar
mania –
adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar
mania in
children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder
(2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with
antipsychotics, including RISPERDAL®. Patients with a history of a
clinically significant low white blood cell count (WBC) or a drug-
induced leukopenia/neutropenia should have their complete blood count
(CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign
of a clinically significant decline in WBC in the absence of other
causative factors. (5.8)
• Potential for cognitive and motor impairment (5.9)
• Seizures (5.10)
• Dysphagia (5.11)
• Priapism (5.12)
• Disruption of body temperature regulation (5.13)
• Antiemetic Effect (5.14)
• Suicide (5.15)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.16)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.16)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, appetite increased, fatigue, rhinitis, upper respiratory tract
infection, vomiting, coughing, urinary incontinence, saliva increased,
constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea,
dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were somnolence, nausea, abdominal pain, dizziness,
vomiting, agitation, and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800
JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower initial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: MM/YYYY
1
5.9
Potential for Cognitive and Motor Impairment
5.10
Seizures
FULL PRESCRIBING INFORMATION: CONTENTS*
5.11
Dysphagia
5.12
Priapism
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
5.13
Body Temperature Regulation
WITH DEMENTIA-RELATED PSYCHOSIS
5.14
Antiemetic Effect
1
INDICATIONS AND USAGE
5.15
Suicide
1.1
Schizophrenia
5.16
Use in Patients with Concomitant Illness
1.2
Bipolar Mania
5.17
Monitoring: Laboratory Tests
1.3
Irritability Associated with Autistic Disorder
6
ADVERSE REACTIONS
2
DOSAGE AND ADMINISTRATION
6.1
Commonly-Observed Adverse Reactions in
2.1
Schizophrenia
Double-Blind, Placebo-Controlled Clinical Trials
2.2
Bipolar Mania
- Schizophrenia
2.3
Irritability Associated with Autistic Disorder –
6.2
Commonly-Observed Adverse Reactions in
Pediatrics (Children and Adolescents)
Double-Blind, Placebo-Controlled Clinical Trials
2.4
Dosage in Special Populations
– Bipolar Mania
2.5
Co-Administration of RISPERDAL® with Certain
6.3
Commonly-Observed Adverse Reactions in
Other Medications
Double-Blind, Placebo-Controlled Clinical Trials
2.6
Administration of RISPERDAL
® Oral Solution
- Autistic Disorder
2.7
Directions for Use of RISPERDAL
® M-
6.4
Other Adverse Reactions Observed During the
TAB
® Orally Disintegrating Tablets
Premarketing Evaluation of RISPERDAL
®
3
DOSAGE FORMS AND STRENGTHS
6.5
Discontinuations Due to Adverse Reactions
4
CONTRAINDICATIONS
6.6
Dose Dependency of Adverse Reactions in
5
WARNINGS AND PRECAUTIONS
Clinical Trials
5.1
Increased Mortality in Elderly Patients with
6.7
Changes in Body Weight
Dementia-Related Psychosis
6.8
Changes in ECG
5.2
Cerebrovascular Adverse Events, Including
6.9
Postmarketing Experience
Stroke, in Elderly Patients with Dementia-
7
DRUG INTERACTIONS
Related Psychosis
7.1
Centrally-Acting Drugs and Alcohol
5.3
Neuroleptic Malignant Syndrome (NMS)
7.2
Drugs with Hypotensive Effects
5.4
Tardive Dyskinesia
7.3
Levodopa and Dopamine Agonists
5.5
Hyperglycemia and Diabetes Mellitus
7.4
Amitriptyline
5.6
Hyperprolactinemia
7.5
Cimetidine and Ranitidine
5.7
Orthostatic Hypotension
7.6
Clozapine
5.8
Leukopenia, Neutropenia, and Agranulocytosis
7.7
Lithium
2
7.8
Valproate
7.9
Digoxin
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
Isozymes
7.11
Carbamazepine and Other Enzyme Inducers
7.12
Drugs Metabolized by CYP 2D6
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10
OVERDOSAGE
10.1
Human Experience
10.2
Management of 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
Schizophrenia
14.2
Bipolar Mania - Monotherapy
14.3
Bipolar Mania – Combination Therapy
14.4
Irritability Associated with Autistic Disorder
16
HOW SUPPLIED/STORAGE AND HANDLING
Storage and Handling
17
PATIENT COUNSELING INFORMATION
17.1
Orthostatic Hypotension
17.2
Interference with Cognitive and Motor
Performance
17.3
Pregnancy
17.4
Nursing
17.5
Concomitant Medication
17.6
Alcohol
17.7
Phenylketonurics
*Sections or subsections omitted from the full prescribing information are not
listed
3
FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which the findings
of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. RISPERDAL®
(risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
4
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of
1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower
titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see
Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not
demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal
symptoms and other adverse effects, and are generally not recommended. In a single study
supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for
4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
5
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above
2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
6
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
7
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.16)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.10)].
8
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating
Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
9
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square),
3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. RISPERDAL® (risperidone) is not approved for the treatment of
dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional
signs
may
include
elevated
creatinine
phosphokinase,
myoglobinuria
(rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
10
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
11
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma
or death, has been reported in patients treated with atypical antipsychotics including
RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and glucose
abnormalities is complicated by the possibility of an increased background risk of diabetes
mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the
general population. Given these confounders, the relationship between atypical antipsychotic use
and hyperglycemia-related adverse events is not completely understood. However,
epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related
adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for
hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not
available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has
resolved when the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
12
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
13
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.12 Priapism
Rare cases of priapism have been reported. While the relationship of the events to RISPERDAL®
use has not been established, other drugs with alpha-adrenergic blocking effects have been
reported to induce priapism, and it is possible that RISPERDAL® may share this capacity.
Severe priapism may require surgical intervention.
5.13 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
14
5.14 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.15 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.16 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.17 Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
15
6
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.13)]
• Antiemetic effect [see Warnings and Precautions (5.14)]
• Suicide [see Warnings and Precautions (5.15)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.16)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.16)]
The most common adverse reactions in clinical trials (≥ 10%) were somnolence, appetite
increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary
incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain,
anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were somnolence,
16
nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia [see Adverse Reactions
(6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using WHOART terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
17
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
Body System
2-8 mg per day >8-16 mg per day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Body as a whole - general disorders
Back pain
3
2
<1
Fatigue
3
1
0
Chest pain
3
1
2
Fever
2
1
1
Asthenia
1
1
<1
Syncope
<1
1
<1
Edema
<1
1
0
Cardiovascular disorders, general
Hypotension postural
2
<1
0
Hypotension
<1
1
0
Central and peripheral nervous system
disorders
Parkinsonism*
12
17
6
Dizziness
10
4
2
Dystonia*
5
5
2
Akathisia*
5
5
2
Dyskinesia
1
1
<1
Gastrointestinal system disorders
Dyspepsia
10
7
6
Nausea
9
4
4
Constipation
8
9
7
Abdominal pain
4
3
0
Mouth dry
4
<1
<1
Saliva increased
3
1
<1
Diarrhea
2
<1
1
Hearing and vestibular disorders
Earache
1
1
0
Heart rate and rhythm disorders
Tachycardia
2
5
0
Arrhythmia
0
1
0
Metabolic and nutritional disorders
Weight increase
1
<1
0
Creatine phosphokinase increased
<1
2
<1
Musculoskeletal system disorders
Arthralgia
2
3
<1
Myalgia
1
0
0
Platelet, bleeding and clotting disorders
Epistaxis
<1
2
0
Psychiatric disorders
Anxiety
16
12
11
Somnolence
14
5
4
Anorexia
2
0
<1
Red blood cell disorders
Anemia
<1
1
0
Reproductive disorders, male
Ejaculation failure
<1
1
0
Respiratory system disorders
18
Rhinitis
7
11
6
Coughing
3
3
3
Upper respiratory tract infection
2
3
<1
Dyspnea
2
2
0
Skin and appendages disorders
Rash
2
4
2
Seborrhea
<1
2
0
Urinary system disorders
Urinary tract infection
<1
3
0
Vision disorders
Vision abnormal
3
1
<1
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia.
Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia includes
hyperkinesia and akathisia.
Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
Body System
1-3 mg per day
4-6 mg per day
Placebo
Adverse Reaction
(N=55)
(N=51)
(N=54)
Central and peripheral nervous system
disorders
Parkinsonism*
13
16
6
Tremor
11
10
6
Dystonia*
9
18
7
Dizziness
7
14
2
Akathisia*
7
10
6
Gastrointestinal system disorders
Saliva increased
0
10
2
Psychiatric disorders
Somnolence
24
12
4
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradykinesia.
Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia includes
hyperkinesia and akathisia.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
19
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients
with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy
Trials
Percentage of Patients Reporting Event
Body System
RISPERDAL®
Placebo
Adverse Reaction
1-6 mg per day
(N=424)
(N=448)
Body as a whole - general disorders
Fatigue
2
<1
Fever
1
<1
Asthenia
1
<1
Edema
1
<1
Central and peripheral nervous system
disorders
Parkinsonism*
20
6
Dystonia*
11
3
Akathisia*
9
3
Tremor
6
4
Dizziness
5
5
Gastrointestinal system disorders
Nausea
5
2
Dyspepsia
4
2
Saliva increased
3
<1
Diarrhea
3
2
Mouth dry
1
1
Heart rate and rhythm disorders
Tachycardia
1
<1
Liver and biliary system disorders
SGOT increased
1
<1
Musculoskeletal disorders
Myalgia
2
2
Psychiatric disorders
Somnolence
12
4
Anxiety
2
2
Reproductive disorders, female
Lactation nonpuerperal
1
0
Respiratory disorders
Rhinitis
2
2
Skin and appendages disorders
Acne
1
0
Vision disorders
Vision abnormal
2
<1
* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia.
Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia
includes hyperkinesia and akathisia.
20
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with Bipolar
Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Percentage of Patients Reporting Event
RISPERDAL® +
Placebo +
Body System
Mood Stabilizer
Mood Stabilizer
Adverse Reaction
(N=127)
(N=126)
Body as a whole – general disorders
Chest pain
2
2
Fatigue
2
2
Central and peripheral nervous system
disorders
Parkinsonism*
9
4
Dizziness
8
2
Dystonia*
6
3
Akathisia*
6
0
Tremor
5
2
Gastrointestinal system disorders
Nausea
6
5
Diarrhea
6
4
Saliva increased
4
0
Abdominal pain
2
0
Heart rate and rhythm disorders
Palpitation
2
0
Metabolic and nutritional disorders
Weight increase
2
2
Psychiatric disorders
Somnolence
12
5
Anxiety
4
2
Respiratory disorders
Pharyngitis
5
2
Coughing
3
1
Skin and appendages disorders
Rash
2
2
Urinary system disorders
Urinary incontinence
2
1
Urinary tract infection
2
1
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Dystonia
includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany,
laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and
akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
21
Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL ®
Body System
0.5-2.5 mg per day
3-6 mg per day
Placebo
Adverse Reaction
(N=50)
(N=61)
(N=58)
Body as a whole - general disorders
Fatigue
18
30
3
Central and peripheral nervous system
disorders
Dizziness
16
13
5
Dystonia*
8
13
2
Parkinsonism*
2
7
2
Akathisia*
0
7
2
Gastrointestinal system disorders
Abdominal pain
18
15
5
Dyspepsia
16
5
3
Nausea
16
13
7
Vomiting
12
10
7
Diarrhea
8
7
2
Heart rate and rhythm disorders
Tachycardia
0
5
2
Psychiatric disorders
Somnolence
42
56
19
Appetite increased
4
7
2
Anxiety
0
8
3
Reproductive disorders, female
Lactation nonpuerperal
2
5
0
Respiratory system disorders
Rhinitis
14
13
10
Dyspnea
2
5
0
Skin and appendages disorders
Rash
0
7
2
Urinary system disorders
Urinary incontinence
0
5
0
Vision disorders
Vision abnormal
4
7
0
* Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary,
tetany, laryngismus, tongue paralysis, and torticollis. Parkinsonism includes extrapyramidal
disorder, hypokinesia, and bradykinesia. Akathisia includes hyperkinesia and akathisia.
22
6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients
Treated for Irritability Associated with Autistic Disorder in Double-Blind,
Placebo-Controlled Trials
Percentage of Patients Reporting Event
Body System
RISPERDAL®
Placebo
Adverse Reaction
0.5-4.0 mg per day
(N=80)
(N=76)
Body as a whole - general disorders
Fatigue
42
13
Fever
20
19
Central and peripheral nervous system
disorders
Dystonia*
12
6
Tremor
12
1
Dizziness
9
3
Parkinsonism*
8
0
Automatism
7
1
Dyskinesia
7
0
Gastrointestinal system disorders
Vomiting
25
21
Saliva increased
22
6
Constipation
21
8
Mouth dry
13
6
Nausea
8
8
Heart rate and rhythm disorders
Tachycardia
7
0
Metabolic and nutritional disorders
Weight increase
5
0
Psychiatric disorders
Somnolence
67
23
Appetite increased
49
19
Anxiety
16
15
Anorexia
8
8
Confusion
5
0
Respiratory system disorders
Rhinitis
36
23
Upper respiratory tract infection
34
15
Coughing
24
18
Skin and appendages disorders
Rash
11
8
Urinary system disorders
Urinary incontinence
22
20
* Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions
involuntary, tetany, laryngismus, tongue paralysis, and torticollis.
Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia.
23
6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of
RISPERDAL®
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder,
and studies in elderly patients with dementia.
Body as a Whole, General Disorders: edema peripheral, pain, influenza-like symptoms, leg
pain, malaise, allergy, crying abnormal, allergic reaction, rigors, allergy aggravated,
anaphylactoid reaction, hypothermia
Central Nervous System Disorders: gait abnormal, speech disorder, coma, ataxia, dysphonia,
stupor, cramps legs, vertigo, hypoesthesia, tardive dyskinesia, neuroleptic malignant syndrome
Endocrine Disorders: hyperprolactinemia, gynecomastia
Gastrointestinal System Disorders: dysphagia, flatulence
Heart Rate and Rhythm Disorders: AV block, bundle branch block
Liver and Biliary Disorders: SGPT increased, hepatic enzymes increased
Metabolic and Nutritional Disorders: thirst, hyperglycemia, xerophthalmia, generalized
edema, diabetes mellitus aggravated, diabetic coma
Musculoskeletal Disorders: muscle weakness, rhabdomyolysis
Platelet, Bleeding, and Clotting Disorders: purpura
Psychiatric Disorders: insomnia, agitation, emotional lability, apathy, nervousness,
concentration impaired, impotence, decreased libido
Reproductive Disorders, Female: amenorrhea, menstrual disorder, leukorrhea
Reproductive Disorders, Male: ejaculation disorder, abnormal sexual function, priapism
Resistance Mechanism Disorders: otitis media, viral infection
Respiratory Disorders: respiratory disorder
24
Skin and Appendages Disorders: skin ulceration, skin discoloration, rash erythematous, skin
exfoliation, rash maculopapular, erythema multiforme
Urinary Disorders: micturition frequency
Vascular Disorders: cerebrovascular disorder
Vision Disorders: conjunctivitis
White Cell Disorders: leucopenia, granulocytopenia
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7.
Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated
Adult Patients in Schizophrenia Trials
RISPERDAL®
2-8 mg/day
>8-16 mg/day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Agitation
1.1%
1.0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0.5%
0%
Dystonia
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Hypotension postural
0.3%
0.5%
0%
Tachycardia
0.3%
0.5%
0%
Akathisia
0%
1.0%
0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54)
placebo-treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were somnolence (2%), dizziness (2%), anorexia (1%), anxiety
(1%), ataxia (1%), hypotension (1%), and palpitation (1%).
25
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
Table 8.
Adverse Reactions Associated With Discontinuation in 2 or More
RISPERDAL®-Treated Adult Patients in Bipolar Mania Clinical Trials
RISPERDAL®
1-6 mg/day
Placebo
Adverse Reaction
(N=448)
(N=424)
Parkinsonism
0.4%
0%
Somnolence
0.2%
0%
Dizziness
0.2%
0%
Dystonia
0.2%
0%
SGOT increased
0.2%
0.2%
SGPT increased
0.2%
0.2%
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were somnolence (5%), nausea (3%), abdominal pain (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
26
Dose Groups
Placebo
RISPERDAL®
2 mg
RISPERDAL®
6 mg
RISPERDAL®
10 mg
RISPERDAL®
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
11%
15%
16%
20%
31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
Dose Groups
RISPERDAL®
RISPERDAL®
RISPERDAL®
RISPERDAL®
RISPERDAL®
1 mg
4 mg
8 mg
12 mg
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS
7%
11%
17%
18%
20%
Incidence
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
27
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of RISPERDAL®;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: anaphylactic reaction, angioedema, atrial
fibrillation, diabetic ketoacidosis in patients with impaired glucose metabolism, intestinal
obstruction, jaundice, mania, QT prolongation, and sleep apnea.
Other adverse events reported since market introduction, which were temporally related to
RISPERDAL® but not necessarily causally related, include the following: pancreatitis, pituitary
adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
28
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
29
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers
Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
30
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of RISPERDAL® during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
31
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than 1200
pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar
mania who were of similar age and weight, and who received similar dosages of RISPERDAL®
as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In 103
adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of
RISPERDAL® treatment. The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55
and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
32
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
33
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated.
8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
34
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
interval and convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
35
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is: structural formula
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
36
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB®
Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin,
gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL® .
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
37
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
38
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)].
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile
typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
patients receiving quinidine have not been evaluated, but observations in a modest number
(n≅70) of poor metabolizers given RISPERDAL® do not suggest important differences between
poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g.,
carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.15)].
39
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.15)].
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
40
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Highest No-
Effect Level
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
41
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
42
of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The
most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
43
significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
44
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
45
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this open-
label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of
1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as ≥
25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much
improved’) during the 4-6 month open-label treatment phase for about 140 days, on average,
were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
46
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either
“Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50, hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50, hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, hospital unit dose blister
packs of 100 NDC 50458-300-01, bottles of 500 NDC 50458-300-50.
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, hospital unit dose blister
packs of 100 NDC 50458-320-01, bottles of 500 NDC 50458-320-50.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, hospital unit dose blister
packs of 100 NDC 50458-330-01, bottles of 500 NDC 50458-330-50.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06, hospital unit dose blister
packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M
TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-395-28, long-term care blister packaging of 30 tablets NDC 50458-395-30.
47
1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-315-28, long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature 15°
25°C (59°-77°F). Protect from light and freezing.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
48
17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
INSERT NEW CODE
Revised July 2009
©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and Oral
Solution are manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
49
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® CONSTA® safely and effectively. See full prescribing
information for RISPERDAL® CONSTA®.
RISPERDAL® CONSTA® (risperidone) LONG-ACTING INJECTION
Initial U.S. Approval: 2003
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. RISPERDAL®
CONSTA® is not approved for use in patients with dementia-related
psychosis. (5.1)
-------------------------RECENT MAJOR CHANGES------------------------
Boxed Warning
October 2008
Indications and Usage, Bipolar Disorder (1.2)
May 2009
Dosage and Administration, Bipolar Disorder (2.2)
May 2009
Warnings and Precautions (5.1)
October 2008
Warnings and Precautions, Leukopenia, Neutropenia,
and Agranulocytosis (5.8)
May 2009
Warnings and Precautions, Priapism (5.12)
October 2008
Warnings and Precautions, Suicide (5.17)
May 2009
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® CONSTA® is an atypical antipsychotic indicated:
• for the treatment of schizophrenia. (1.1)
• as monotherapy or as adjunctive therapy to lithium or valproate for the
maintenance treatment of Bipolar I Disorder. (1.2)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
• For patients who have never taken oral RISPERDAL®, tolerability should
be established with oral RISPERDAL® prior to initiating treatment with
RISPERDAL® CONSTA® (2)
• Administer by deep intramuscular (IM) deltoid or gluteal injection. Each
injection should be administered by a health care professional using the
appropriate enclosed safety needle (1-inch for deltoid administration
alternating injections between the two arms and 2-inch for gluteal
administration alternating injections between the two buttocks). Do not
administer intravenously. (2)
• 25 mg intramuscular (IM) every 2 weeks. Patients not responding to 25 mg
may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose
should not exceed 50 mg every 2 weeks. (2)
• Oral RISPERDAL® (or another antipsychotic medication) should be given
with the first injection of RISPERDAL® CONSTA®, and continued for 3
weeks (and then discontinued) to ensure adequate therapeutic plasma
concentrations from RISPERDAL® CONSTA®. (2)
• Upward dose adjustment of RISPERDAL® CONSTA® should not be made
more frequently than every 4 weeks. Clinical effects of each upward dose
adjustment should not be anticipated earlier than 3 weeks after injection.
(2)
• Avoid inadvertent administration into a blood vessel. (5.15)
• See Full Prescribing Information Section 2.6 for instructions for use.
--------------------DOSAGE FORMS AND STRENGTHS----------------------
Vial kits: 12.5 mg, 25 mg, 37.5 mg, and 50 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® CONSTA® is not approved for use in
patients with dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation
and close monitoring (5.3)
• Tardive Dyskinesia: Discontinue treatment if clinically appropriate (5.4)
• Hyperglycemia and Diabetes Mellitus- in some cases extreme and
associated with ketoacidosis or hyperosmolar coma or death, has been
reported in patients taking risperidone. Patients with diabetes mellitus
should have glucose levels monitored regularly. Patients with risk
factors for diabetes mellitus should undergo fasting glucose testing at the
beginning of treatment and periodically during treatment. All patients
taking risperidone should be monitored for symptoms of hyperglycemia.
Symptomatic patients should undergo fasting glucose testing. (5.5)
• Hyperprolactinemia: Risperidone treatment may elevate prolactin levels.
Long-standing hyperprolactinemia, when associated with
hypogonadism, can lead to decreased bone density in men and women.
(5.6)
• Orthostatic hypotension: associated with dizziness, tachycardia,
bradycardia, and syncope can occur, especially during initial dose
titration with oral risperidone. Use caution in patients with
cardiovascular disease, cerebrovascular disease, and conditions that
could affect hemodynamic responses. (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis have been reported with
antipsychotics, including RISPERDAL. Patients with history of a
clinically significant low white blood cell count (WBC) or a drug-
induced leukopenia/neutropenia should have their complete blood cell
count (CBC) monitored frequently during the first few months of
therapy and discontinuation of RISPERDAL® CONSTA® should be
considered at the first sign of a clinically significant decline in WBC in
the absence of other causative factors. (5.8)
• Potential for cognitive and motor impairment: has potential to impair
judgment, thinking, and motor skills. Use caution when operating
machinery, including automobiles. (5.9)
• Seizures: Use cautiously in patients with a history of seizures or with
conditions that potentially lower the seizure threshold. (5.10)
• Dysphagia: Esophageal dysmotility and aspiration can occur. Use
cautiously in patients at risk for aspiration pneumonia. (5.11)
• Priapism: has been reported. Severe priapism may require surgical
intervention. (5.12)
• Thrombotic Thrombocytopenic Purpura (TTP): has been reported. (5.13)
• Avoid inadvertent administration into a blood vessel (5.15)
• Suicide: There is increased risk of suicide attempt in patients with
schizophrenia or bipolar disorder, and close supervision of high-risk
patients should accompany drug therapy. (5.17)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies: has been reported. Manifestations include
mental status changes, motor impairment, extrapyramidal symptoms,
and features consistent with Neuroleptic Malignant Syndrome. (5.18)
• Diseases or conditions that could affect metabolism or hemodynamic
responses: Use with caution in patients with such medical conditions
(e.g., recent myocardial infarction or unstable cardiac disease) (5.18)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials in patients with
schizophrenia (≥ 5%) were headache, parkinsonism, dizziness, akathisia,
fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity,
and dry mouth. The most common adverse reactions in clinical trials in
patients with bipolar disorder were weight increased (5% in monotherapy
trial) and tremor and parkinsonism (≥10% in adjunctive therapy trial). (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials in patients with schizophrenia were agitation, depression,
anxiety, and akathisia. Adverse reactions that were associated with
discontinuation from bipolar disorder trials were hyperglycemia (one subject
monotherapy trial) and hypokinesia and tardive dyskinesia (one subject each
in adjunctive therapy trial). (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800
JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
1
• Clozapine may decrease clearance of risperidone. (7.6)
• Pediatric Use: safety and effectiveness not established in patients less than
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.11)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.12)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Renal or Hepatic Impairment: dose appropriately with oral RISPERDAL®
prior to initiating treatment with RISPERDAL® CONSTA®. A lower
starting dose of RISPERDAL® CONSTA® of 12.5 mg may be appropriate
in some patients. (2.4)
• Nursing Mothers: should not breast feed. (8.3)
18 years of age. (8.4)
• Elderly: dosing for otherwise healthy elderly patients is the same as for
healthy nonelderly. Elderly may be more predisposed to orthostatic effects
than nonelderly. (8.5)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: June 2009
2
1
6.6
Changes in Body Weight
FULL PRESCRIBING INFORMATION: CONTENTS*
6.7
Changes in ECG
6.8
Pain Assessment and Local Injection
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
Site Reactions
WITH DEMENTIA-RELATED PSYCHOSIS
6.9
Postmarketing Experience
INDICATIONS AND USAGE
1.1
Schizophrenia
1.2
Bipolar Disorder
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
2.2
Bipolar Disorder
2.3
General Dosing Information
2.4
Dosage in Special Populations
2.5
Reinitiation of Treatment in Patients
Previously Discontinued
2.6
Switching from Other Antipsychotics
2.7
Co-Administration of RISPERDAL®
CONSTA® with Certain Other
Medications
2.8
Instructions for Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Increased Mortality in Elderly Patients
with Dementia-Related Psychosis
5.2
Cerebrovascular Adverse Events,
Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
5.3
Neuroleptic Malignant Syndrome (NMS)
5.4
Tardive Dyskinesia
5.5
Hyperglycemia and Diabetes Mellitus
5.6
Hyperprolactinemia
5.7
Orthostatic Hypotension
5.8
Leukopenia, Neutropenia, and
Agranulocytosis
5.9
Potential for Cognitive and Motor
Impairment
5.10
Seizures
5.11
Dysphagia
5.12
Priapism
5.13
Thrombotic Thrombocytopenic Purpura
(TTP)
5.14
Body Temperature Regulation
5.15
Administration
5.16
Antiemetic Effect
5.17
Suicide
5.18
Use in Patients with Concomitant Illness
5.19
Osteodystrophy and Tumors in Animals
5.20
Monitoring: Laboratory Tests
6
ADVERSE REACTIONS
6.1
Commonly-Observed Adverse
Reactions in Double-Blind, Placebo-
Controlled Clinical Trials
Schizophrenia
6.2
Commonly-Observed Adverse
Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar
Disorder
6.3
Other Adverse Reactions Observed
During the Premarketing Evaluation of
RISPERDAL® CONSTA
®
6.4
Discontinuations Due to Adverse
Reactions
6.5
Dose Dependency of Adverse
Reactions in Clinical Trials
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
7.2
Drugs with Hypotensive Effects
7.3
Levodopa and Dopamine Agonists
7.4
Amitriptyline
7.5
Cimetidine and Ranitidine
7.6
Clozapine
7.7
Lithium
7.8
Valproate
7.9
Digoxin
7.10
Topiramate
7.11
Drugs That Inhibit CYP 2D6 and Other
CYP Isozymes
7.12
Carbamazepine and Other CYP 3A4
Enzyme Inducers
7.13
Drugs Metabolized by CYP 2D6
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10
OVERDOSAGE
10.1
Human Experience
10.2
Management of 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
Schizophrenia
14.2
Bipolar Disorder - Monotherapy
14.3
Bipolar Disorder - Adjunctive Therapy
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1
Orthostatic Hypotension
17.2
Interference with Cognitive and Motor
Performance
17.3
Pregnancy
17.4
Nursing
17.5
Concomitant Medication
17.6
Alcohol
*Sections or subsections omitted from the full prescribing information
are not listed
3
FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are
at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration
of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of
death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-
treated patients. Over the course of a typical 10-week controlled trial, the rate of death
in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the
placebo group. Although the causes of death were varied, most of the deaths appeared
to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g.,
pneumonia) in nature. Observational studies suggest that, similar to atypical
antipsychotic drugs, treatment with conventional antipsychotic drugs may increase
mortality. The extent to which the findings of increased mortality in observational
studies may be attributed to the antipsychotic drug as opposed to some
characteristic(s) of the patients is not clear. RISPERDAL® CONSTA®(risperidone) is
not approved for the treatment of patients with dementia-related psychosis. [See
Warnings and Precautions (5.1)]
1 INDICATIONS AND USAGE
1.1 Schizophrenia
RISPERDAL® CONSTA® (risperidone) is indicated for the treatment of schizophrenia [see
Clinical Studies (14.1)].
1.2 Bipolar Disorder
RISPERDAL® CONSTA® is indicated as monotherapy or as adjunctive therapy to lithium
or valproate for the maintenance treatment of Bipolar I Disorder [see Clinical Studies (14.2,
14.3)].
2 DOSAGE AND ADMINISTRATION
For patients who have never taken oral RISPERDAL®, it is recommended to establish
tolerability with oral RISPERDAL® prior to initiating treatment with RISPERDAL®
CONSTA® .
RISPERDAL® CONSTA® should be administered every 2 weeks by deep intramuscular
(IM) deltoid or gluteal injection. Each injection should be administered by a health care
professional using the appropriate enclosed safety needle [see Dosage and Administration
(2.8)]. For deltoid administration, use the 1-inch needle alternating injections between the
two arms. For gluteal administration, use the 2-inch needle alternating injections between
the two buttocks. Do not administer intravenously.
4
2.1
2.2
2.3
Schizophrenia
The recommended dose for the treatment of schizophrenia is 25 mg IM every 2 weeks.
Although dose response for effectiveness has not been established for RISPERDAL®
CONSTA®, some patients not responding to 25 mg may benefit from a higher dose of
37.5 mg or 50 mg. The maximum dose should not exceed 50 mg RISPERDAL® CONSTA®
every 2 weeks. No additional benefit was observed with dosages greater than 50 mg
RISPERDAL® CONSTA®; however, a higher incidence of adverse effects was observed.
The efficacy of RISPERDAL® CONSTA® in the treatment of schizophrenia has not been
evaluated in controlled clinical trials for longer than 12 weeks. Although controlled studies
have not been conducted to answer the question of how long patients with schizophrenia
should be treated with RISPERDAL® CONSTA®, oral risperidone has been shown to be
effective in delaying time to relapse in longer-term use. It is recommended that responding
patients be continued on treatment with RISPERDAL® CONSTA® at the lowest dose
needed. The physician who elects to use RISPERDAL® CONSTA® for extended periods
should periodically re-evaluate the long-term risks and benefits of the drug for the individual
patient.
Bipolar Disorder
The recommended dose for monotherapy or adjunctive therapy to lithium or valproate for
the maintenance treatment of Bipolar I Disorder is 25 mg IM every 2 weeks. Some patients
may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been
studied in this population. The physician who elects to use RISPERDAL® CONSTA® for
extended periods should periodically re-evaluate the long-term risks and benefits of the drug
for the individual patient.
General Dosing Information
A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose
adjustment, such as in patients with hepatic or renal impairment, for certain drug interactions
that increase risperidone plasma concentrations [see Drug Interactions (7.11)] or in patients
who have a history of poor tolerability to psychotropic medications. The efficacy of the
12.5 mg dose has not been investigated in clinical trials.
Oral RISPERDAL® (or another antipsychotic medication) should be given with the first
injection of RISPERDAL® CONSTA® and continued for 3 weeks (and then discontinued) to
ensure that adequate therapeutic plasma concentrations are maintained prior to the main
release phase of risperidone from the injection site [see Clinical Pharmacology (12.3)].
5
Upward dose adjustment should not be made more frequently than every 4 weeks. The
clinical effects of this dose adjustment should not be anticipated earlier than 3 weeks after
the first injection with the higher dose.
In patients with clinical factors such as hepatic or renal impairment or certain drug
interactions that increase risperidone plasma concentrations [see Drug Interactions (7.11)],
dose reduction as low as 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has
not been investigated in clinical trials.
Do not combine two different dose strengths of RISPERDAL® CONSTA® in a single
administration.
2.4 Dosage in Special Populations
Elderly
For elderly patients treated with RISPERDAL® CONSTA®, the recommended dosage is
25 mg IM every 2 weeks. Oral RISPERDAL® (or another antipsychotic medication) should
be given with the first injection of RISPERDAL® CONSTA® and should be continued for
3 weeks to ensure that adequate therapeutic plasma concentrations are maintained prior to
the main release phase of risperidone from the injection site [see Clinical Pharmacology
(12.3)].
Renal or Hepatic Impairment
Patients with renal or hepatic impairment should be treated with titrated doses of oral
RISPERDAL® prior to initiating treatment with RISPERDAL® CONSTA® . The
recommended starting dose is 0.5 mg oral RISPERDAL® twice daily during the first week,
which can be increased to 1 mg twice daily or 2 mg once daily during the second week. If a
total daily dose of at least 2 mg oral RISPERDAL® is well tolerated, an injection of 25 mg
RISPERDAL® CONSTA® can be administered every 2 weeks. Oral supplementation should
be continued for 3 weeks after the first injection until the main release of risperidone from
the injection site has begun. In some patients, slower titration may be medically appropriate.
Alternatively, a starting dose of RISPERDAL® CONSTA® of 12.5 mg may be appropriate.
The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
Patients with renal impairment may have less ability to eliminate risperidone than normal
adults. Patients with impaired hepatic function may have an increase in the free fraction of
the risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)].
Elderly patients and patients with a predisposition to hypotensive reactions or for whom
such reactions would pose a particular risk should be instructed in nonpharmacologic
interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on
6
the edge of the bed for several minutes before attempting to stand in the morning and slowly
rising from a seated position). These patients should avoid sodium depletion or dehydration,
and circumstances that accentuate hypotension (alcohol intake, high ambient temperature,
etc.). Monitoring of orthostatic vital signs should be considered [see Warnings and
Precautions (5.7)].
2.5 Reinitiation of Treatment in Patients Previously Discontinued
There are no data to specifically address reinitiation of treatment. When restarting patients
who have had an interval off treatment with RISPERDAL® CONSTA®, supplementation
with oral RISPERDAL® (or another antipsychotic medication) should be administered.
2.6 Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients from
other
antipsychotics
to
RISPERDAL®
CONSTA® ,
or
concerning
concomitant
administration with other antipsychotics. Previous antipsychotics should be continued for
3 weeks after the first injection of RISPERDAL® CONSTA® to ensure that therapeutic
concentrations are maintained until the main release phase of risperidone from the injection
site has begun [see Clinical Pharmacology (12.3)]. For patients who have never taken oral
RISPERDAL®, it is recommended to establish tolerability with oral RISPERDAL® prior to
initiating treatment with RISPERDAL® CONSTA®. As recommended with other
antipsychotic medications, the need for continuing existing EPS medication should be
re-evaluated periodically.
2.7 Co-Administration of RISPERDAL® CONSTA® with Certain Other Medications
Co-administration of carbamazepine and other CYP 3A4 enzyme inducers (e.g., phenytoin,
rifampin, phenobarbital) with risperidone would be expected to cause decreases in the
plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which
could lead to decreased efficacy of RISPERDAL® CONSTA® treatment. The dose of
risperidone needs to be titrated accordingly for patients receiving these enzyme inducers,
especially during initiation or discontinuation of therapy with these inducers [see Drug
Interactions (7.11)]. At the initiation of therapy with carbamazepine or other known CYP
3A4 hepatic enzyme inducers, patients should be closely monitored during the first
4-8 weeks, since the dose of RISPERDAL® CONSTA® may need to be adjusted. A dose
increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation
of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL®
CONSTA® should be re-evaluated and, if necessary, decreased. Patients may be placed on a
lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned
discontinuation of carbamazepine or other CYP 3A4 inducers to adjust for the expected
7
increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients
treated with the recommended dose of 25 mg RISPERDAL® CONSTA® and discontinuing
from carbamazepine or other CYP3A4 enzyme inducers, it is recommended to continue
treatment with the 25-mg dose unless clinical judgment necessitates lowering the
RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL®
CONSTA® treatment. The efficacy of the12.5 mg dose has not been investigated in clinical
trials.
Fluoxetine and paroxetine, CYP 2D6 inhibitors, have been shown to increase the plasma
concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect
the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of
9-hydroxyrisperidone by about 10%. The dose of risperidone needs to be titrated
accordingly when fluoxetine or paroxetine is co-administered. When either concomitant
fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the
dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is
considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between
2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the
expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is
initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it
is recommended to continue treatment with the 25-mg dose unless clinical judgment
necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates
interruption of RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is
initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg
can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical
trials. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the
pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. [See Drug
Interactions (7.11)]
2.8 Instructions for Use
8
Usage Illustration
RISPERDAL® CONSTA® must be reconstituted only in the diluent supplied in the dose
pack, and must be administered with only the appropriate needle supplied in the dose pack
for gluteal (2-inch needle) or deltoid (1-inch needle) administration. All components are
required for administration. Do not substitute any components of the dose pack. To assure
that the intended dose of risperidone is delivered, the full contents from the vial must be
administered. Administration of partial contents may not deliver the intended dose of
risperidone.
Remove the dose pack of RISPERDAL® CONSTA® from the refrigerator and allow it to
come to room temperature prior to reconstitution.
1. Flip off the plastic colored cap from the vial. Usage Illustration
9
2. Peel back the blister pouch and remove the SmartSite® Needle-Free Vial Access Device
by holding the white luer cap. Do not touch the spike tip of the access device at any time. Usage Illustration
3. Place vial on a hard surface. Hold the base of the vial. Orient the SmartSite® Access
Device vertically over the vial so that the spike tip is at the center of the vial’s rubber
stopper. With a straight downward push, press the spike tip of the SmartSite® Access
Device through the center of the vial’s rubber stopper until the device securely snaps onto
the vial top.
4. Swab the syringe connection point (blue circle) of the SmartSiteUsage Illustration® Access Device with
preferred antiseptic prior to attaching the syringe to the SmartSite® Access Device. Usage Illustration
10
5. The prefilled syringe has a white cap consisting of 2 parts: a knurled collar and a smooth
cap. To open the syringe, hold the syringe by the knurled collar and snap off the smooth
cap (DO NOT TWIST OFF THE CAP). Remove the white cap together with the rubber
tip cap inside. Usage Illustration
For all syringe assembly steps, hold the syringe only by the white collar, located at the tip
of the syringe. Be careful to not overtighten components when assembling.
Overtightening connections may cause syringe component parts to loosen from the
syringe body.
6. While holding the white collar of the syringe, press the syringe tip into the blue circle of
the SmartSite® Access Device and twist in a clockwise motion to attach the syringe to
the SmartSite® Access Device. Hold the skirt of the SmartSite® Access Device during
attachment to prevent it from spinning. Keep the syringe and SmartSite® Access Device
aligned. Usage Illustration
7. Inject the entire contents of the syringe containing the diluent into the vial.
11
Usage Illustration
8. Shake the vial vigorously while holding the plunger rod down with the thumb for a
minimum of 10 seconds to ensure a homogeneous suspension. When properly mixed, the
suspension appears uniform, thick, and milky in color. The particles will be visible in
liquid, but no dry particles remain. Usage Illustration
9. Do not store the vial after reconstitution or the suspension may settle. If 2 minutes pass
before injection, re-suspend by shaking vigorously.
10. Invert the vial completely and slowly withdraw the suspension from the vial into the
syringe. Tear section of the vial label at the perforation and apply detached label to
syringe for identification purposes. Usage Illustration
12
11. While holding the white collar of the syringe, unscrew the syringe from the SmartSite®
Access Device. Discard both the vial and access device appropriately. Usage Illustration
12. Select the appropriate needle:
For GLUTEAL injection, select the 20G TW 2-inch needle (longer needle with yellow
colored hub in blister with yellow print)
For DELTOID injection, select the 21G UTW 1-inch needle (shorter needle with green
colored hub in blister with green print)
13. Peel the blister pouch of the Needle-Pro® device open halfway. Grasp sheath using the
plastic peel pouch. While holding the white collar of the syringe, attach the luer
connection of the Needle-Pro® device to the syringe with an easy clockwise twisting
motion. Usage Illustration
14. If 2 minutes pass before injection, re-suspend by shaking vigorously.
13
15. While holding the white collar of the syringe, pull the sheath away from the needle- do
not twist the sheath because it could result in loosening the needle. Usage Illustration
16. Tap the syringe gently to make any air bubbles rise to the top. De-aerate syringe by
moving plunger rod carefully forward, with the needle in an upright position. Inject the
entire contents of the syringe intramuscularly (IM) into the selected gluteal or deltoid
muscle of the patient within 2 minutes to avoid settling. Gluteal injection should be made
into the upper-outer quadrant of the gluteal area. DO NOT ADMINISTER
INTRAVENOUSLY. Usage Illustration
WARNING: To avoid a needle stick injury with a contaminated needle, do not:
•
intentionally disengage the Needle-Pro® device
•
attempt to straighten the needle or engage Needle-Pro® device if the needle is bent
or damaged
•
mishandle the needle protection device that could lead to protrusion of the needle
from it
17. After injection is complete, use only one hand and tabletop or other hard surface to snap
needle into the orange needle protector device before discarding. Discard needle
appropriately. Also discard the other (unused) needle.
14
Usage Illustration
Upon suspension in the diluent, it is recommended to use RISPERDAL® CONSTA®
immediately. RISPERDAL® CONSTA® must be used within 6 hours of suspension.
Resuspension of RISPERDAL® CONSTA® will be necessary prior to administration, as
settling will occur over time once the product is in suspension. Keeping the vial upright,
shake vigorously back and forth for as long as it takes to resuspend the microspheres. Once
in suspension, the product should not be exposed to temperatures above 77°F (25°C).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
3 DOSAGE FORMS AND STRENGTHS
RISPERDAL® CONSTA® is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and
50 mg risperidone. It is provided as a dose pack, consisting of a vial containing the
risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for RISPERDAL®
CONSTA®, a SmartSite® Needle-Free Vial Access Device, and two Needle-Pro® safety
needles for intramuscular injection (a 21 G UTW 1-inch needle with needle protection
device for deltoid administration and a 20 G TW 2-inch needle with needle protection
device for gluteal administration).
4
CONTRAINDICATIONS
RISPERDAL® CONSTA® (risperidone) is contraindicated in patients with a known
hypersensitivity to the product.
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are
at an increased risk of death. RISPERDAL®CONSTA®(risperidone) is not approved
for the treatment of dementia-related psychosis (see Boxed Warning).
15
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities,
were reported in patients (mean age 85 years; range 73-97) in trials of oral risperidone in
elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a
significantly higher incidence of cerebrovascular adverse events in patients treated with oral
risperidone compared to patients treated with placebo. RISPERDAL® CONSTA® is not
approved for the treatment of patients with dementia-related psychosis [See also Boxed
Warning and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and
evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,
diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine
phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both
serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or
inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic
drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic
treatment and medical monitoring; and (3) treatment of any concomitant serious medical
problems for which specific treatments are available. There is no general agreement about
specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be
carefully monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to
be highest among the elderly, especially elderly women, it is impossible to rely upon
16
prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are
likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to
cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and
symptoms of the syndrome and thereby may possibly mask the underlying process. The
effect that symptomatic suppression has upon the long-term course of the syndrome is
unknown.
Given these considerations, RISPERDAL® CONSTA® should be prescribed in a manner
that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness that:
(1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally
effective, but potentially less harmful treatments are not available or appropriate. In patients
who do require chronic treatment, the smallest dose and the shortest duration of treatment
producing a satisfactory clinical response should be sought. The need for continued
treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®
CONSTA®, drug discontinuation should be considered. However, some patients may require
treatment with RISPERDAL® CONSTA® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar
coma or death, has been reported in patients treated with atypical antipsychotics including
RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes
mellitus in the general population. Given these confounders, the relationship between
atypical antipsychotic use and hyperglycemia-related adverse events is not completely
understood. However, epidemiological studies suggest an increased risk of treatment-
emergent hyperglycemia-related adverse events in patients treated with the atypical
17
antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients
treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients with
risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting
treatment with atypical antipsychotics should undergo fasting blood glucose testing at the
beginning of treatment and periodically during treatment. Any patient treated with atypical
antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia,
polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia
during treatment with atypical antipsychotics should undergo fasting blood glucose testing.
In some cases, hyperglycemia has resolved when the atypical antipsychotic was
discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of the suspect drug.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin
levels and the elevation persists during chronic administration. Risperidone is associated
with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing
gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea,
gynecomastia, and impotence have been reported in patients receiving prolactin-elevating
compounds. Long-standing hyperprolactinemia when associated with hypogonadism may
lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers
are prolactin dependent in vitro, a factor of potential importance if the prescription of these
drugs is contemplated in a patient with previously detected breast cancer. An increase in
pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary
adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone
carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)].
Neither clinical studies nor epidemiologic studies conducted to date have shown an
association between chronic administration of this class of drugs and tumorigenesis in
humans; the available evidence is considered too limited to be conclusive at this time.
18
5.7
5.8
Orthostatic Hypotension
RISPERDAL® CONSTA® may induce orthostatic hypotension associated with dizziness,
tachycardia, and in some patients, syncope, especially during the initial dose-titration period
with oral risperidone, probably reflecting its alpha-adrenergic antagonistic properties.
Syncope was reported in 0.8% (12/1499 patients) of patients treated with RISPERDAL®
CONSTA® in multiple-dose studies. Patients should be instructed in nonpharmacologic
interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on
the edge of the bed for several minutes before attempting to stand in the morning and slowly
rising from a seated position).
RISPERDAL® CONSTA® should be used with particular caution in (1) patients with known
cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or
conduction abnormalities), cerebrovascular disease, and conditions which would predispose
patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients
with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in
all such patients, and a dose reduction should be considered if hypotension occurs. Clinically
significant hypotension has been observed with concomitant use of oral RISPERDAL® and
antihypertensive medication.
Leukopenia, Neutropenia, and Agranulocytosis
Class
Effect:
In
clinical
trial
and/or
postmarketing
experience,
events
of
leukopenia/neutropenia have been reported temporally related to antipsychotic agents,
including RISPERDAL. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell
count (WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history
of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have
their complete blood count (CBC) monitored frequently during the first few months of
therapy and discontinuation of RISPERDAL® CONSTA® should be considered at the first
sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or
other symptoms or signs of infection and treated promptly if such symptoms or signs occur.
Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® CONSTA® and have their WBC followed until recovery.
Potential for Cognitive and Motor Impairment
Somnolence was reported by 5% of patients treated with RISPERDAL® CONSTA® in
multiple-dose trials. Since risperidone has the potential to impair judgment, thinking, or
19
5.9
motor skills, patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that treatment with RISPERDAL® CONSTA®
does not affect them adversely.
5.10 Seizures
During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated
with RISPERDAL® CONSTA®. Therefore, RISPERDAL® CONSTA® should be used
cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with
advanced Alzheimer’s dementia. RISPERDAL® CONSTA® and other antipsychotic drugs
should be used cautiously in patients at risk for aspiration pneumonia. [See also Boxed
Warning and Warnings and Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9)].
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL®
in a large, open premarketing experience (approximately 1300 patients). She experienced
jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The
relationship to RISPERDAL® therapy is unknown.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® or
RISPERDAL® CONSTA® use. Caution is advised when prescribing RISPERDAL®
CONSTA® for patients who will be exposed to temperature extremes.
5.15 Administration
RISPERDAL® CONSTA® should be injected into the deltoid or gluteal muscle, and care
must be taken to avoid inadvertent injection into a blood vessel. [See Dosage and
Administration (2) and Adverse Reactions (6.8)]
5.16 Antiemetic Effect
20
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.17 Suicide
There is an increased risk of suicide attempt in patients with schizophrenia or bipolar disorder,
and close supervision of high-risk patients should accompany drug therapy. RISPERDAL®
CONSTA® is to be administered by a health care professional [see Dosage and Administration
(2)]; therefore, suicide due to an overdose is unlikely.
5.18 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® CONSTA® in patients with certain concomitant
systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy
Bodies who receive antipsychotics, including RISPERDAL® CONSTA®, are reported to
have an increased sensitivity to antipsychotic medications. Manifestations of this increased
sensitivity have been reported to include confusion, obtundation, postural instability with
frequent falls, extrapyramidal symptoms, and clinical features consistent with the
neuroleptic malignant syndrome.
Caution is advisable when using RISPERDAL® CONSTA® in patients with diseases or
conditions that could affect metabolism or hemodynamic responses. RISPERDAL®
CONSTA® has not been evaluated or used to any appreciable extent in patients with a recent
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
excluded from clinical studies during the product’s premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) treated with oral
RISPERDAL®; an increase in the free fraction of risperidone is also seen in patients with
severe hepatic impairment. Patients with renal or hepatic impairment should be carefully
titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at
a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors
warrant dose adjustment, such as in patients with renal or hepatic impairment [see Dosage and
Administration (2.4)].
5.19 Osteodystrophy and Tumors in Animals
RISPERDAL® CONSTA® produced osteodystrophy in male and female rats in a 1-year
toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM
every 2 weeks.
21
6
RISPERDAL® CONSTA® produced renal tubular tumors (adenoma, adenocarcinoma) and
adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at
40 mg/kg administered IM every 2 weeks. In addition, RISPERDAL® CONSTA® produced
an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity
study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg
administered IM every 2 weeks. (Cellular proliferation was not measured at the low dose or
in females in either study.)
The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum
recommended human dose (MRHD) (50 mg) on a mg/m2 basis and is associated with a
plasma exposure (AUC) 2 times the expected plasma exposure (AUC) at the IM MRHD.
The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m2
basis). Plasma exposure (AUC) at the no-effect dose was one third the expected plasma
exposure (AUC) at the IM MRHD.
Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally
administered risperidone. Osteodystrophy was not observed in dogs at doses up to
14 times (based on AUC) the IM MRHD in a 1-year toxicity study.
The renal tubular and adrenomedullary tumors in male rats and other tumor findings are
described in more detail in Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of
Fertility).
The relevance of these findings to human risk is unknown.
5.20 Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
•
Increased mortality in elderly patients with dementia-related psychosis [see Boxed
Warning and Warnings and Precautions (5.1)]
•
Cerebrovascular adverse events, including stroke, in elderly patients with
dementia-related psychosis [see Warnings and Precautions (5.2)]
•
Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
•
Tardive dyskinesia [see Warnings and Precautions (5.4)]
•
Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
•
Hyperprolactinemia [see Warnings and Precautions (5.6)]
22
•
Orthostatic hypotension [see Warnings and Precautions (5.7)]
•
Leukopenia/Neutropenia and Agranulocytosis [see Warnings and Precautions
(5.8)]
•
Potential for cognitive and motor impairment [see Warnings and Precautions
(5.9)]
•
Seizures [see Warnings and Precautions (5.10)]
•
Dysphagia [see Warnings and Precautions (5.11)]
•
Priapism [see Warnings and Precautions (5.12)]
•
Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions
(5.13)]
•
Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
•
Avoidance of inadvertent injection into a blood vessel [see Warnings and
Precautions (5.15)]
•
Antiemetic effect [see Warnings and Precautions (5.16)]
•
Suicide [see Warnings and Precautions (5.17)]
•
Increased sensitivity in patients with Parkinson’s disease or those with dementia
with Lewy bodies [see Warnings and Precautions (5.18)]
•
Diseases or conditions that could affect metabolism or hemodynamic responses
[see Warnings and Precautions (5.18)]
•
Osteodystrophy and tumors in animals [see Warnings and Precautions (5.19)]
The most common adverse reactions in clinical trials in patients with schizophrenia (≥ 5%)
were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia,
sedation, weight increased, pain in extremity, and dry mouth. The most common adverse
reactions in the double-blind, placebo-controlled periods of the bipolar disorder trials were
weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥ 10% in the
adjunctive treatment trial).
The most common adverse reactions that were associated with discontinuation from the
12-week double-blind, placebo-controlled trial in patients with schizophrenia (causing
discontinuation in ≥ 1% of patients) were agitation, depression, anxiety, and akathisia.
Adverse reactions that were associated with discontinuation from the double-blind, placebo-
controlled periods of the bipolar disorder trials were hyperglycemia (one patient in the
monotherapy trial) and hypokinesia and tardive dyskinesia (one patient each in the
adjunctive treatment trial).
23
The data described in this section are derived from a clinical trial database consisting of
2392 patients exposed to one or more doses of RISPERDAL® CONSTA® for the treatment
of schizophrenia. Of these 2392 patients, 332 were patients who received RISPERDAL®
CONSTA® while participating in a 12-week double-blind, placebo-controlled trial.
Two hundred two (202) of the 332 were schizophrenia patients who received 25 mg or
50 mg RISPERDAL® CONSTA®. The conditions and duration of treatment with
RISPERDAL® CONSTA® in the other clinical trials varied greatly and included (in
overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled
studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12
weeks) and longer-term (up to 4 years) exposures. Safety was assessed by collecting adverse
events and performing physical examinations, vital signs, body weights, laboratory analyses,
and ECGs.
In addition to the studies in patients with schizophrenia, safety data are presented from a
trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as
monotherapy for maintenance treatment in patients with bipolar I disorder. The subjects in
this multi-center, double-blind, placebo-controlled study were adult patients who met DSM
IV criteria for Bipolar Disorder Type I and who were stable on risperidone (oral or long-
acting injection), were stable on other antipsychotics or mood stabilizers, or were
experiencing an acute episode. After a 3-week period of treatment with open-label oral
risperidone (n=440), subjects who demonstrated an initial response to oral risperidone in this
period and those who were stable on risperidone (oral or long-acting injection) at study entry
entered into a 26-week stabilization period of open-label RISPERDAL® CONSTA®
(n=501). Subjects who demonstrated a maintained response during this period were then
randomized into a 24-month double-blind, placebo-controlled period in which they received
RISPERDAL® CONSTA® (n=154) or placebo (n=149) as monotherapy. Subjects who
relapsed or who completed the double-blind period could choose to enter an 8-week open-
label RISPERDAL® CONSTA® extension period (n=160).
Safety data are also presented from a trial assessing the efficacy and safety of RISPERDAL®
CONSTA® when administered as adjunctive maintenance treatment in patients with bipolar
disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult
patients who met DSM-IV criteria for Bipolar Disorder Type I or Type II and who
experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention
in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of
the study. At the start of this study, all patients (n = 275) entered into a 16-week open-label
treatment phase in which they received RISPERDAL® CONSTA® in addition to continuing
their treatment as usual, which consisted of various mood stabilizers (primarily lithium and
24
valproate), antidepressants, and/or anxiolytics. Patients who reached remission at the end of
this 16-week open-label treatment phase (n = 139) were then randomized into a 52-week
double-blind, placebo-controlled phase in which they received RISPERDAL® CONSTA®
(n = 72) or placebo (n = 67) as adjunctive treatment in addition to continuing their treatment
as usual. Patients who did not reach remission at the end of the 16-week open-label
treatment phase could choose to continue to receive RISPERDAL® CONSTA® as adjunctive
therapy in an open-label manner, in addition to continuing their treatment as usual, for up to
an additional 36 weeks as clinically indicated for a total period of up to 52 weeks; these
patients (n = 70) were also included in the evaluation of safety.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events
were grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse
events that were considered to be reasonably associated with the use of RISPERDAL®
CONSTA® (adverse drug reactions) based on the comprehensive assessment of the available
adverse event information. A causal association for RISPERDAL® CONSTA® often cannot
be reliably established in individual cases. Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Table 1 lists the adverse reactions reported in 2% or more of RISPERDAL® CONSTA®
treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial.
25
Table 1.
Adverse Reactions in ≥ 2% of RISPERDAL® CONSTA®-Treated Patients with Schizophrenia in a
12-Week Double-Blind, Placebo-Controlled Trial
Percentage of Patients Reporting Event
RISPERDAL® CONSTA®
Placebo
System/Organ Class
25 mg
50 mg
Adverse Reaction
(N=99)
(N=103)
(N=98)
Eye disorders
Vision blurred
2
3
0
Gastrointestinal disorders
Constipation
5
7
1
Dry mouth
0
7
1
Dyspepsia
6
6
0
Nausea
3
4
5
Toothache
1
3
0
Salivary hypersecretion
4
1
0
General disorders and administration site conditions
Fatigue*
3
9
0
Edema peripheral
2
3
1
Pain
4
1
0
Pyrexia
2
1
0
Infections and infestations
Upper respiratory tract infection
2
0
1
Investigations
Weight increased
5
4
2
Weight decreased
4
1
1
Musculoskeletal and connective tissue disorders
Pain in extremity
6
2
1
Nervous system disorders
Headache
15
21
12
Parkinsonism*
8
15
9
Dizziness
7
11
6
Akathisia*
4
11
6
Sedation*
5
6
3
Tremor
0
3
0
Syncope
2
1
0
Hypoesthesia
2
0
0
Respiratory, thoracic and mediastinal disorders
Cough
4
2
3
Sinus congestion
2
0
0
Skin and subcutaneous tissue disorders
Acne
2
2
0
Dry skin
2
0
0
* Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal
stiffness, muscle rigidity, and bradykinesia. Akathisia includes akathisia and restlessness. Sedation
includes sedation and somnolence.
26
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Disorder
Table 2 lists the treatment-emergent adverse reactions reported in 2% or more of
RISPERDAL® CONSTA®-treated patients in the 24-month double-blind, placebo-controlled
treatment period of the trial assessing the efficacy and safety of RISPERDAL® CONSTA®
when administered as monotherapy for maintenance treatment in patients with Bipolar I
Disorder.
Table 2.
Adverse Reactions in ≥ 2% of Patients with Bipolar I Disorder Treated with
RISPERDAL® CONSTA® as Monotherapy in a 24-Month Double-Blind, Placebo-
Controlled Trial
Percentage of Patients Reporting Event
System/Organ Class
Adverse Reaction
Investigations
Weight increased
RISPERDAL®
CONSTA®
(N=154)
5
Placebo
(N=149)
1
Nervous system disorders
Dizziness
3
1
Vascular disorders
Hypertension
3
1
Table 3 lists the treatment-emergent adverse reactions reported in 4% or more of patients in
the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the
efficacy and safety of RISPERDAL® CONSTA® when administered as adjunctive
maintenance treatment in patients with bipolar disorder.
27
Table 3.
Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with
RISPERDAL® CONSTA® as Adjunctive Therapy in a 52-Week Double-Blind,
Placebo-Controlled Trial
Percentage of Patients
Reporting Event
RISPERDAL®
CONSTA® +
Placebo +
Treatment
Treatment
System/Organ Class
as Usuala
as Usuala
Adverse Reaction
(N=72)
(N=67)
General disorders and administration site conditions
Gait abnormal
4
0
Infections and infestations
Upper respiratory tract infection
6
3
Investigations
Weight increased
7
1
Metabolism and nutrition disorders
Decreased appetite
6
1
Increased appetite
4
0
Musculoskeletal and connective tissue disorders
Arthralgia
4
3
Nervous system disorders
Tremor
24
16
Parkinsonismb
15
6
Dyskinesiab
6
3
Sedationc
7
1
Disturbance in attention
4
0
Reproductive system and breast disorders
Amenorrhea
4
1
Respiratory, thoracic and mediastinal disorders
Cough
4
1
a Patients received double-blind RISPERDAL® CONSTA® or placebo in addition to continuing their
treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics.
b Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia
includes muscle twitching and dyskinesia.
c Sedation includes sedation and somnolence.
6.3 Other Adverse Reactions Observed During the Premarketing Evaluation of
RISPERDAL® CONSTA®
The following additional adverse reactions occurred in < 2% of the RISPERDAL®
CONSTA®-treated patients in the above schizophrenia double-blind, placebo-controlled trial
dataset, in < 2% of the RISPERDAL® CONSTA®-treated patients in the above double-blind,
placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the
RISPERDAL® CONSTA®-treated patients in the above double-blind, placebo-controlled
28
period of the adjunctive treatment bipolar disorder trial dataset. The following also includes
additional adverse reactions reported at any frequency in RISPERDAL® CONSTA®-treated
patients who participated in other studies, including double-blind, active-controlled and
open-label studies in schizophrenia, and in the open-label phases of the bipolar disorder
studies.
Blood and lymphatic system disorders: anemia, neutropenia
Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus
bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block
right
Ear and labyrinth disorders: ear pain, vertigo
Endocrine disorders: hyperprolactinemia
Eye disorders: conjunctivitis, visual acuity reduced
Gastrointestinal disorders: diarrhea, vomiting, abdominal pain, stomach discomfort,
gastritis
General disorders and administration site conditions: injection site pain, chest
discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site
induration, injection site swelling, injection site reaction, face edema
Immune system disorders: hypersensitivity
Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection,
rhinitis, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis,
viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess
Injury and poisoning: fall, procedural pain
Investigations:
blood
prolactin
increased,
alanine
aminotransferase
increased,
electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose
increased,
hepatic
enzyme
increased,
aspartate
aminotransferase
increased,
electrocardiogram QT prolonged
Metabolism and nutritional disorders: anorexia, hyperglycemia
Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back
pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain
29
Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling,
paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria
Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, libido
decreased, nervousness
Renal and urinary disorders: urinary incontinence
Reproductive system and breast disorders: oligomenorrhea, erectile dysfunction,
galactorrhea, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort,
menstruation irregular, menstruation delayed, menstrual disorder
Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal
pain, dyspnea, rhinorrhea
Skin and subcutaneous tissue disorders: rash, eczema, pruritus
Vascular disorders: hypotension, orthostatic hypotension
6.4 Discontinuations Due to Adverse Reactions
Schizophrenia
Approximately 11% (22/202) of RISPERDAL® CONSTA®-treated patients in the 12-week
double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an
adverse event, compared with 13% (13/98) who received placebo. The adverse reactions
associated with discontinuation in two or more RISPERDAL® CONSTA®-treated patients
were: agitation (3%), depression (2%), anxiety (1%), and akathisia (1%).
Bipolar Disorder
In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the
efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for
maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 RISPERDAL®
CONSTA®-treated patients discontinued due to an adverse reaction (hyperglycemia).
In the 52-week double-blind phase of the placebo-controlled trial in which RISPERDAL®
CONSTA® was administered as adjunctive therapy to patients with bipolar disorder in
addition to continuing with their treatment as usual, approximately 4% (3/72) of
RISPERDAL® CONSTA®-treated patients discontinued treatment due to an adverse event,
compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with
discontinuation in RISPERDAL® CONSTA®-treated patients were: hypokinesia (one
patient) and tardive dyskinesia (one patient).
30
6.5 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms:
Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-
blind, placebo-controlled trial comparing three doses of RISPERDAL® CONSTA® (25 mg,
50 mg, and 75 mg) with placebo in patients with schizophrenia, including: (1) the incidence of
spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the
total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the
Extrapyramidal Symptom Rating Scale (ESRS).
As shown in Table 1, the overall incidence of EPS-related adverse reactions (akathisia,
dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL®
CONSTA® was comparable to that of patients treated with placebo; the incidence of
EPS-related adverse reactions was higher in patients treated with 50 mg RISPERDAL®
CONSTA® .
The median change from baseline to endpoint in total ESRS score showed no worsening in
patients treated with RISPERDAL® CONSTA® compared with patients treated with
placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and
0 (50-mg group).
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups,
may occur in susceptible individuals during the first few days of treatment. Dystonic
symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the
throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While
these symptoms can occur at low doses, they occur more frequently and with greater
severity with high potency and at higher doses of first generation antipsychotic drugs. An
elevated risk of acute dystonia is observed in males and younger age groups.
6.6 Changes in Body Weight
In the 12-week double-blind, placebo-controlled trial in patients with schizophrenia, 9% of
patients treated with RISPERDAL® CONSTA®, compared with 6% of patients treated with
placebo, experienced a weight gain of >7% of body weight at endpoint.
In the 24-month double-blind, placebo-controlled treatment period of a trial assessing the
efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for
maintenance treatment in patients with bipolar I disorder, 11.6% of patients treated with
RISPERDAL® CONSTA® compared with 2.8% of patients treated with placebo experienced
a weight gain of >7% of body weight at endpoint.
31
In the 52-week double-blind, placebo-controlled trial in patients with bipolar disorder,
26.8% of patients treated with RISPERDAL® CONSTA® as adjunctive treatment in addition
to continuing their treatment as usual, compared with 27.3% of patients treated with placebo
in addition to continuing their treatment as usual, experienced a weight gain of >7% of body
weight at endpoint.
6.7 Changes in ECG
The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg
RISPERDAL® CONSTA® and 98 schizophrenic patients treated with placebo in the 12-week
double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no
statistically significant differences in QTc intervals (using Fridericia’s and linear correction
factors) during treatment with RISPERDAL® CONSTA® .
The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month
double-blind, placebo-controlled period. There were no clinically relevant differences in QTc
intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL®
CONSTA® compared to placebo.
The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week
double-blind, placebo-controlled trial. There were no statistically significant differences in QTc
intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL®
CONSTA® 25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition
to continuing treatment as usual compared to placebo.
6.8 Pain Assessment and Local Injection Site Reactions
The mean intensity of injection pain reported by patients with schizophrenia using a visual
analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from
the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8).
After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated
with 25 mg or 50 mg RISPERDAL® CONSTA® experienced redness, swelling, or
induration at the injection site.
In a separate study to observe local-site tolerability in which RISPERDAL® CONSTA® was
administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no patient
discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated
that only mild redness, swelling, or induration at the injection site was observed in subjects
treated with 37.5 mg or 50 mg RISPERDAL® CONSTA® at 2 hours after deltoid injection.
All ratings returned to baseline at the predose assessment of the next injection 2 weeks later.
No moderate or severe reactions were observed in any subject.
32
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic
reaction, angioedema, atrial fibrillation, diabetic ketoacidosis in patients with impaired
glucose metabolism, inappropriate antidiuretic hormone secretion, hypothermia, intestinal
obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea
syndrome, thrombocytopenia, and water intoxication. In addition, the following adverse
reactions have been observed during postapproval use of RISPERDAL® CONSTA®:
cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus
aggravated.
Retinal artery occlusion after injection of RISPERDAL® CONSTA® has been reported
during postmarketing surveillance. This has been reported in the presence of abnormal
arteriovenous anastomosis.
7
DRUG INTERACTIONS
The interactions of RISPERDAL® CONSTA® with coadministration of other drugs have not
been systematically evaluated. The drug interaction data provided in this section is based on
studies with oral RISPERDAL®.
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL®
CONSTA® is administered in combination with other centrally-acting drugs or alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® CONSTA® may enhance the
hypotensive effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® CONSTA® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9
hydroxyrisperidone
combined
following
concomitant
administration
with
oral
RISPERDAL®.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%,
respectively. However, cimetidine did not affect the AUC of risperidone and 9
33
hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9
hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with risperidone may decrease the clearance of
risperidone.
7.7 Lithium
Repeated doses of oral RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC)
or peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated doses of oral RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of oral RISPERDAL®.
7.9 Digoxin
Oral RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Topiramate
Oral RISPERDAL® administered at doses from 1-6 mg/day concomitantly with topiramate
400 mg/day resulted in a 23% decrease in risperidone Cmax and a 33% decrease in
risperidone AUC0-12 hour at steady state. Minimal reductions in the exposure to risperidone
and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were
observed. This interaction is unlikely to be of clinical significance. There was no clinically
relevant effect of oral RISPERDAL® on the pharmacokinetics of topiramate.
7.11 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone
and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70 patients) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
34
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have
been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold
respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.
Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either
concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re
evaluate the dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine
is considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between
2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the
expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is
initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it
is recommended to continue treatment with the 25-mg dose unless clinical judgment
necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates
interruption of RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is
initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg
can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
[See also DOSAGE AND ADMINISTRATION (2.5)]. The effects of discontinuation of
concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and
9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between oral RISPERDAL® and erythromycin.
7.12 Carbamazepine and Other CYP 3A4 Enzyme Inducers
Carbamazepine co-administration with oral RISPERDAL® decreased the steady-state
plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma
concentrations of carbamazepine did not appear to be affected. Co-administration of other
known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with
risperidone may cause similar decreases in the combined plasma concentrations of
risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of
RISPERDAL® CONSTA® treatment. At the initiation of therapy with carbamazepine or
other known hepatic enzyme inducers, patients should be closely monitored during the first
4-8 weeks, since the dose of RISPERDAL® CONSTA® may need to be adjusted. A dose
increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation of
carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL®
35
CONSTA® should be re-evaluated and, if necessary, decreased. Patients may be placed on a
lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned
discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the
expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For
patients treated with the recommended dose of 25 mg RISPERDAL® CONSTA® and
discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to
continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the
RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL®
CONSTA® treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical
trials. [See also DOSAGE AND ADMINSTRATION (2.5)]
7.13 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® CONSTA® is not expected to substantially inhibit the clearance of drugs that
are metabolized by this enzymatic pathway. In drug interaction studies, oral RISPERDAL® did
not significantly affect the pharmacokinetics of donepezil and galantamine, which are
metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of oral risperidone was studied in three embryofetal development
studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the oral
maximum recommended human dose [MRHD] on a mg/m2 basis) and in one embryofetal
development study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the oral MRHD
on a mg/m2 basis). The incidence of malformations was not increased compared to control in
offspring of rats or rabbits given 0.4 to 6 times the oral MRHD on a mg/m2 basis. In three
reproductive studies in rats (two peri/post-natal development studies and a multigenerational
study), there was an increase in pup deaths during the first 4 days of lactation at doses of
0.16-5 mg/kg or 0.1 to 3 times the oral MRHD on a mg/m2 basis. It is not known whether these
deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one peri/post-natal development
study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the oral
MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus
or pups, as evidenced by a decrease in the number of live pups and an increase in the
number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated
dams were observed. In addition, there was an increase in deaths by Day 1 among pups of
36
drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone
also appeared to impair maternal behavior in that pup body weight gain and survival (from
Days 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated
dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or
3 times the oral MRHD on a mg/m2 basis.
No studies were conducted with RISPERDAL® CONSTA® .
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to oral
RISPERDAL® therapy is unknown. Reversible extrapyramidal symptoms in the neonate
were observed following postmarketing use of risperidone during the last trimester of
pregnancy.
RISPERDAL® CONSTA® should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® CONSTA® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore,
women should not breast-feed during treatment with RISPERDAL® CONSTA® and for at
least 12 weeks after the last injection.
8.4 Pediatric Use
RISPERDAL® CONSTA® has not been studied in children younger than 18 years old.
8.5 Geriatric Use
In an open-label study, 57 clinically stable, elderly patients (≥65 years old) with schizophrenia
or schizoaffective disorder received RISPERDAL® CONSTA® every 2 weeks for up to
12 months. In general, no differences in the tolerability of RISPERDAL® CONSTA® were
observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing
recommendations for otherwise healthy elderly patients are the same as for nonelderly patients.
Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly
patients, elderly patients should be instructed in nonpharmacologic interventions that help to
reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several
minutes before attempting to stand in the morning and slowly rising from a seated position). In
37
addition, monitoring of orthostatic vital signs should be considered in elderly patients for whom
orthostatic hypotension is of concern [see Warnings and Precautions (5.7)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related
Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus oral
risperidone when compared to patients treated with oral risperidone alone or with oral
placebo plus furosemide. No pathological mechanism has been identified to explain this
finding, and no consistent pattern for cause of death was observed. An increase of mortality
in elderly patients with dementia-related psychosis was seen with the use of oral risperidone
regardless of concomitant use with furosemide. RISPERDAL® CONSTA® is not approved
for the treatment of patients with dementia-related psychosis. [See Boxed Warning and
Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® CONSTA® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its
potential for abuse. Because RISPERDAL® CONSTA® is to be administered by health care
professionals, the potential for misuse or abuse by patients is low.
9.3 Dependence
RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its
potential for tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
No cases of overdose were reported in premarketing studies with RISPERDAL®
CONSTA®. Because RISPERDAL® CONSTA® is to be administered by health care
professionals, the potential for overdosage by patients is low.
In premarketing experience with oral RISPERDAL®, there were eight reports of acute
RISPERDAL® overdosage, with estimated doses ranging from 20 to 300 mg and no
fatalities. In general, reported signs and symptoms were those resulting from an
exaggeration of the drug’s known pharmacological effects, i.e., drowsiness and sedation,
tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an
38
estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged
QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was
associated with a seizure.
Postmarketing experience with oral RISPERDAL® includes reports of acute overdose, with
estimated doses of up to 360 mg. In general, the most frequently reported signs and
symptoms are those resulting from an exaggeration of the drug’s known pharmacological
effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms.
Other adverse reactions reported since market introduction related to oral RISPERDAL®
overdose include prolonged QT interval and convulsions. Torsade de pointes has been
reported in association with combined overdose of oral RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate
oxygenation and ventilation. Cardiovascular monitoring should commence immediately and
should include continuous electrocardiographic monitoring to detect possible arrhythmias. If
antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a
theoretical hazard of QT prolonging effects that might be additive to those of risperidone.
Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be
additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to risperidone. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced
alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication
should be administered. Close medical supervision and monitoring should continue until the
patient recovers.
11 DESCRIPTION
Risperidone is a psychotropic agent belonging to the chemical class of benzisoxazole
derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1
piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Its
molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The structural
formula is:
39
Usage Illustration
Risperidone is practically insoluble in water, freely soluble in methylene chloride, and
soluble in methanol and 0.1 N HCl.
RISPERDAL® CONSTA® (risperidone) Long-Acting Injection is a combination of
extended-release microspheres for injection and diluent for parenteral use.
The extended-release microspheres formulation is a white to off-white, free-flowing powder
that is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg risperidone per
vial. Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide (PLG) at a
concentration of 381 mg risperidone per gram of microspheres.
The diluent for parenteral use is a clear, colorless solution. Composition of the diluent
includes polysorbate 20, sodium carboxymethyl cellulose, disodium hydrogen phosphate
dihydrate, citric acid anhydrous, sodium chloride, sodium hydroxide, and water for
injection. The microspheres are suspended in the diluent prior to injection.
RISPERDAL® CONSTA® is provided as a dose pack, consisting of a vial containing the
microspheres, a pre-filled syringe containing the diluent, a SmartSite® Needle-Free Vial
Access Device, and two Needle-Pro® safety needles (a 21 G UTW 1-inch needle with needle
protection device for deltoid administration and a 20 G TW 2-inch needle with needle
protection device for gluteal administration).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL® CONSTA®, as with other drugs used to treat
schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic
activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and
serotonin Type 2 (5HT2) receptor antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to
7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and
H1 histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with
40
lower potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the
serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the
dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at
concentrations >10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® CONSTA® results from the combined
concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone [see Clinical
Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 [see Clinical
Pharmacology (12.1)] may explain some of the other effects of RISPERDAL® CONSTA®.
12.3 Pharmacokinetics
Absorption
After a single intramuscular (gluteal) injection of RISPERDAL® CONSTA®, there is a small
initial release of the drug (< 1% of the dose), followed by a lag time of 3 weeks. The main
release of the drug starts from 3 weeks onward, is maintained from 4 to 6 weeks, and
subsides by 7 weeks following the intramuscular (IM) injection. Therefore, oral
antipsychotic supplementation should be given during the first 3 weeks of treatment with
RISPERDAL® CONSTA® to maintain therapeutic levels until the main release of
risperidone from the injection site has begun [see Dosage and Administration (2)].
Following single doses of RISPERDAL® CONSTA®, the pharmacokinetics of risperidone,
9-hydroxyrisperidone (the major metabolite), and risperidone plus 9-hydroxyrisperidone
were linear in the dosing range of 12.5 mg to 50 mg.
The combination of the release profile and the dosage regimen (IM injections every
2 weeks) of RISPERDAL® CONSTA® results in sustained therapeutic concentrations.
Steady-state plasma concentrations are reached after 4 injections and are maintained for 4 to
6 weeks after the last injection. Following multiple doses of 25 mg and 50 mg
RISPERDAL® CONSTA®, plasma concentrations of risperidone, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone were linear.
Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and,
therefore, interchangeable.
Distribution
Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In
plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein
binding of risperidone is approximately 90%, and that of its major metabolite,
9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each
41
other from plasma binding sites. High therapeutic concentrations of sulfamethazine
(100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight
increase in the free fraction of risperidone at 10 ng/mL and of 9-hydroxyrisperidone at
50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone,
has similar pharmacological activity as risperidone. Consequently, the clinical effect of the
drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians,
have little or no activity and are “poor metabolizers”) and to inhibition by a variety of
substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers
convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers
convert it much more slowly. Although extensive metabolizers have lower risperidone and
higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar
in extensive and poor metabolizers.
The interactions of RISPERDAL® CONSTA® with coadministration of other drugs have not
been systematically evaluated in human subjects. Drug interactions are based primarily on
experience with oral RISPERDAL®. Risperidone could be subject to two kinds of drug-drug
interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to
9-hydroxyrisperidone [see Drug Interactions (7.11)]. This occurs with quinidine, giving
essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers.
The therapeutic benefits and adverse effects of RISPERDAL® in patients receiving
quinidine have not been evaluated, but observations in a modest number (n≅70) of poor
metabolizers given oral RISPERDAL® do not suggest important differences between poor
and extensive metabolizers. Second, co-administration of carbamazepine and other known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with oral RISPERDAL®
cause a decrease in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone [see Drug Interactions (7.12)]. It would also be possible for
risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively
42
weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions
(7.11)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via
the feces. As illustrated by a mass balance study of a single 1 mg oral dose of
14C-risperidone administered as solution to three healthy male volunteers, total recovery of
radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone plus 9-hydroxyrisperidone following RISPERDAL®
CONSTA® administration is 3 to 6 days, and is associated with a monoexponential decline
in plasma concentrations. This half-life of 3-6 days is related to the erosion of the
microspheres and subsequent absorption of risperidone. The clearance of risperidone and
risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP
2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. No
accumulation of risperidone was observed during long-term use (up to 12 months) in
patients treated every 2 weeks with 25 mg or 50 mg RISPERDAL® CONSTA®. The
elimination phase is complete approximately 7 to 8 weeks after the last injection.
Renal Impairment
In patients with moderate to severe renal disease treated with oral RISPERDAL®, clearance
of the sum of risperidone and its active metabolite decreased by 60% compared with young
healthy subjects. Although patients with renal impairment were not studied with
RISPERDAL® CONSTA®, it is recommended that patients with renal impairment be
carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is
initiated at a dose of 25 mg. A lower initial dose of 12. 5 mg may be appropriate when
clinical factors warrant dose adjustment, such as in patients with renal impairment [see
Dosage and Administration (2.4)].
Hepatic Impairment
While the pharmacokinetics of oral RISPERDAL® in subjects with liver disease were
comparable to those in young healthy subjects, the mean free fraction of risperidone in
plasma was increased by about 35% because of the diminished concentration of both
albumin and α1-acid glycoprotein. Although patients with hepatic impairment were not
studied with RISPERDAL® CONSTA®, it is recommended that patients with hepatic
impairment be carefully titrated on oral RISPERDAL® before treatment with RISPERDAL®
CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be
43
appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic
impairment [see Dosage and Administration (2.4)].
Elderly
In an open-label trial, steady-state concentrations of risperidone plus 9-hydroxyrisperidone
in otherwise healthy elderly patients (≥65 years old) treated with RISPERDAL® CONSTA®
for up to 12 months fell within the range of values observed in otherwise healthy nonelderly
patients. Dosing recommendations are the same for otherwise healthy elderly patients and
nonelderly patients [see Dosage and Administration (2)].
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but
a population pharmacokinetic analysis did not identify important differences in the
disposition of risperidone due to gender (whether or not corrected for body weight) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis - Oral
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for
25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the oral maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis, or
0.2, 0.75, and 3 times the oral MRHD (mice) or 0.4, 1.5, and 6 times the oral MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There was a
significant increase in pituitary gland adenomas in female mice at doses 0.75 and 3 times the
oral MRHD on a mg/m2 basis. There was a significant increase in endocrine pancreatic
adenomas in male rats at doses 1.5 and 6 times the oral MRHD on a mg/m2 basis. Mammary
gland adenocarcinomas were significantly increased in female mice at all doses tested
(0.2, 0.75, and 3 times the oral MRHD on a mg/m2 basis), in female rats at all doses tested
(0.4, 1.5, and 6 times the oral MRHD on a mg/m2 basis), and in male rats at a dose 6 times
the oral MRHD on a mg/m2 basis.
Carcinogenesis - Intramuscular
RISPERDAL® CONSTA® was evaluated in a 24-month carcinogenicity study in which
SPF Wistar rats were treated every 2 weeks with intramuscular (IM) injections of either
5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a
mg/m2 basis. A control group received injections of 0.9% NaCl, and a vehicle control group
was injected with placebo microspheres. There was a significant increase in pituitary gland
adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times
44
the IM MRHD on a mg/m2 basis. The incidence of mammary gland adenocarcinomas was
significantly increased in female rats at both doses (1 and 8 times the IM MRHD on a
mg/m2 basis). A significant increase in renal tubular tumors (adenoma, adenocarcinomas)
was observed in male rats at 8 times the IM MRHD on a mg/m2 basis. Plasma exposures
(AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma
exposure (AUC) at the IM MRHD.
Dopamine D2 receptor antagonists have been shown to chronically elevate prolactin levels in
rodents. Serum prolactin levels were not measured during the carcinogenicity studies of oral
risperidone; however, measurements taken during subchronic toxicity studies showed that oral
risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used
in the oral carcinogenicity studies. Serum prolactin levels increased in a dose-dependent
manner up to 6- and 1.5-fold in male and female rats, respectively, at the end of the 24-month
treatment with RISPERDAL® CONSTA® every 2 weeks. Increases in the incidence of
pituitary gland, endocrine pancreas, and mammary gland neoplasms have been found in
rodents after chronic administration of other antipsychotic drugs and may be prolactin-
mediated.
The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents
is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for oral risperidone was found in the in vitro Ames reverse
mutation test, in vitro mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay,
in vivo oral micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the
in vitro chromosomal aberration test in human lymphocytes or in Chinese hamster cells.
In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse
mutation test for RISPERDAL® CONSTA® .
Impairment of Fertility
Oral risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats
in three reproductive studies (two mating and fertility studies and a multigenerational study) at
doses 0.1 to 3 times the oral maximum recommended human dose (MRHD) (16 mg/day) on
a mg/m2 basis. The effect appeared to be in females, since impaired mating behavior was not
noted in the mating and fertility study in which males only were treated. In a subchronic study
in Beagle dogs in which oral risperidone was administered at doses of 0.31 to 5 mg/kg, sperm
motility and concentration were decreased at doses 0.6 to 10 times the oral MRHD on a
mg/m2 basis. Dose-related decreases were also noted in serum testosterone at the same doses.
45
Serum testosterone and sperm values partially recovered, but remained decreased after
treatment was discontinued. No no-effect doses were noted in either rat or dog.
No mating and fertility studies were conducted with RISPERDAL® CONSTA® .
14 CLINICAL STUDIES
14.1 Schizophrenia
The effectiveness of RISPERDAL® CONSTA® in the treatment of schizophrenia was
established, in part, on the basis of extrapolation from the established effectiveness of the
oral formulation of risperidone. In addition, the effectiveness of RISPERDAL® CONSTA®
in the treatment of schizophrenia was established in a 12-week, placebo-controlled trial in
adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia.
Efficacy data were obtained from 400 patients with schizophrenia who were randomized to
receive injections of 25 mg, 50 mg, or 75 mg RISPERDAL® CONSTA® or placebo every
2 weeks. During a 1-week run-in period, patients were discontinued from other
antipsychotics and were titrated to a dose of 4 mg oral RISPERDAL®. Patients who received
RISPERDAL® CONSTA® were given doses of oral RISPERDAL® (2 mg for patients in the
25-mg group, 4 mg for patients in the 50-mg group, and 6 mg for patients in the 75-mg
group) for the 3 weeks after the first injection to provide therapeutic plasma concentrations
until the main release phase of risperidone from the injection site had begun. Patients who
received placebo injections were given placebo tablets.
Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a
validated, multi-item inventory, composed of five subscales to evaluate positive symptoms,
negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and
anxiety/depression.
The primary efficacy variable in this trial was change from baseline to endpoint in the total
PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this
study was 81.5.
Total PANSS scores showed significant improvement in the change from baseline to
endpoint in schizophrenic patients treated with each dose of RISPERDAL® CONSTA®
(25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there were no
statistically significant differences between the treatment effects for the three dose groups,
the effect size for the 75 mg dose group was actually numerically less than that observed for
the 50 mg dose group.
46
Subgroup analyses did not indicate any differences in treatment outcome as a function of
age, race, or gender.
14.2 Bipolar Disorder - Monotherapy
The effectiveness of RISPERDAL® CONSTA® for the maintenance treatment of Bipolar I
Disorder was established in a multicenter, double-blind, placebo-controlled study of adult
patients who met DSM-IV criteria for Bipolar Disorder Type I, who were stable on
medications or experiencing an acute manic or mixed episode.
A total of 501 patients were treated during a 26-week open-label period with RISPERDAL®
CONSTA® (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg
or 50 mg; in patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg).
In the open-label phase, 303 (60%) patients were judged to be stable and were randomized
to double-blind treatment with either the same dose of RISPERDAL® CONSTA® or placebo
and monitored for relapse. The primary endpoint was time to relapse to any mood episode
(depression, mania, hypomania, or mixed).
Time to relapse was delayed in patients receiving RISPERDAL® CONSTA® monotherapy
as compared to placebo. The majority of relapses were due to manic rather than depressive
symptoms. Based on their bipolar disorder history, subjects entering this study had had, on
average, more manic episodes than depressive episodes.
14.3 Bipolar Disorder - Adjunctive Therapy
The effectiveness of RISPERDAL® CONSTA® as an adjunct to treatment with lithium or
valproate for the maintenance treatment of Bipolar Disorder was established in a multi
center, randomized, double-blind, placebo-controlled study of adult patients who met DSM
IV criteria for Bipolar Disorder Type I and who experienced at least 4 episodes of mood
disorder requiring psychiatric/clinical intervention in the previous 12 months, including at
least 2 episodes in the 6 months prior to the start of the study.
A total of 240 patients were treated during a 16-week open-label period with RISPERDAL®
CONSTA® (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg
or 50 mg), as adjunctive therapy in addition to continuing their treatment as usual for their
bipolar disorder, which consisted of mood stabilizers (primarily lithium and valproate),
antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first
three weeks of the initial RISPERDAL® CONSTA® injection. In the open-label phase, 124
(51.7%) were judged to be stable for at least the last 4 weeks and were randomized to
double-blind treatment with either the same dose of RISPERDAL® CONSTA® or placebo in
47
addition to continuing their treatment as usual and monitored for relapse during a 52-week
period. The primary endpoint was time to relapse to any new mood episode (depression,
mania, hypomania, or mixed).
Time to relapse was delayed in patients receiving adjunctive therapy with RISPERDAL®
CONSTA® as compared to placebo. The relapse types were about half depressive and half
manic or mixed episodes.
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® CONSTA® (risperidone) is available in dosage strengths of 12.5 mg, 25 mg,
37.5 mg, or 50 mg risperidone. It is provided as a dose pack, consisting of a vial containing
the risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for
RISPERDAL® CONSTA®, a SmartSite® Needle-Free Vial Access Device, and two Needle-
Pro® safety needles for intramuscular injection (a 21 G UTW 1-inch needle with needle
protection device for deltoid administration and a 20 G TW 2-inch needle with needle
protection device for gluteal administration).
12.5-mg vial/kit (NDC 50458-309-11): 41 mg (equivalent to 12.5 mg of risperidone) of a
white to off-white powder provided in a vial with a violet flip-off cap (NDC 50458-309-01).
25-mg vial/kit (NDC 50458-306-11): 78 mg (equivalent to 25 mg of risperidone) of a white
to off-white powder provided in a vial with a pink flip-off cap (NDC 50458-306-01).
37.5-mg vial/kit (NDC 50458-307-11): 116 mg (equivalent to 37.5 mg of risperidone) of a
white to off-white powder provided in a vial with a green flip-off cap (NDC 50458-307-01).
50-mg vial/kit (NDC 50458-308-11): 152 mg (equivalent to 50 mg of risperidone) of a white
to off-white powder provided in a vial with a blue flip-off cap (NDC 50458-308-01).
Storage and Handling
The entire dose pack should be stored in the refrigerator (36°- 46°F; 2°- 8°C) and protected
from light.
If refrigeration is unavailable, RISPERDAL® CONSTA® can be stored at temperatures not
exceeding 77°F (25°C) for no more than 7 days prior to administration. Do not expose
unrefrigerated product to temperatures above 77°F (25°C).
Keep out of reach of children.
48
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL® CONSTA® .
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension and instructed in
nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension
(e.g., sitting on the edge of the bed for several minutes before attempting to stand in the
morning and slowly rising from a seated position) [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Because RISPERDAL® CONSTA® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that treatment with RISPERDAL® CONSTA®
does not affect them adversely [see Warnings and Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy and for at least 12 weeks after the last injection of
RISPERDAL® CONSTA® [see Use in Specific Populations (8.1)].
17.4 Nursing
Patients should be advised not to breast-feed an infant during treatment and for at least
12 weeks after the last injection of RISPERDAL® CONSTA® [see Use in Specific
Populations (8.2)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol during treatment with RISPERDAL® CONSTA®
[see Drug Interactions (7.1)].
Revised June 2009
©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
49
10130503
Risperidone is manufactured by:
Janssen Pharmaceutical Ltd.
Wallingstown, Little Island, County Cork, Ireland
Microspheres are manufactured by:
Alkermes, Inc.
Wilmington, Ohio
Diluent is manufactured by:
Vetter Pharma Fertigung GmbH & Co. KG
Ravensburg or Langenargen, Germany
or
Cilag AG
Schaffhausen, Switzerland
or
Ortho Biotech Products, L.P.
Raritan, NJ
RISPERDAL® CONSTA® is manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
50
|
custom-source
|
2025-02-12T13:47:19.306374
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020272s056,020588s044,021346s033,021444s03lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 56}
|
12,405
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. RISPERDAL® is
not approved for use in patients with dementia-related psychosis. (5.1)
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophreni
a- adults
(2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophreni
a –
adolescents
(2.1)
0.5mg
/day
0.5- 1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar
mania –
adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar
mania in
children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder
(2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with
antipsychotics, including RISPERDAL®. Patients with a history of a
clinically significant low white blood cell count (WBC) or a drug-
induced leukopenia/neutropenia should have their complete blood count
(CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign
of a clinically significant decline in WBC in the absence of other
causative factors. (5.8)
• Potential for cognitive and motor impairment (5.9)
• Seizures (5.10)
• Dysphagia (5.11)
• Priapism (5.12)
• Thrombotic Thrombocytopenic Purpura (TTP) (5.13)
• Disruption of body temperature regulation (5.14)
• Antiemetic Effect (5.15)
• Suicide (5.16)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.17)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.17)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism,
akathisia, vomiting, cough, constipation, nasopharyngitis, drooling,
rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety,
headache, nasal congestion, rhinitis, tremor, and rash. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were nausea, somnolence, sedation, vomiting, dizziness,
and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800
JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower initial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 07/2011
1
Reference ID: 3004972
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
6.9
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
7.2
Drugs with Hypotensive Effects
WITH DEMENTIA-RELATED PSYCHOSIS
7.3
Levodopa and Dopamine Agonists
1
INDICATIONS AND USAGE
7.4
Amitriptyline
1.1
Schizophrenia
7.5
Cimetidine and Ranitidine
1.2
Bipolar Mania
7.6
Clozapine
1.3
Irritability Associated with Autistic Disorder
7.7
Lithium
2
DOSAGE AND ADMINISTRATION
7.8
Valproate
2.1
Schizophrenia
7.9
Digoxin
2.2
Bipolar Mania
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
2.3
Irritability Associated with Autistic Disorder –
Isozymes
Pediatrics (Children and Adolescents)
7.11
Carbamazepine and Other Enzyme Inducers
2.4
Dosage in Special Populations
7.12
Drugs Metabolized by CYP 2D6
2.5
Co-Administration of RISPERDAL® with Certain
8
USE IN SPECIFIC POPULATIONS
Other Medications
8.1
Pregnancy
8.2
r
2.6
Administration of RISPERDAL
® Oral Solution
Labor and Delive y
2.7
Directions for Use of RISPERDAL
® M-
8.3
Nursing Mothers
TAB
® Orally Disintegrating Tablets
8.4
Pediatric Use
3
DOSAGE FORMS AND STRENGTHS
8.5
Geriatric Use
4
CONTRAINDICATIONS
9
DRUG ABUSE AND DEPENDENCE
5
WARNINGS AND PRECAUTIONS
9.1
Controlled Substance
5.1
Increased Mortality in Elderly Patients with
9.2
Abuse
Dementia-Related Psychosis
9.3
Dependence
5.2
Cerebrovascular Adverse Events, Including
10
OVERDOSAGE
Stroke, in Elderly Patients with Dementia-
10.1
Human Experience
Related Psychosis
10.2
Management of Overdosage
5.3
Neuroleptic Malignant Syndrome (NMS)
11
DESCRIPTION
5.4
Tardive Dyskinesia
12
CLINICAL PHARMACOLOGY
5.5
Hyperglycemia and Diabetes Mellitus
12.1
Mechanism of Action
5.6
Hyperprolactinemia
12.2
Pharmacodynamics
5.7
Orthostatic Hypotension
12.3
Pharmacokinetics
5.8
Leukopenia, Neutropenia, and Agranulocytosis
13
NONCLINICAL TOXICOLOGY
5.9
Potential for Cognitive and Motor Impairment
13.1
Carcinogenesis, Mutagenesis, Impairment of
5.10
Seizures
Fertility
5.11
Dysphagia
14
CLINICAL STUDIES
5.12
Priapism
14.1
Schizophrenia
5.13
Thrombotic Thrombocytopenic Purpura (TTP)
14.2
Bipolar Mania - Monotherapy
5.14
Body Temperature Regulation
14.3
Bipolar Mania – Combination Therapy
5.15
Antiemetic Effect
14.4
Irritability Associated with Autistic Disorder
5.16
Suicide
16
HOW SUPPLIED/STORAGE AND HANDLING
5.17
Use in Patients with Concomitant Illness
Storage and Handling
5.18
Monitoring: Laboratory Tests
17
PATIENT COUNSELING INFORMATION
6
ADVERSE REACTIONS
17.1
Orthostatic Hypotension
6.1
Commonly-Observed Adverse Reactions in
17.2
Interference with Cognitive and Motor
Double-Blind, Placebo-Controlled Clinical Trials
Performance
- Schizophrenia
17.3
Pregnancy
6.2
Commonly-Observed Adverse Reactions in
17.4
Nursing
Double-Blind, Placebo-Controlled Clinical Trials
17.5
Concomitant Medication
– Bipolar Mania
17.6
Alcohol
6.3
Commonly-Observed Adverse Reactions in
17.7
Phenylketonurics
Double-Blind, Placebo-Controlled Clinical Trials
- Autistic Disorder
6.4
Other Adverse Reactions Observed During the
*Sections or subsections omitted from the full prescribing information are not
Clinical Trial Evaluation of Risperidone
listed
6.5
Discontinuations Due to Adverse Reactions
6.6
Dose Dependency of Adverse Reactions in
Clinical Trials
6.7
Changes in Body Weight
6.8
Changes in ECG
Reference ID: 3004972
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: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which the findings
of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. RISPERDAL®
(risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
Reference ID: 3004972
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of
1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower
titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see
Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not
demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal
symptoms and other adverse effects, and are generally not recommended. In a single study
supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for
4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Reference ID: 3004972
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above
2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Reference ID: 3004972
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
Reference ID: 3004972
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.17)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.10)].
Reference ID: 3004972
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
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RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square),
3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. RISPERDAL® (risperidone) is not approved for the treatment of
dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
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The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics
including RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus
in the general population. Given these confounders, the relationship between atypical
antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL®, should be monitored regularly for worsening of
glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history
of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL® ,
should undergo fasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL® ,
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing. In some
cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL® ,
was discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of RISPERDAL® .
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
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impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
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complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9)].
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a
large, open premarketing experience (approximately 1300 patients). She experienced jaundice,
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For current labeling information, please visit https://www.fda.gov/drugsatfda
fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.16 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.17 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.18 Monitoring: Laboratory Tests
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No specific laboratory tests are recommended.
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
• Antiemetic effect [see Warnings and Precautions (5.15)]
• Suicide [see Warnings and Precautions (5.16)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.17)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.17)]
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The most common adverse reactions in clinical trials (≥ 10%) were somnolence, increased
appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation,
nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea,
anxiety, headache, nasal congestion, rhinitis, tremor, and rash.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea,
somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions (6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
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6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
2-8 mg per day >8-16 mg per day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Blood and Lymphatic System
Disorders
Anemia
<1
1
0
Cardiac Disorders
Tachycardia
1
3
0
Ear and Labyrinth Disorders
Ear pain
<1
1
0
Eye Disorders
Vision blurred
3
1
1
Gastrointestinal Disorders
Nausea
9
4
4
Constipation
8
9
6
Dyspepsia
8
6
5
Vomiting
7
5
7
Dry mouth
4
0
1
Abdominal discomfort
3
1
1
Salivary hypersecretion
2
1
<1
Diarrhea
2
1
1
Abdominal pain
1
1
0
Abdominal pain upper
1
1
0
Stomach discomfort
1
1
1
General Disorders
Fatigue
3
1
0
Chest pain
2
2
1
Asthenia
2
1
<1
Immune System Disorders
Hypersensitivity
<1
1
0
Infections and Infestations
Nasopharyngitis
3
4
3
Upper respiratory tract infection
2
3
1
Sinusitis
1
2
1
Urinary tract infection
1
3
0
Investigations
Weight increased
1
1
0
Blood creatine phosphokinase
1
2
<1
increased
Heart rate increased
<1
2
0
Metabolism and Nutrition Disorders
Decreased appetite
1
0
<1
Musculoskeletal and Connective
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Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
2-8 mg per day >8-16 mg per day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Tissue Disorders
Back pain
4
1
1
Arthralgia
2
3
<1
Pain in extremity
2
1
1
Joint stiffness
1
1
0
Nervous System Disorders
Parkinsonism*
14
17
8
Akathisia*
10
10
3
Dizziness
7
4
2
Somnolence
7
2
1
Dystonia*
3
4
2
Sedation
3
3
1
Tremor*
2
3
1
Dizziness postural
2
0
0
Dyskinesia*
1
2
2
Syncope
1
1
0
Psychiatric Disorders
Insomnia
32
25
27
Anxiety
16
11
11
Nervousness
1
1
<1
Renal and Urinary Disorders
Urinary incontinence
1
1
0
Reproductive System and Breast
Disorders
Ejaculation failure
<1
1
0
Respiratory, Thoracic and
Mediastinal Disorders
Nasal congestion
4
6
2
Dyspnea
1
2
0
Epistaxis
<1
2
0
Skin and Subcutaneous Tissue
Disorders
Rash
1
4
1
Dry skin
1
3
0
Dandruff
1
1
0
Seborrheic dermatitis
<1
1
0
Hyperkeratosis
0
1
1
Vascular Disorders
Orthostatic hypotension
2
1
0
Hypotension
1
1
0
* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism,
cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity,
and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia
includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture,
oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis.
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Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
1-3 mg per day 4-6 mg per day
Placebo
Adverse Reaction
(N=55)
(N=51)
(N=54)
Gastrointestinal Disorders
Salivary hypersecretion
0
10
2
Nervous System Disorders
Parkinsonism*
16
28
11
Sedation
13
8
2
Somnolence
11
4
2
Tremor
11
10
6
Akathisia*
9
10
4
Dizziness
7
14
2
Dystonia*
2
6
0
Psychiatric Disorders
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, muscle
rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and
restlessness. Dystonia includes dystonia and oculogyration.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
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Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult
Patients with Bipolar Mania in Double-Blind, Placebo-
Controlled Monotherapy Trials
Percentage of Patients Reporting Event
System/Organ Class
RISPERDAL®
Placebo
Adverse Reaction
1-6 mg per day
(N=424)
(N=448)
Cardiac Disorders
Tachycardia
1
<1
Eye Disorders
Vision blurred
2
1
Gastrointestinal Disorders
Nausea
5
2
Diarrhea
3
2
Salivary hypersecretion
3
1
Dyspepsia
2
2
Stomach discomfort
2
<1
General Disorders
Fatigue
2
1
Asthenia
1
1
Pyrexia
1
1
Infections and Infestations
Nasopharyngitis
1
1
Investigations
Aspartate aminotransferase increased
1
<1
Nervous System Disorders
Parkinsonism*
25
9
Akathisia*
9
3
Tremor*
6
3
Dizziness
6
5
Sedation
6
2
Somnolence
5
2
Dystonia*
5
1
Lethargy
2
1
Dyskinesia*
1
<1
Reproductive System and Breast
Disorders
Galactorrhea
1
0
Skin and Subcutaneous Tissue
Disorders
Acne
1
0
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal
stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel
rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and
parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration,
torticollis. Dyskinesia includes muscle twitching and dyskinesia.
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Percentage of Patients Reporting Event
RISPERDAL® + Mood
Placebo +
System/Organ Class
Stabilizer
Mood Stabilizer
Adverse Reaction
(N=127)
(N=126)
Cardiac Disorders
Palpitations
2
0
Gastrointestinal Disorders
Dyspepsia
9
8
Nausea
6
4
Diarrhea
6
4
Dry mouth
4
4
Vomiting
4
6
Constipation
3
3
Salivary hypersecretion
2
0
General Disorders
Chest pain
2
1
Fatigue
2
2
Infections and Infestations
Nasopharyngitis
2
3
Urinary tract infection
2
1
Investigations
Weight increased
2
2
Nervous System Disorders
Parkinsonism*
14
4
Headache
14
15
Akathisia*
8
0
Dizziness
7
2
Sedation
6
3
Tremor
6
2
Somnolence
3
1
Lethargy
2
1
Psychiatric Disorders
Insomnia
4
8
Anxiety
3
2
Respiratory, Thoracic and
Mediastinal Disorders
Pharyngolaryngeal pain
5
2
Cough
2
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia.
Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients
with Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
RISPERDAL ®
System/Organ Class
0.5-2.5 mg per 3-6 mg per Placebo
Adverse Reaction
day
day
(N=58)
(N=50)
(N=61)
Eye Disorders
Vision blurred
4
7
0
Gastrointestinal Disorders
Abdominal pain upper
16
13
5
Nausea
16
13
7
Vomiting
10
10
5
Diarrhea
8
7
2
Dyspepsia
10
3
2
Stomach discomfort
6
0
2
General Disorders
Fatigue
18
30
3
Metabolism and Nutrition Disorders
Increased appetite
4
7
2
Nervous System Disorders
Somnolence
22
30
12
Sedation
20
23
7
Dizziness
16
13
5
Parkinsonism*
6
12
3
Dystonia*
6
5
0
Akathisia*
0
8
2
Psychiatric Disorders
Anxiety
0
8
3
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain
10
3
5
Skin and Subcutaneous Tissue Disorders
Rash
0
7
2
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity.
Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric
Patients Treated for Irritability Associated with Autistic
Disorder in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
System/Organ Class
RISPERDAL®
Placebo
Adverse Reaction
0.5-4.0 mg per day
(N=80)
(N=76)
Cardiac Disorders
Tachycardia
5
0
Gastrointestinal Disorders
Vomiting
25
21
Constipation
21
8
Dry mouth
15
6
Salivary hypersecretion
9
0
Nausea
8
6
General Disorders
Fatigue
42
13
Feeling abnormal
5
0
Infections and Infestations
Nasopharyngitis
21
10
Rhinitis
13
10
Upper respiratory tract infection
8
3
Investigations
Weight increased
5
0
Metabolism and Nutrition Disorders
Increased appetite
47
19
Nervous System Disorders
Somnolence
49
18
Sedation
29
3
Drooling
16
5
Tremor
12
1
Parkinsonism*
11
1
Dizziness
9
3
Dyskinesia
7
3
Lethargy
5
3
Respiratory, Thoracic and
Mediastinal Disorders
Cough
24
18
Rhinorrhea
16
13
Nasal congestion
13
5
Skin and Subcutaneous Tissue
Disorders
Rash
11
8
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder,
muscle rigidity, cogwheel rigidity, and muscle tightness.
Reference ID: 3004972
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In another study with patients treated for irritability associated with autistic disorder, headache
(6%), epistaxis (6%) and pyrexia (6%) were also observed in RISPERDAL®-treated pediatric
subjects.
6.4 Other Adverse Reactions Observed During the Clinical Trial Evaluation of
Risperidone
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder,
and studies in elderly patients with dementia.
Blood and Lymphatic System Disorders: granulocytopenia, neutropenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree,
bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye
swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual
acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling,
cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting
edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort,
generalized edema, drug withdrawal syndrome, peripheral coldness
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis,
tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media,
onychomycosis,
acarodermatitis,
bronchopneumonia,
respiratory
tract
infection,
tracheobronchitis, otitis media chronic
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Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase
increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count
decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body
temperature decreased, blood pressure decreased, transaminases increased
Metabolism and Nutrition Disorders: polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest
pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria,
unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia,
transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss
of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder,
neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep
disorder, listlessness, libido decreased, anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea,
gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation,
ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus
congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion,
rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus,
skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular
Vascular Disorders: flushing
Additional Adverse Reactions Reported with RISPERDAL® CONSTA®
The following is a list of additional adverse reactions that have been reported during the
premarketing evaluation of RISPERDAL® CONSTA®, regardless of frequency of occurrence:
Cardiac Disorders: bradycardia
Ear and Labyrinth Disorders: vertigo
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Eye Disorders: blepharospasm
Gastrointestinal Disorders: toothache, tongue spasm
General Disorders and Administration Site Conditions: pain
Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis,
subcutaneous abscess
Injury and Poisoning: fall
Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme
increased
Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain
Nervous System Disorders: convulsion, paresthesia
Psychiatric Disorders: depression
Skin and Subcutaneous Tissue Disorders: eczema
Vascular Disorders: hypertension
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®
Treated Adult Patients in Schizophrenia Trials
RISPERDAL®
2-8 mg/day
>8-16 mg/day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Vomiting
0.8%
0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0%
0%
Dystonia
0.5%
0%
0%
Agitation
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Orthostatic hypotension
0.3%
0.5%
0%
Akathisia
0.3%
2.0%
0%
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Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54)
placebo-treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy
(1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
Table 8. Adverse Reactions Associated With Discontinuation in 2 or
More RISPERDAL®-Treated Adult Patients in Bipolar Mania
Clinical Trials
RISPERDAL®
1-6 mg/day
Placebo
Adverse Reaction
(N=448)
(N=424)
Parkinsonism
0.4%
0%
Lethargy
0.2%
0%
Dizziness
0.2%
0%
Alanine aminotransferase
0.2%
0.2%
increased
Aspartate aminotransferase
0.2%
0.2%
increased
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
Reference ID: 3004972
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adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
RISPERDAL®
2 mg
RISPERDAL®
6 mg
RISPERDAL®
10 mg
RISPERDAL®
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
17%
21%
21%
35%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
Dose Groups
RISPERDAL®
RISPERDAL®
RISPERDAL
RISPERDAL®
RISPERDAL®
1 mg
4 mg
® 8 mg
12 mg
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
17%
18%
20%
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing
difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur
at low doses, they occur more frequently and with greater severity with high potency and at
higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is
observed in males and younger age groups.
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
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palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
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The following adverse reactions have been identified during postapproval use of risperidone;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction,
angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased,
diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug
withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate
antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT
prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water
intoxication.
Other adverse events reported since market introduction, which were temporally related to
risperidone but not necessarily causally related, include the following: pituitary adenoma,
pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
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7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers
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Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
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Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown.
Non-Teratogenic Effects
Neonates exposed to antipsychotic drugs (including RISPERDAL®) during the third trimester of
pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There
have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress,
and feeding disorder in these neonates. These complications have varied in severity; while in
some cases symptoms have been self-limited, in other cases neonates have required intensive
care unit support and prolonged hospitalization.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
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Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than 1200
pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar
mania who were of similar age and weight, and who received similar dosages of RISPERDAL®
as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In 103
adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of
RISPERDAL® treatment. The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55
and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
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group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5
mg/kg/day. Decreased bone length and density were seen, with a no-effect dose of 0.31
mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its active metabolite
paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents
receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in
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sexual maturation was seen at all doses in both males and females. The above effects showed
little or no reversibility in females after a 12 week drug-free recovery period.
In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a
reversible impairment of performance in a test of learning and memory was seen, in females
only, with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma levels (AUC) of
risperidone plus paliperidone about half those observed in humans at the MRHD. No other
consistent effects on neurobehavioral or reproductive development were seen up to the highest
testable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus
paliperidone which were about two thirds of those observed in humans at the MRHD.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated in children and adolescents.
8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
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concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
interval and convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
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In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is: structural formula
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Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB®
Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin,
gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
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The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL® .
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
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Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)].
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile
typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
patients receiving quinidine have not been evaluated, but observations in a modest number
(n≅70) of poor metabolizers given RISPERDAL® do not suggest important differences between
poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g.,
carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
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metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.17)].
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.17)].
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
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0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Highest No-
Effect Level
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
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testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
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(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The
most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this open-
label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of
1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as ≥
25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much
improved’) during the 4-6 month open-label treatment phase for about 140 days, on average,
were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either
“Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, bottles of 500 NDC
50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01.
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, bottles of 500 NDC
50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01.
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, bottles of 500 NDC
50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06 and hospital unit dose
blister packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M
TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature 15°
25°C (59°-77°F). Protect from light and freezing.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
Reference ID: 3004972
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For current labeling information, please visit https://www.fda.gov/drugsatfda
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Reference ID: 3004972
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised July 2011
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and
RISPERDAL® Oral Solution are manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Reference ID: 3004972
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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|
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1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, for oral use
RISPERDAL® (risperidone) oral solution
RISPERDAL® M-TAB® (risperidone) orally disintegrating tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
•Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death.
•RISPERDAL® is not approved for use in patients with dementia-related
psychosis. (5.1)
----------------------------RECENT MAJOR CHANGES--------------------------
Warnings and Precautions, Metabolic Changes (5.5) September 2011
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic indicated for:
Treatment of schizophrenia (1.1)
As monotherapy or adjunctive therapy with lithium or valproate, for the
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder (1.2)
Treatment of irritability associated with autistic disorder (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Recommended daily dosage:
Initial Dose
Target Dose
Effective Dose
Range
Schizophrenia:
adults (2.1)
2 mg
4 to 8 mg
4 to 16 mg
Schizophrenia:
adolescents
(2.1)
0.5 mg
3 mg
1 to 6 mg
Bipolar mania:
Adults (2.2)
2 to 3 mg
1 to 6 mg
1 to 6 mg
Bipolar mania: in
children and
adolescents
(2.2)
0.5 mg
1 to 2.5 mg
1 to 6 mg
Irritability
associated with
autistic disorder
(2.3)
0.25 mg
(Weight < 20
kg)
0.5 mg
(Weight 20
kg)
0.5 mg
(<20 kg)
1 mg
(20 kg)
0.5 to 3 mg
Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of
0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at
intervals of at least one week. (2.4)
Oral Solution: Can be administered directly from calibrated pipette or
mixed with beverage (water, coffee, orange juice, or low-fat milk. (2.6)
M-TAB Orally Disintegrating Tablets: Open the blister only when ready to
administer, and immediately place tablet under tongue. Can be swallowed
with or without liquid. (2.7)
--------------------DOSAGE FORMS AND STRENGTHS----------------------
Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
Oral solution: 1 mg per mL (3)
Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
Known hypersensitivity to RISPERDAL® (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis: RISPERDAL® is not approved for use in patients with
dementia-related psychosis. (5.2)
Neuroleptic Malignant Syndrome: Manage with immediate discontinuation
of RISPERDAL® and close monitoring. (5.3)
Tardive dyskinesia: Consider discontinuing RISPERDAL® if clinically
indicated. (5.4)
Metabolic Changes: Atypical antipsychotic drugs have been associated
with
metabolic
changes
that
may
increase
cardiovascular/
cerebrovascular risk. These metabolic changes include hyperglycemia,
dyslipidemia, and weight gain. (5.5)
o Hyperglycemia and Diabetes Mellitus: Monitor patients for
symptoms
of
hyperglycemia
including
polydipsia,
polyuria,
polyphagia, and weakness. Monitor glucose regularly in patients with
diabetes or at risk for diabetes. (5.5)
o Dyslipidemia: Undesirable alterations have been observed in patients
treated with atypical antipsychotics. (5.5)
o Weight Gain: Significant weight gain has been reported. Monitor
weight gain. (5.5)
Hyperprolactinemia: Prolactin elevations occur and persist during chronic
administration. (5.6)
Orthostatic hypotension: For patients at risk, consider a lower starting dose
and slower titration. (5.7)
Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood
counts in patients with a history of clinically significant low white blood
cell count (WBC). Consider discontinuing RISPERDAL if a clinically
significant decline in WBC occurs in the absence of other causative
factors. (5.8)
Potential for cognitive and motor impairment: Use caution when operating
machinery. (5.9)
Seizures: Use cautiously in patients with a history of seizures or with
conditions that lower the seizure threshold. (5.10)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (>5% and twice placebo)
were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety,
blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort,
dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth,
increased appetite, increased weight, fatigue, rash, nasal congestion, upper
respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen
Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-
800-FDA-1088 or www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. Increase the RISPERDAL® dose up to double the patient’s
usual dose. Titrate slowly. (7.1)
Fluoxetine, paroxetine, and other CYP 2D6 enzyme inhibitors increase
plasma concentrations of risperidone. Reduce the initial dose. Do not
exceed a final dose of 8 mg per day of RISPERDAL®. (7.1)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Nursing Mothers: Discontinue drug or nursing, taking into consideration
the importance of drug to the mother. (8.3)
See 17 for PATIENT COUNSELING INFORMATION
Revised: MM/YYYY
Reference ID: 3168771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
1
INDICATIONS AND USAGE
1.1
Schizophrenia
1.2
Bipolar Mania
1.3
Irritability Associated with Autistic Disorder
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
2.2
Bipolar Mania
2.3
Irritability Associated with Autistic Disorder –
Pediatrics (Children and Adolescents)
2.4
Dosing in Patients with Severe Renal or Hepatic
Impairment
2.5
Dose Adjustments for Specific Drug Interactions
2.6
Administration of RISPERDAL
® Oral Solution
2.7
Directions for Use of RISPERDAL
® M-TAB
®
Orally Disintegrating Tablets
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Increased Mortality in Elderly Patients with
Dementia-Related Psychosis
5.2
Cerebrovascular Adverse Reactions, Including
Stroke, in Elderly Patients with Dementia-
Related Psychosis
5.3
Neuroleptic Malignant Syndrome
5.4
Tardive Dyskinesia
5.5
Metabolic Changes
5.6
Hyperprolactinemia
5.7
Orthostatic Hypotension
5.8
Leukopenia, Neutropenia, and Agranulocytosis
5.9
Potential for Cognitive and Motor Impairment
5.10
Seizures
5.11
Dysphagia
5.12
Priapism
5.13
Body Temperature Regulation
5.14
Patients with Phenylketonuria
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Pharmacokinetic-related Interactions
7.2
Pharmacodynamic-related Interactions
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
8.8
Patients with Parkinson’s Disease or Lewy Body
Dementia
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10
OVERDOSAGE
10.1
Human Experience
10.2
Management of 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
13.2
Animal Toxicology
14
CLINICAL STUDIES
14.1
Schizophrenia
14.2
Bipolar Mania - Monotherapy
14.3
Bipolar Mania – Adjunctive Therapy with Lithium
or Valproate
14.4
Irritability Associated with Autistic Disorder
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17
PATIENT COUNSELING INFORMATION
17.1
Orthostatic Hypotension
17.2
Interference with Cognitive and Motor
Performance
17.3
Pregnancy
17.4
Nursing
17.5
Concomitant Medication
17.6
Alcohol
17.7
Phenylketonurics
17.8
Metabolic Changes
17.9
Tardive Dyskinesia
*Sections or subsections omitted from the full prescribing information are not
listed
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FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. RISPERDAL (risperidone) is not approved for the treatment of
patients with dementia-related psychosis. [See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
RISPERDAL (risperidone) is indicated for the treatment of schizophrenia. Efficacy was
established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years),
and one long-term maintenance trial in adults [see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy
RISPERDAL is indicated for the treatment of acute manic or mixed episodes associated with
Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term
trial in children and adolescents (ages 10 to 17 years) [see Clinical Studies (14.2)].
Adjunctive Therapy
RISPERDAL adjunctive therapy with lithium or valproate is indicated for the treatment of
acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in
one short-term trial in adults [see Clinical Studies (14.3)].
1.3 Irritability Associated with Autistic Disorder
RISPERDAL is indicated for the treatment of irritability associated with autistic disorder,
including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums,
and quickly changing moods. Efficacy was established in 3 short-term trials in children and
adolescents (ages 5 to 17 years) [see Clinical Studies (14.4)].
2
DOSAGE AND ADMINISTRATION
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Table 1. Recommended Daily Dosage by Indication
Initial Dose
Titration
(Increments)
Target Dose
Effective Dose
Range
Schizophrenia: adults
(2.1)
2 mg
1 to 2 mg
4 to 8 mg
4 to 16 mg
Schizophrenia:
adolescents
(2.2
0.5 mg
0.5 to 1 mg
3 mg
1 to 6 mg
Bipolar mania: adults
(2.2)
2 to 3 mg
1mg
1 to 6mg
1 to 6 mg
Bipolar mania:
children and
adolescents
(2.2)
0.5 mg
0.5 to 1mg
1 to 2.5 mg
1 to 6 mg
Irritability in autistic
disorder (2.3)
0.25 mg
Can increase to
0.5 mg by Day 4:
(body weight less
than 20 kg)
0.5 mg
Can increase to
1 mg by Day 4:
(body weight
greater than or
equal to 20 kg)
After Day 4, at
intervals of > 2
weeks:
0.25 mg
(body weight less
than 20 kg)
0.5 mg
(body weight
greater than or
equal to 20 kg)
0.5 mg:
(body weight less
than 20 kg)
1 mg:
(body weight
greater than or
equal to 20 kg)
0.5 to 3 mg
Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily.
May increase to dosages above 1.5 mg twice daily at intervals of at one week or longer
2.1 Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is 2 mg per day. May
increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as
tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be
appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per. However, doses
above 6 mg per day for twice daily dosing were not demonstrated to be more efficacious than
lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and
are generally not recommended. In a single study supporting once-daily dosing, the efficacy
results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day
has not been evaluated in clinical trials [see Clinical Studies (14.1)].
Adolescents
The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or
evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or
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5
1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been
demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg
per day, no additional benefit was observed above 3 mg per day, and higher doses were
associated with more adverse events. Doses higher than 6 mg per day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL 2 mg per day to 8 mg per day at delaying relapse was
demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4
weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Both
adult and adolescent patients who respond acutely should generally be maintained on their
effective dose beyond the acute episode. Patients should be periodically reassessed to determine
the need for maintenance treatment.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL, or treating patients with concomitant
antipsychotics.
2.2 Bipolar Mania
Usual Dose
Adults
The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours
or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as
studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic
efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day [see Clinical
Studies (14.2, 14.3)]. RISPERDAL doses higher than 6 mg per day were not studied.
Pediatrics
The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or
evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or
1 mg per day, as tolerated, to the recommended target dose of 1mg to 2.5 mg per day. Although
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efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses
between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and
higher doses were associated with more adverse events. Doses higher than 6 mg per day have not
been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The dosage of RISPERDAL should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients
with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a
minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day
for patients less than 20 kg and 1.0 mg per day for patients greater than or equal to 20 kg.
Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical
response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg
per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or
equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available
for children who weigh less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consider gradually lowering
the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use
RISPERDAL for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
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Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosing in Patients with Severe Renal or Hepatic Impairment
For patients with severe renal impairment (CLcr < 30 mL/min) or hepatic impairment (10-15
points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be
increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg
twice daily, increase in intervals of one week or greater [see Use in Specific Populations (8.6 and
8.7)].
2.5 Dose Adjustments for Specific Drug Interactions
When RISPERDAL® is co-administered with enzyme inducers (e.g., carbamazepine), the dose of
RISPERDAL® should be increased up to double the patient’s usual dose. It may be necessary to
decrease the RISPERDAL® dose when enzyme inducers such as carbamazepine are discontinued
[see Drug Interactions (7.1)]. Similar effect may be expected with co-administration of
RISPERDAL® with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).
When fluoxetine or paroxetine is co-administered with RISPERDAL®, the dose of
RISPERDAL® should be reduced. The RISPERDAL® dose should not exceed 8 mg per day in
adults when co-administered with these drugs. When initiating therapy, RISPERDAL® should be
titrated slowly. It may be necessary to increase the RISPERDAL® dose when enzyme inhibitors
such as fluoxetine or paroxetine are discontinued [see Drug Interactions (7.1)].
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
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RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL M-TAB Orally Disintegrating Tablet on the tongue. The RISPERDAL M-
TAB Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL M-TAB Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square),
3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
4
CONTRAINDICATIONS
RISPERDAL® is contraindicated in patients with a known hypersensitivity to RISPERDAL®.
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks),
largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated
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patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course
of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%,
compared to a rate of about 2.6% in the placebo group. Although the causes of death were
varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death)
or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical
antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies may be attributed
to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed.
RISPERDAL (risperidone) is not approved for the treatment of dementia-related psychosis [see
Boxed Warning].
5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients
with Dementia-Related Psychosis
Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities,
were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly
patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly
higher incidence of cerebrovascular adverse events in patients treated with risperidone compared
to patients treated with placebo. RISPERDAL is not approved for the treatment of patients with
dementia-related psychosis. [see Boxed Warning and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome
Antipsychotic drugs including RISPERDAL® can cause a potentially fatal symptom complex
referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include
hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or
blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include
elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
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diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. The risk of developing tardive dyskinesia and the
likelihood that it will become irreversible are believed to increase as the duration of treatment
and the total cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively brief
treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, prescribe RISPERDAL in a manner that is most likely to minimize
the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be
reserved for patients who suffer from a chronic illness that: (1) is known to respond to
antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful
treatments are not available or appropriate. In patients who do require chronic treatment, the
smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL,
consider drug discontinuation. However, some patients may require treatment with
RISPERDAL despite the presence of the syndrome.
5.5 Metabolic Changes
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Atypical antipsychotic drugs have been associated with metabolic changes that may increase
cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia,
dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to
produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics
including RISPERDAL. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus
in the general population. Given these confounders, the relationship between atypical
antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL, should be monitored regularly for worsening of
glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history
of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL,
should undergo fasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL,
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics, including RISPERDAL, should undergo fasting blood glucose testing. In some
cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL,
was discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of RISPERDAL.
Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-
blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.
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Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose
Studies in Adult Subjects with Schizophrenia or Bipolar Mania
RISPERDAL
Placebo
1-8 mg/day
>8-16 mg/day
Mean change from baseline (mg/dL)
n=555
n=748
n=164
Serum Glucose
-1.4
0.8
0.6
Proportion of patients with shifts
Serum Glucose
(<140 mg/dL to ≥200 mg/dL)
0.6%
(3/525)
0.4%
(3/702)
0%
(0/158)
In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean
change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).
Data from the placebo-controlled 3- to 6-week study in children and adolescents with
schizophrenia (13-17 years of age), bipolar mania (10-17 years of age), or autistic disorder (5 to
17 years of age) are presented in Table 3.
Table 3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in
Children and Adolescents with Schizophrenia (13-17 years of age), Bipolar Mania (10-17 years of
age), or Autistic Disorder (5 to 17 years of age)
RISPERDAL
Placebo
0.5-6 mg/day
Mean change from baseline (mg/dL)
n=76
n=135
Serum Glucose
-1.3
2.6
Proportion of patients with shifts
Serum Glucose
(<100 mg/dL to ≥126 mg/dL)
0%
(0/64)
0.8%
(1/120)
In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was
associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical
antipsychotics.
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Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult
subjects with schizophrenia or bipolar mania are presented in Table 4.
Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose
Studies in Adult Subjects with Schizophrenia or Bipolar Mania
RISPERDAL
Placebo
1-8 mg/day
>8-16 mg/day
Mean change from baseline (mg/dL)
Cholesterol
n=559
n=742
n=156
Change from baseline
0.6
6.9
1.8
Triglycerides
n=183
n=307
n=123
Change from baseline
-17.4
-4.9
-8.3
Proportion of patients With Shifts
Cholesterol
(<200 mg/dL to ≥240 mg/dL)
2.7%
(10/368)
4.3%
(22/516)
6.3%
(6/96)
Triglycerides
(<500 mg/dL to ≥500 mg/dL)
1.1%
(2/180)
2.7%
(8/301)
2.5%
(3/121)
In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean
change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at
Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).
Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and
adolescents with schizophrenia (13-17 years of age), bipolar mania (10-17 years of age), or
autistic disorder (5-17 years of age) are presented in Table 5.
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Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in
Children and Adolescents with Schizophrenia (13-17 Years of Age), Bipolar Mania (10-17 Years
of Age), or Autistic Disorder (5 to 17 Years of Age)
RISPERDAL
Placebo
0.5-6 mg/day
Mean change from baseline (mg/dL)
Cholesterol
n=74
n=133
Change from baseline
0.3
-0.3
LDL
n=22
n=22
Change from baseline
3.7
0.5
HDL
n=22
n=22
Change from baseline
1.6
-1.9
Triglycerides
n=77
n=138
Change from baseline
-9.0
-2.6
Proportion of patients with shifts
Cholesterol
(<170 mg/dL to ≥200 mg/dL)
2.4%
(1/42)
3.8%
(3/80)
LDL
(<110 mg/dL to ≥130 mg/dL)
0%
(0/16)
0%
(0/16)
HDL
(≥40 mg/dL to <40 mg/dL)
0%
(0/19)
10%
(2/20)
Triglycerides
(<150 mg/dL to ≥200 mg/dL)
1.5%
(1/65)
7.1%
(8/113)
In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was
associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b)
fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24
(n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is
recommended.
Data on mean changes in body weight and the proportion of subjects meeting a weight gain
criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or
flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table
6.
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Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight
From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects
With Schizophrenia or Bipolar Mania
RISPERDAL
Placebo
(n=597)
1-8 mg/day
(n=769)
>8-16 mg/day
(n=158)
Weight (kg)
Change from baseline
-0.3
0.7
2.2
Weight Gain
≥7% increase from baseline
2.9%
8.7%
20.9%
In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean
change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).
Data on mean changes in body weight and the proportion of subjects meeting the criterion of
≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in
children and adolescents with schizophrenia (13-17 years of age), bipolar mania (10-17 years of
age), autistic disorder (5-17 years of age), or other psychiatric disorders (5-17 years of age) are
presented in Table 7.
Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight
From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents
With Schizophrenia (13-17 Years of Age), Bipolar Mania (10-17 Years of Age), Autistic Disorder
(5 to 17 Years of Age) or Other Psychiatric Disorders (5-17 Years of Age)
Placebo
(n=375)
RISPERDAL 0.5-6 mg/day
(n=448)
Weight (kg)
Change from baseline
0.6
2.0
Weight Gain
≥7% increase from baseline
6.9%
32.6%
In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was
associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48
(n=242).
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In 103
adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of
RISPERDAL® treatment. The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55
and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL treatment was observed,
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which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
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5.7 Orthostatic Hypotension
RISPERDAL may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse reaction associated with RISPERDAL
treatment, especially when ascertained by direct questioning of patients. This adverse reaction is
dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose
patients (RISPERDAL 16 mg/day) reported somnolence compared to 16% of placebo patients.
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Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by
which 8% of RISPERDAL 16 mg/day patients and 1% of placebo patients reported somnolence
as an adverse reaction. Since RISPERDAL has the potential to impair judgment, thinking, or
motor skills, patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that RISPERDAL therapy does not affect them
adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL-treated patients, two in association with hyponatremia.
RISPERDAL should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [see Boxed Warning and Warnings and Precautions
(5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance. Severe priapism may require
surgical intervention.
5.13 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.14 Patients with Phenylketonuria
Inform patients that RISPERDAL M-TAB Orally Disintegrating Tablets contain
phenylalanine. Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL M-TAB
Orally Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL M-
TAB Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL
M-TAB Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg
RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each
0.5 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
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6
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
Tardive dyskinesia [see Warnings and Precautions (5.4)]
Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain)
[see Warnings and Precautions (5.5)]
Hyperprolactinemia [see Warnings and Precautions (5.6)]
Orthostatic hypotension [see Warnings and Precautions (5.7)]
Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8)]
Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
Seizures [see Warnings and Precautions (5.10)]
Dysphagia [see Warnings and Precautions (5.11)]
Priapism [see Warnings and Precautions (5.12)]
Disruption of body temperature regulation [see Warnings and Precautions (5.13)]
Patients with Phenylketonuria [see Warnings and Precautions (5.14)].
The most common adverse reactions in clinical trials (>5% and twice placebo) were
parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea,
vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary
hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal
congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea,
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somnolence,
sedation,
vomiting,
dizziness,
and
akathisia
[see
Adverse
Reactions,Discontinuations Due to Adverse Reactions (6.1)].
The data described in this section are derived from a clinical trial database consisting of 9803
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9803 patients, 2687 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
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.
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Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical
Trials – Schizophrenia
Adult Patients with Schizophrenia
Table 8 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 8.
Adverse Reactions in >2% of RISPERDAL®-Treated Adult Patients (and greater than placebo)
with Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Reaction
RISPERDAL®
System/Organ Class
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per day
(N=198)
Placebo
(N=225)
Cardiac Disorders
Tachycardia
1
3
0
Eye Disorders
Vision blurred
3
1
1
Gastrointestinal Disorders
Nausea
9
4
4
Constipation
8
9
6
Dyspepsia
8
6
5
Dry mouth
4
0
1
Abdominal discomfort
3
1
1
Salivary hypersecretion
2
1
<1
Diarrhea
2
1
1
General Disorders
Fatigue
3
1
0
Chest pain
2
2
1
Asthenia
2
1
<1
Infections and Infestations
Nasopharyngitis
3
4
3
Upper respiratory tract infection
2
3
1
Sinusitis
1
2
1
Urinary tract infection
1
3
0
Investigations
Blood creatine phosphokinase increased
1
2
<1
Heart rate increased
<1
2
0
Musculoskeletal and Connective Tissue
Disorders
Back pain
4
1
1
Arthralgia
2
3
<1
Pain in extremity
2
1
1
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Percentage of Patients Reporting Reaction
RISPERDAL®
System/Organ Class
Adverse Reaction
2-8 mg per day
(N=366)
>8-16 mg per day
(N=198)
Placebo
(N=225)
Nervous System Disorders
Parkinsonism*
14
17
8
Akathisia*
10
10
3
Sedation
10
5
2
Dizziness
7
4
2
Dystonia*
3
4
2
Tremor*
2
3
1
Dizziness postural
2
0
0
Psychiatric Disorders
Insomnia
32
25
27
Anxiety
16
11
11
Respiratory, Thoracic and Mediastinal
Disorders
Nasal congestion
4
6
2
Dyspnea
1
2
0
Epistaxis
<1
2
0
Skin and Subcutaneous Tissue Disorders
Rash
1
4
1
Dry skin
1
3
0
Vascular Disorders
Orthostatic hypotension
2
1
0
* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity,
akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes
akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle
contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
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Pediatric Patients with Schizophrenia
Table 9 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 9.
Adverse Reactions in 5% of RISPERDAL®-Treated Pediatric Patients (and greater than
placebo) with Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Reaction
RISPERDAL®
System/Organ Class
Adverse Reaction
1-3 mg per day
(N=55)
4-6 mg per day
(N=51)
Placebo
(N=54)
Gastrointestinal Disorders
Salivary hypersecretion
0
10
2
Nervous System Disorders
Sedation
24
12
4
Parkinsonism*
16
28
11
Tremor
11
10
6
Akathisia*
9
10
4
Dizziness
7
14
2
Dystonia*
2
6
0
Psychiatric Disorders
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, muscle
rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia
includes dystonia and oculogyration.
Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical
Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 10 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
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Table 10.
Adverse Reactions in >2% of RISPERDAL®-Treated Adult
Patients (and greater than placebo) with Bipolar Mania in
Double-Blind, Placebo-Controlled Monotherapy Trials
Percentage of Patients Reporting Reaction
System/Organ Class
Adverse Reaction
RISPERDAL®
1-6 mg per day
(N=448)
Placebo
(N=424)
Eye Disorders
Vision blurred
2
1
Gastrointestinal Disorders
Nausea
5
2
Diarrhea
3
2
Salivary hypersecretion
3
1
Stomach discomfort
2
<1
General Disorders
Fatigue
2
1
Nervous System Disorders
Parkinsonism*
25
9
Sedation
11
4
Akathisia*
9
3
Tremor*
6
3
Dizziness
6
5
Dystonia*
5
1
Lethargy
2
1
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle
rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor
includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration,
torticollis.
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Table 11 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Pediatric Patients with Bipolar Mania
Table 12 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Table 11. Adverse Reactions in 2% of RISPERDAL®-Treated Adult Patients (and
greater than placebo) with Bipolar Mania in Double-Blind, Placebo-
Controlled Adjunctive Therapy Trials
Percentage of Patients Reporting Reaction
System/Organ Class
RISPERDAL® + Mood Stabilizer
Placebo +
Mood Stabilizer
Adverse Reaction
(N=127)
(N=126)
Cardiac Disorders
Palpitations
2
0
Gastrointestinal Disorders
Dyspepsia
9
8
Nausea
6
4
Diarrhea
6
4
Salivary hypersecretion
2
0
General Disorders
Chest pain
2
1
Infections and Infestations
Urinary tract infection
2
1
Nervous System Disorders
Parkinsonism*
14
4
Sedation
9
4
Akathisia*
8
0
Dizziness
7
2
Tremor
6
2
Lethargy
2
1
Psychiatric Disorders
Anxiety
3
2
Respiratory, Thoracic and
Mediastinal Disorders
Pharyngolaryngeal pain
5
2
Cough
2
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia
and akathisia.
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Table 12.
Adverse Reactions in 5% of RISPERDAL®-Treated Pediatric Patients
(and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-
Controlled Trials
Percentage of Patients Reporting
Reaction
RISPERDAL ®
System/Organ Class
Adverse Reaction
0.5-2.5 mg per
day
(N=50)
3-6 mg per
day
(N=61)
Placebo
(N=58)
Eye Disorders
Vision blurred
4
7
0
Gastrointestinal Disorders
Abdominal pain upper
16
13
5
Nausea
16
13
7
Vomiting
10
10
5
Diarrhea
8
7
2
Dyspepsia
10
3
2
Stomach discomfort
6
0
2
General Disorders
Fatigue
18
30
3
Metabolism and Nutrition Disorders
Increased appetite
4
7
2
Nervous System Disorders
Sedation
42
56
19
Dizziness
16
13
5
Parkinsonism*
6
12
3
Dystonia*
6
5
0
Akathisia*
0
8
2
Psychiatric Disorders
Anxiety
0
8
3
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain
10
3
5
Skin and Subcutaneous Tissue Disorders
Rash
0
7
2
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity.
Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
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Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical
Trials - Autistic Disorder
Table 13 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials and one 6-week double-blind, placebo-controlled study.
Table 13.
Adverse Reactions in 5% of RISPERDAL®-Treated Pediatric
Patients (and greater than placebo) Treated for Irritability
Associated with Autistic Disorder in Double-Blind, Placebo-
Controlled Trials
Percentage of Patients Reporting Reaction
System/Organ Class
RISPERDAL®
0.5-4.0 mg/day
Placebo
Adverse Reaction
(N=107)
(N=115)
Gastrointestinal Disorders
Vomiting
20
17
Constipation
17
6
Dry mouth
10
4
Nausea
8
5
Salivary hypersecretion
7
1
General Disorders and Administration Site Conditions
Fatigue
31
9
Pyrexia
16
13
Thirst
7
4
Infections and Infestations
Nasopharyngitis
19
9
Rhinitis
9
7
Upper respiratory tract infection
8
3
Investigations
Weight increased
8
2
Metabolism and Nutrition Disorders
Increased appetite
44
15
Nervous System Disorders
Sedation
63
15
Drooling
12
4
Headache
12
10
Tremor
8
1
Dizziness
8
2
Parkinsonism*
8
1
Renal and Urinary Disorders
Enuresis
16
10
Respiratory, Thoracic and Mediastinal Disorders
Cough
17
12
Rhinorrhea
12
10
Nasal congestion
10
4
Skin and Subcutaneous Tissue Disorders
Rash
8
5
*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle
tightness.
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Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone
The following additional adverse reactions occurred across all placebo-controlled, active-
controlled, and open-label studies of RISPERDAL in adults and pediatric patients.
Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree,
bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: ear pain, tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye
swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual
acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling,
cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting
edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort,
generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis,
tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media,
onychomycosis,
acarodermatitis,
bronchopneumonia,
respiratory
tract
infection,
tracheobronchitis, otitis media chronic
Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase
increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count
decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body
temperature decreased, blood pressure decreased, transaminases increased
Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia
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Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling,
musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness,
rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria,
unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic
attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of
consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular
disorder, neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia,
nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea,
gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction,
retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus
congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion,
rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus,
skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne,
hyperkeratosis, seborrheic dermatitis
Vascular Disorders: hypotension, flushing
Additional Adverse Reactions Reported with RISPERDAL® CONSTA®
The following is a list of additional adverse reactions that have been reported during the
premarketing evaluation of RISPERDAL® CONSTA®, regardless of frequency of occurrence:
Cardiac Disorders: bradycardia
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blepharospasm
Gastrointestinal Disorders: toothache, tongue spasm
General Disorders and Administration Site Conditions: pain
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Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis,
subcutaneous abscess
Injury and Poisoning: fall
Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme
increased
Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain
Nervous System Disorders: convulsion, paresthesia
Psychiatric Disorders: depression
Skin and Subcutaneous Tissue Disorders: eczema
Vascular Disorders: hypertension
Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 14. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-
Treated Adult Patients in Schizophrenia Trials
RISPERDAL
Adverse Reaction
2-8 mg/day
(N=366)
>8-16 mg/day
(N=198)
Placebo
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Vomiting
0.8%
0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0%
0%
Dystonia
0.5%
0%
0%
Agitation
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Orthostatic hypotension
0.3%
0.5%
0%
Akathisia
0.3%
2.0%
0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
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Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL-treated patients discontinued treatment due to an
adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54)
placebo-treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy
(1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
Table 15. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-
Treated Adult Patients in Bipolar Mania Clinical Trials
Adverse Reaction
RISPERDAL®
1-6 mg/day
(N=448)
Placebo
(N=424)
Parkinsonism
0.4%
0%
Lethargy
0.2%
0%
Dizziness
0.2%
0%
Alanine aminotransferase increased
0.2%
0.2%
Aspartate aminotransferase increased
0.2%
0.2%
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients.
The adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
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Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Table 16.
Dose Groups
Placebo
RISPERDAL® 2
mg
RISPERDAL® 6
mg
RISPERDAL® 10
mg
RISPERDAL® 16
mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
17%
21%
21%
35%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
Table 17.
Dose Groups
RISPERDAL® 1
mg
RISPERDAL® 4
mg
RISPERDAL® 8
mg
RISPERDAL®
12 mg
RISPERDAL®
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
17%
18%
20%
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing
difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur
at low doses, they occur more frequently and with greater severity with high potency and at
higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is
observed in males and younger age groups.
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
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Changes in Body Weight
Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in
adult and pediatric patients [see Warnings and Precautions (5.5), Adverse Reactions (6), and Use
in Specific Populations (8.4)].
Changes in ECG Parameters
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone.
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. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial
fibrillation, cardiopulmonary arrest, diabetic ketoacidosis in patients with impaired glucose
metabolism, dysgeusia, hypoglycemia, hypothermia, inappropriate antidiuretic hormone
secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious
puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, sudden death,
thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water
intoxication.
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7
DRUG INTERACTIONS
7.1 Pharmacokinetic-related Interactions
The dose of RISPERDAL should be adjusted when used in combination with CYP2D6 enzyme
inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see
Table 18 and Dosage and Administration (2.5)]. Dose adjustment is not recommended for
RISPERDAL when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin
[see Table 18].
Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety
(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with
Schizophrenia
Dosing Schedule
Effect on Active
Moiety
(Risperidone + 9-
Hydroxy-
Risperidone
(Ratio*)
Coadministered Drug
Coadministered Drug
Risperidone
AUC
Cmax
Enzyme (CYP2D6)
Inhibitors
Risperidone Dose
Recommendation
Fluoxetine
20 mg/day
2 or 3 mg twice
daily
1.4
1.5
Re-evaluate dosing. Do
not exceed 8 mg/day
Paroxetine
10 mg/day
4 mg/day
1.3
-
20 mg/day
4 mg/day
1.6
-
40 mg/day
4 mg/day
1.8
-
Re-evaluate dosing. Do
not exceed 8 mg/day
Enzyme (CYP3A/
PgP inducers)
Inducers
Carbamazepine
573 ± 168 mg/day
3 mg twice daily
0.51
0.55
Titrate dose upwards.
Do not exceed twice the
patient’s usual dose
Enzyme (CYP3A)
Inhibitors
Ranitidine
150 mg twice daily
1 mg single dose
1.2
1.4
Dose adjustment not
needed
Cimetidine
400 mg twice daily
1 mg single dose
1.1
1.3
Dose adjustment not
needed
Erythromycin
500 mg four times
daily
1 mg single dose
1.1
0.94
Dose adjustment not
needed
Other Drugs
Amitriptyline
50 mg twice daily
3 mg twice daily
1.2
1.1
Dose adjustment not
needed
*Change relative to reference
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Effect of Risperidone on other drugs
Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13). Dose adjustment for lithium is not
recommended.
Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®. Dose adjustment for
valproate is not recommended.
Digoxin
RISPERDAL (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.
7.2 Pharmacodynamic-related Interactions
Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL is
taken in combination with other centrally-acting drugs and alcohol.
Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL may enhance the hypotensive
effects of other therapeutic agents with this potential.
Levodopa and Dopamine Agonists
RISPERDAL may antagonize the effects of levodopa and dopamine agonists.
Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Risk Summary
Adequate and well controlled studies with RISPERDAL have not been conducted in pregnant
women. Neonates exposed to antipsychotic drugs (including RISPERDAL®) during the third
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trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following
delivery. There was no increase in the incidence of malformations in embryo-fetal studies in rats
and rabbits at 0.4–6 times MHRD. Increased pup mortality was noted at all doses in peri-
postnatal studies in rats. RISPERDAL should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover
within hours or days without specific treatment; others may require prolonged hospitalization.
Data
Human Data
There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory
distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the
third trimester. These complications have varied in severity; while in some cases symptoms have
been self-limited, in other cases neonates have required intensive care unit support and prolonged
hospitalization.
There was one report of a case of agenesis of the corpus callosum in an infant exposed to
risperidone in utero. The causal relationship to RISPERDAL therapy is unknown
Animal Data
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 body surface area basis) and in one Segment II study in New Zealand
rabbits (0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 body surface area basis). There
were no teratogenic effects in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a
mg/m2 body surface area basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 body surface area basis. It is
not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on
the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 body
surface area basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups
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were observed, as evidenced by a decrease in the number of live pups and an increase in the
number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated
dams. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams,
regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair
maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were
reduced in pups born to control but reared by drug-treated dams. These effects were all noted at
the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 body surface
area basis.
Placental transfer of risperidone occurs in rat pups.
8.2 Labor and Delivery
The effect of RISPERDAL on labor and delivery in humans is unknown.
8.3 Nursing Mothers
Risperidone and 9-hydroxyrisperidone are present in human breast milk. Because of the potential
for serious adverse reactions in nursing infants from risperidone, 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.
8.4 Pediatric Use
Approved Pediatric Indications
Schizophrenia
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
Bipolar I Disorder
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications
and Usage (1.2), Adverse Reactions (6.1), and Clinical Studies (14.2)].
Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
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Autistic Disorder
The efficacy and safety of RISPERDAL in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.1) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than 1200
pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar
mania who were of similar age and weight, and who received similar dosages of RISPERDAL®
as patients treated for irritability associated with autistic disorder.
A third study was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-
dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone
in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related
behavioral symptoms. There were two weight-based, fixed doses of risperidone (high-dose and
low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was
1.75 mg per day for patients weighing > 45 kg. The low dose was 0.125 mg per day for patients
for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing > 45 kg.
The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy
for low-dose risperidone.
Adverse Reactions in Pediatric Patients
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
Weight gain has been observed in children and adolescents during treatment with RISPERDAL®.
Clinical monitoring of weight is recommended during treatment.
Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in
pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or
other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for
RISPERDAL®-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In
these trials, approximately 33% of the RISPERDAL® group had weight gain >7%, compared to
7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean
weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [see Warnings and Precautions (5.5)
and Adverse Reactions (6.1)].
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Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in
the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse
reactions were most often of early onset and transient in duration [see Adverse Reactions (6.1
and 6.2)]. Patients experiencing persistent somnolence may benefit from a change in dosing
regimen [see Dosage and Administration (2.1, 2.2, and 2.3)].
Hyperprolactinemia
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
Growth and Sexual Maturation
The long-term effects of RISPERDAL on growth and sexual maturation have not been fully
evaluated in children and adolescents.
Juvenile Animal Studies
Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5
mg/kg/day. Decreased bone length and density were seen, with a no-effect dose of 0.31
mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its active metabolite
paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents
receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in
sexual maturation was seen at all doses in both males and females. The above effects showed
little or no reversibility in females after a 12 week drug-free recovery period.
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In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a
reversible impairment of performance in a test of learning and memory was seen, in females
only, with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma levels (AUC) of
risperidone plus paliperidone about half those observed in humans at the MRHD. No other
consistent effects on neurobehavioral or reproductive development were seen up to the highest
testable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus
paliperidone which were about two thirds of those observed in humans at the MRHD.
8.5 Geriatric Use
Clinical studies of RISPERDAL in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
8.6 Renal Impairment
In patients with moderate to severe (Clcr 59 to 15 mL/min) renal disease, clearance of the sum of
risperidone and its active metabolite decreased by 60%, compared to young healthy subjects.
RISPERDAL doses should be reduced in patients with renal disease [see Dosage and
Administration (2.4)].
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8.7 Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and 1-acid glycoprotein.
RISPERDAL doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4)].
8.8 Patients with Parkinson’s Disease or Lewy Body Dementia
Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased
sensitivity to RISPERDAL®. Manifestations can include confusion, obtundation, postural instability
with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic
malignant syndrome.
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
such patients should be observed closely for signs of RISPERDAL misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
RISPERDAL has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
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Premarketing experience included eight reports of acute RISPERDAL overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL overdose include prolonged QT
interval and convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
For the most up to date information on the management of RISPERDAL® overdosage, contact a
certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care
including close medical supervision and monitoring. Treatment should consist of general
measures employed in the management of overdosage with any drug. Consider the possibility of
multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor
cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific
antidote to RISPERDAL®.
11 DESCRIPTION
RISPERDAL contains risperidone, an atypical antipsychotic belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
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Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL Tablets are for oral administration and available in 0.25 mg (dark yellow), 0.5 mg
(red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths.
RISPERDAL® tablets contain the following inactive ingredients: colloidal silicon dioxide,
hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium
lauryl sulfate, and starch (corn). The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain
talc and titanium dioxide. The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets
contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg
and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No.
2 Aluminum Lake.
RISPERDAL is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
RISPERDAL M-TAB Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL M-TAB
Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite resin,
gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL M-TAB Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL, in schizophrenia, is unknown. However, it has been
proposed that the drug's therapeutic activity in schizophrenia could be mediated through a
combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. The
clinical effect from RISPERDAL® results from the combined concentrations of risperidone and
its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism at
receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL.
12.2 Pharmacodynamics
RISPERDAL is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1
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histaminergic receptors. RISPERDAL acts as an antagonist at other receptors, but with lower
potency. RISPERDAL has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or 1 and 2 adrenergic receptors.
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL M-TAB Orally Disintegrating Tablets and
RISPERDAL Oral Solution are bioequivalent to RISPERDAL Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and 1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
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Metabolism
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7)].
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile
typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
patients receiving quinidine have not been evaluated, but observations in a modest number
(n70) of poor metabolizers given RISPERDAL® do not suggest important differences between
poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g.,
carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7)]. It would also be possible for risperidone to interfere with metabolism of
other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions (7)].
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly affect
the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1,
1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
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Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Drug-Drug Interaction Studies
[See Drug Interactions (7)].
Specific Populations
Renal and Hepatic Impairment
[See Use in Specific Populations (8.6 and 8.7)].
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Use in Specific Populations
(8.5)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
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and for 25 months to rats. These doses are equivalent to approximately 2, 9, and 38 times the
maximum recommended human dose (MRHD) for schizophrenia of 16 mg/day on a mg/kg basis
or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 body surface basis. A maximum tolerated dose was not achieved in male mice. There
were statistically significant increases in pituitary gland adenomas, endocrine pancreas
adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of
the human dose on a mg/m2 (mg/kg) basis at which these tumors occurred.
Multiples of Maximum Human
Dose in mg/m2 (mg/kg)
Tumor Type
Species
Sex
Lowest Effect
Level
Highest No-Effect
Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic or clastogenic potential for risperidone was found in the Ames gene
mutation test, the mouse lymphoma assay, the in vitro rat hepatocyte DNA-repair assay, the in
vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the
chromosomal aberration test in human lymphocytes or Chinese hamster ovary cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 body surface area basis. The
effect appeared to be in females, since impaired mating behavior was not noted in the Segment I
study in which males only were treated. In a subchronic study in Beagle dogs in which
risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and
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concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 body surface area
basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum
testosterone and sperm parameters partially recovered, but remained decreased after treatment
was discontinued. A no-effect dose could not be determined in either rat or dog.
13.2 Animal Toxicology
Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5
mg/kg/day. Decreased bone length and density were observed with a no-effect dose of 0.31
mg/kg/day. This dose produced plasma AUC levels of risperidone plus its active metabolite
paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents
receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in
sexual maturation was seen at all doses in both males and females. The above effects showed
little or no reversibility in females after a 12 week drug-free recovery period.
In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a
reversible impairment of performance in a test of learning and memory was observed in females
only with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma AUC levels of
risperidone plus paliperidone about half those observed in humans at the MRHD. No other
consistent effects on neurobehavioral or reproductive development were seen up to the highest
testable dose of 1.25 mg/kg/day. This dose produced plasma AUC levels of risperidone plus
paliperidone which were about two thirds of those observed in humans at the MRHD.
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
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Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL dose groups were generally superior to the 1 mg RISPERDAL
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The
most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL (4 and 8 mg/day on a once-daily schedule), both RISPERDAL dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL experienced a
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
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Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
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(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Adjunctive Therapy with Lithium or Valproate
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
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(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on
lithium, valproate, or carbamazepine therapy with inadequately controlled manic or
mixed symptoms were randomized to receive RISPERDAL or placebo, in combination
with their original therapy. RISPERDAL, in a dose range of 1-6 mg/day, once daily,
starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate,
or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50
mcg/mL to 125 mcg/mL for valproate, or 4-12 mcg/mL for carbamazepine, respectively)
was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS
total score. A possible explanation for the failure of this trial was induction of risperidone
and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels
of risperidone and 9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
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equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
A third trial was a 6-week, multicenter, randomized, double-blind, placebo-controlled, fixed-
dose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone
in subjects (N=96) 5 to 17 years of age with autistic disorder (defined by DSM-IV criteria) and
associated irritability and related behavioral symptoms. Approximately 77% of patients were
younger than 12 years of age (mean age = 9), and 88% were male. Most patients (73%) weighed
less than 45 kg (mean weight = 40 kg). Approximately 90% of patients were antipsychotic-naïve
before entering the study.
There were two weight-based, fixed doses of risperidone (high-dose and low-dose). The high
dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for
patients weighing > 45 kg. The low dose was 0.125 mg per day for patients weighing 20 to < 45
kg, and it was 0.175 mg per day for patients weighing > 45 kg. The dose was administered once
daily in the morning, or in the evening if sedation occurred.
The primary efficacy endpoint was the mean change in the Aberrant Behavior Checklist –
Irritability subscale (ABC-I) score from baseline to the end of Week 6. The study demonstrated
the efficacy of high-dose risperidone, as measured by the mean change in ABC-I score. It did not
demonstrate efficacy for low-dose risperidone. The mean baseline ABC-I scores were 29 in the
placebo group (n = 35), 27 in the risperidone low-dose group (n = 30), and 28 in the risperidone
high-dose group (n = 31). The mean changes in ABC-I scores were -3.5, -7.4, and -12.4 in the
placebo, low-dose, and high-dose group respectively. The results in the high-dose group were
statistically significant (p< 0.001) but not in the low-dose group (p=0.164).
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this open-
label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of
1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as
25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much
improved’) during the 4-6 month open-label treatment phase for about 140 days, on average,
were randomized to receive RISPERDAL or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Reference ID: 3168771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
defined as 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
RISPERDAL® (risperidone) Tablets
RISPERDAL (risperidone) Tablets are imprinted "JANSSEN" on one side and either
“Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, bottles of 500 NDC
50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01.
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, bottles of 500 NDC
50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, bottles of 500 NDC
50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06 and hospital unit dose
blister packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL M-TAB (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M-
TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
Reference ID: 3168771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
16.2 Storage and Handling
RISPERDAL Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL 1 mg/mL Oral Solution should be stored at controlled room temperature 15°-
25°C (59°-77°F). Protect from light and freezing.
RISPERDAL M-TAB Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL and their caregivers:
17.1 Orthostatic Hypotension
Advise patients and caregivers about the risk of orthostatic hypotension, especially during the
period of initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Inform patients and caregivers that RISPERDAL has the potential to impair judgment, thinking,
or motor skills. Advise caution about operating hazardous machinery, including automobiles,
until patients are reasonably certain that RISPERDAL therapy does not affect them adversely
[see Warnings and Precautions (5.9)].
Reference ID: 3168771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
56
17.3 Pregnancy
Advise patients and caregivers to notify their physician if the patient becomes pregnant or
intends to become pregnant during therapy [see Use in Specific Populations (8.1)].
17.4 Nursing
Inform patients and caregivers that risperidone and its active metabolite are present in human
breast milk; there is a potential for serious adverse reactions from RISPERDAL in nursing
infants. Advise patients that the decision whether to discontinue nursing or to discontinue the
RISPERDAL should take into account the importance of the drug to the patient [see Use in
Specific Populations (8.3)].
17.5 Concomitant Medication
Advise patients and caregivers to inform their physicians if the patient is taking, or plans to take,
any prescription or over-the-counter drugs, because there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Advise patients to avoid alcohol while taking RISPERDAL [see Drug Interactions (7.2)].
17.7 Phenylketonurics
Inform patients with Phenylketonuria and caregivers that RISPERDAL M-TAB Orally
Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame. Each
4 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.84 mg phenylalanine;
each 3 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.63 mg
phenylalanine; each 2 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.42
mg phenylalanine; each 1 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains
0.28 mg phenylalanine; and each 0.5 mg RISPERDAL M-TAB Orally Disintegrating Tablet
contains 0.14 mg phenylalanine [see Warnings and Precautions (5.14)].
17.8 Metabolic Changes
Inform patients and caregivers that treatment with RISPERDAL can be associated with
hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain[see Warnings and
Precautions (5.5)].
17.9 Tardive Dyskinesia
Inform patients and caregivers about the risk of tardive dyskinesia [see Warnings and
Precautions (5.4)].
Reference ID: 3168771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
57
RISPERDAL Tablets
Active ingredient is made in Ireland
Finished product is manufactured by:
Janssen Ortho, LLC
Gurabo, Puerto Rico 00778
RISPERDAL Oral Solution
Active ingredient is made in Belgium
Finished product is manufactured by:
Janssen Pharmaceutica NV
Beerse, Belgium
RISPERDAL M-TAB Orally Disintegrating Tablets
Active ingredient is made in Ireland
Finished product is manufactured by:
Janssen Ortho, LLC
Gurabo, Puerto Rico 00778
RISPERDAL Tablets, RISPERDAL M-TAB Orally Disintegrating Tablets, and
RISPERDAL® Oral Solution are manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Revised July 2012
© Janssen Pharmaceuticals, Inc. 2007
Reference ID: 3168771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:21.338967
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020272s065,020588s053,021444s041lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 65}
|
12,407
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. RISPERDAL® is
not approved for use in patients with dementia-related psychosis. (5.1)
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophreni
a- adults
(2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophreni
a –
adolescents
(2.1)
0.5mg
/day
0.5- 1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar
mania –
adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar
mania in
children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder
(2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with
antipsychotics, including RISPERDAL®. Patients with a history of a
clinically significant low white blood cell count (WBC) or a drug-
induced leukopenia/neutropenia should have their complete blood count
(CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign
of a clinically significant decline in WBC in the absence of other
causative factors. (5.8)
• Potential for cognitive and motor impairment (5.9)
• Seizures (5.10)
• Dysphagia (5.11)
• Priapism (5.12)
• Thrombotic Thrombocytopenic Purpura (TTP) (5.13)
• Disruption of body temperature regulation (5.14)
• Antiemetic Effect (5.15)
• Suicide (5.16)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.17)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.17)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism,
akathisia, vomiting, cough, constipation, nasopharyngitis, drooling,
rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety,
headache, nasal congestion, rhinitis, tremor, and rash. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were nausea, somnolence, sedation, vomiting, dizziness,
and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800
JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower initial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 04/2011
1
Reference ID: 2960771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
6.9
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
7.2
Drugs with Hypotensive Effects
WITH DEMENTIA-RELATED PSYCHOSIS
7.3
Levodopa and Dopamine Agonists
1
INDICATIONS AND USAGE
7.4
Amitriptyline
1.1
Schizophrenia
7.5
Cimetidine and Ranitidine
1.2
Bipolar Mania
7.6
Clozapine
1.3
Irritability Associated with Autistic Disorder
7.7
Lithium
2
DOSAGE AND ADMINISTRATION
7.8
Valproate
2.1
Schizophrenia
7.9
Digoxin
2.2
Bipolar Mania
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
2.3
Irritability Associated with Autistic Disorder –
Isozymes
Pediatrics (Children and Adolescents)
7.11
Carbamazepine and Other Enzyme Inducers
2.4
Dosage in Special Populations
7.12
Drugs Metabolized by CYP 2D6
2.5
Co-Administration of RISPERDAL® with Certain
8
USE IN SPECIFIC POPULATIONS
Other Medications
8.1
Pregnancy
8.2
r
2.6
Administration of RISPERDAL
® Oral Solution
Labor and Delive y
2.7
Directions for Use of RISPERDAL
® M-
8.3
Nursing Mothers
TAB
® Orally Disintegrating Tablets
8.4
Pediatric Use
3
DOSAGE FORMS AND STRENGTHS
8.5
Geriatric Use
4
CONTRAINDICATIONS
9
DRUG ABUSE AND DEPENDENCE
5
WARNINGS AND PRECAUTIONS
9.1
Controlled Substance
5.1
Increased Mortality in Elderly Patients with
9.2
Abuse
Dementia-Related Psychosis
9.3
Dependence
5.2
Cerebrovascular Adverse Events, Including
10
OVERDOSAGE
Stroke, in Elderly Patients with Dementia-
10.1
Human Experience
Related Psychosis
10.2
Management of Overdosage
5.3
Neuroleptic Malignant Syndrome (NMS)
11
DESCRIPTION
5.4
Tardive Dyskinesia
12
CLINICAL PHARMACOLOGY
5.5
Hyperglycemia and Diabetes Mellitus
12.1
Mechanism of Action
5.6
Hyperprolactinemia
12.2
Pharmacodynamics
5.7
Orthostatic Hypotension
12.3
Pharmacokinetics
5.8
Leukopenia, Neutropenia, and Agranulocytosis
13
NONCLINICAL TOXICOLOGY
5.9
Potential for Cognitive and Motor Impairment
13.1
Carcinogenesis, Mutagenesis, Impairment of
5.10
Seizures
Fertility
5.11
Dysphagia
14
CLINICAL STUDIES
5.12
Priapism
14.1
Schizophrenia
5.13
Thrombotic Thrombocytopenic Purpura (TTP)
14.2
Bipolar Mania - Monotherapy
5.14
Body Temperature Regulation
14.3
Bipolar Mania – Combination Therapy
5.15
Antiemetic Effect
14.4
Irritability Associated with Autistic Disorder
5.16
Suicide
16
HOW SUPPLIED/STORAGE AND HANDLING
5.17
Use in Patients with Concomitant Illness
Storage and Handling
5.18
Monitoring: Laboratory Tests
17
PATIENT COUNSELING INFORMATION
6
ADVERSE REACTIONS
17.1
Orthostatic Hypotension
6.1
Commonly-Observed Adverse Reactions in
17.2
Interference with Cognitive and Motor
Double-Blind, Placebo-Controlled Clinical Trials
Performance
- Schizophrenia
17.3
Pregnancy
6.2
Commonly-Observed Adverse Reactions in
17.4
Nursing
Double-Blind, Placebo-Controlled Clinical Trials
17.5
Concomitant Medication
– Bipolar Mania
17.6
Alcohol
6.3
Commonly-Observed Adverse Reactions in
17.7
Phenylketonurics
Double-Blind, Placebo-Controlled Clinical Trials
- Autistic Disorder
6.4
Other Adverse Reactions Observed During the
*Sections or subsections omitted from the full prescribing information are not
Clinical Trial Evaluation of Risperidone
listed
6.5
Discontinuations Due to Adverse Reactions
6.6
Dose Dependency of Adverse Reactions in
Clinical Trials
6.7
Changes in Body Weight
6.8
Changes in ECG
Reference ID: 2960771
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: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which the findings
of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. RISPERDAL®
(risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
Reference ID: 2960771
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of
1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower
titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see
Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not
demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal
symptoms and other adverse effects, and are generally not recommended. In a single study
supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for
4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Reference ID: 2960771
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above
2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
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Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
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physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.17)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.10)].
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2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
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RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square),
3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. RISPERDAL® (risperidone) is not approved for the treatment of
dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
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The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics
including RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus
in the general population. Given these confounders, the relationship between atypical
antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL®, should be monitored regularly for worsening of
glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history
of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL® ,
should undergo fasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL® ,
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing. In some
cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL® ,
was discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of RISPERDAL® .
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
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impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
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complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9)].
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a
large, open premarketing experience (approximately 1300 patients). She experienced jaundice,
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fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.16 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.17 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.18 Monitoring: Laboratory Tests
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No specific laboratory tests are recommended.
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
• Antiemetic effect [see Warnings and Precautions (5.15)]
• Suicide [see Warnings and Precautions (5.16)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.17)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.17)]
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The most common adverse reactions in clinical trials (≥ 10%) were somnolence, increased
appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation,
nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea,
anxiety, headache, nasal congestion, rhinitis, tremor, and rash.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea,
somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions (6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
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6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
2-8 mg per day >8-16 mg per day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Blood and Lymphatic System
Disorders
Anemia
<1
1
0
Cardiac Disorders
Tachycardia
1
3
0
Ear and Labyrinth Disorders
Ear pain
<1
1
0
Eye Disorders
Vision blurred
3
1
1
Gastrointestinal Disorders
Nausea
9
4
4
Constipation
8
9
6
Dyspepsia
8
6
5
Vomiting
7
5
7
Dry mouth
4
0
1
Abdominal discomfort
3
1
1
Salivary hypersecretion
2
1
<1
Diarrhea
2
1
1
Abdominal pain
1
1
0
Abdominal pain upper
1
1
0
Stomach discomfort
1
1
1
General Disorders
Fatigue
3
1
0
Chest pain
2
2
1
Asthenia
2
1
<1
Immune System Disorders
Hypersensitivity
<1
1
0
Infections and Infestations
Nasopharyngitis
3
4
3
Upper respiratory tract infection
2
3
1
Sinusitis
1
2
1
Urinary tract infection
1
3
0
Investigations
Weight increased
1
1
0
Blood creatine phosphokinase
1
2
<1
increased
Heart rate increased
<1
2
0
Metabolism and Nutrition Disorders
Decreased appetite
1
0
<1
Musculoskeletal and Connective
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Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
2-8 mg per day >8-16 mg per day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Tissue Disorders
Back pain
4
1
1
Arthralgia
2
3
<1
Pain in extremity
2
1
1
Joint stiffness
1
1
0
Nervous System Disorders
Parkinsonism*
14
17
8
Akathisia*
10
10
3
Dizziness
7
4
2
Somnolence
7
2
1
Dystonia*
3
4
2
Sedation
3
3
1
Tremor*
2
3
1
Dizziness postural
2
0
0
Dyskinesia*
1
2
2
Syncope
1
1
0
Psychiatric Disorders
Insomnia
32
25
27
Anxiety
16
11
11
Nervousness
1
1
<1
Renal and Urinary Disorders
Urinary incontinence
1
1
0
Reproductive System and Breast
Disorders
Ejaculation failure
<1
1
0
Respiratory, Thoracic and
Mediastinal Disorders
Nasal congestion
4
6
2
Dyspnea
1
2
0
Epistaxis
<1
2
0
Skin and Subcutaneous Tissue
Disorders
Rash
1
4
1
Dry skin
1
3
0
Dandruff
1
1
0
Seborrheic dermatitis
<1
1
0
Hyperkeratosis
0
1
1
Vascular Disorders
Orthostatic hypotension
2
1
0
Hypotension
1
1
0
* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism,
cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity,
and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia
includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture,
oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis.
Reference ID: 2960771
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
1-3 mg per day 4-6 mg per day
Placebo
Adverse Reaction
(N=55)
(N=51)
(N=54)
Gastrointestinal Disorders
Salivary hypersecretion
0
10
2
Nervous System Disorders
Parkinsonism*
16
28
11
Sedation
13
8
2
Somnolence
11
4
2
Tremor
11
10
6
Akathisia*
9
10
4
Dizziness
7
14
2
Dystonia*
2
6
0
Psychiatric Disorders
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, muscle
rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and
restlessness. Dystonia includes dystonia and oculogyration.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
Reference ID: 2960771
19
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult
Patients with Bipolar Mania in Double-Blind, Placebo-
Controlled Monotherapy Trials
Percentage of Patients Reporting Event
System/Organ Class
RISPERDAL®
Placebo
Adverse Reaction
1-6 mg per day
(N=424)
(N=448)
Cardiac Disorders
Tachycardia
1
<1
Eye Disorders
Vision blurred
2
1
Gastrointestinal Disorders
Nausea
5
2
Diarrhea
3
2
Salivary hypersecretion
3
1
Dyspepsia
2
2
Stomach discomfort
2
<1
General Disorders
Fatigue
2
1
Asthenia
1
1
Pyrexia
1
1
Infections and Infestations
Nasopharyngitis
1
1
Investigations
Aspartate aminotransferase increased
1
<1
Nervous System Disorders
Parkinsonism*
25
9
Akathisia*
9
3
Tremor*
6
3
Dizziness
6
5
Sedation
6
2
Somnolence
5
2
Dystonia*
5
1
Lethargy
2
1
Dyskinesia*
1
<1
Reproductive System and Breast
Disorders
Galactorrhea
1
0
Skin and Subcutaneous Tissue
Disorders
Acne
1
0
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal
stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel
rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and
parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration,
torticollis. Dyskinesia includes muscle twitching and dyskinesia.
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Reference ID: 2960771
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Percentage of Patients Reporting Event
RISPERDAL® + Mood
Placebo +
System/Organ Class
Stabilizer
Mood Stabilizer
Adverse Reaction
(N=127)
(N=126)
Cardiac Disorders
Palpitations
2
0
Gastrointestinal Disorders
Dyspepsia
9
8
Nausea
6
4
Diarrhea
6
4
Dry mouth
4
4
Vomiting
4
6
Constipation
3
3
Salivary hypersecretion
2
0
General Disorders
Chest pain
2
1
Fatigue
2
2
Infections and Infestations
Nasopharyngitis
2
3
Urinary tract infection
2
1
Investigations
Weight increased
2
2
Nervous System Disorders
Parkinsonism*
14
4
Headache
14
15
Akathisia*
8
0
Dizziness
7
2
Sedation
6
3
Tremor
6
2
Somnolence
3
1
Lethargy
2
1
Psychiatric Disorders
Insomnia
4
8
Anxiety
3
2
Respiratory, Thoracic and
Mediastinal Disorders
Pharyngolaryngeal pain
5
2
Cough
2
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia.
Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Reference ID: 2960771
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients
with Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
RISPERDAL ®
System/Organ Class
0.5-2.5 mg per 3-6 mg per Placebo
Adverse Reaction
day
day
(N=58)
(N=50)
(N=61)
Eye Disorders
Vision blurred
4
7
0
Gastrointestinal Disorders
Abdominal pain upper
16
13
5
Nausea
16
13
7
Vomiting
10
10
5
Diarrhea
8
7
2
Dyspepsia
10
3
2
Stomach discomfort
6
0
2
General Disorders
Fatigue
18
30
3
Metabolism and Nutrition Disorders
Increased appetite
4
7
2
Nervous System Disorders
Somnolence
22
30
12
Sedation
20
23
7
Dizziness
16
13
5
Parkinsonism*
6
12
3
Dystonia*
6
5
0
Akathisia*
0
8
2
Psychiatric Disorders
Anxiety
0
8
3
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain
10
3
5
Skin and Subcutaneous Tissue Disorders
Rash
0
7
2
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity.
Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
Reference ID: 2960771
22
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric
Patients Treated for Irritability Associated with Autistic
Disorder in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
System/Organ Class
RISPERDAL®
Placebo
Adverse Reaction
0.5-4.0 mg per day
(N=80)
(N=76)
Cardiac Disorders
Tachycardia
5
0
Gastrointestinal Disorders
Vomiting
25
21
Constipation
21
8
Dry mouth
15
6
Salivary hypersecretion
9
0
Nausea
8
6
General Disorders
Fatigue
42
13
Feeling abnormal
5
0
Infections and Infestations
Nasopharyngitis
21
10
Rhinitis
13
10
Upper respiratory tract infection
8
3
Investigations
Weight increased
5
0
Metabolism and Nutrition Disorders
Increased appetite
47
19
Nervous System Disorders
Somnolence
49
18
Sedation
29
3
Drooling
16
5
Tremor
12
1
Parkinsonism*
11
1
Dizziness
9
3
Dyskinesia
7
3
Lethargy
5
3
Respiratory, Thoracic and
Mediastinal Disorders
Cough
24
18
Rhinorrhea
16
13
Nasal congestion
13
5
Skin and Subcutaneous Tissue
Disorders
Rash
11
8
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder,
muscle rigidity, cogwheel rigidity, and muscle tightness.
Reference ID: 2960771
23
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In another study with patients treated for irritability associated with autistic disorder, headache
(6%), epistaxis (6%) and pyrexia (6%) were also observed in RISPERDAL®-treated pediatric
subjects.
6.4 Other Adverse Reactions Observed During the Clinical Trial Evaluation of
Risperidone
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder,
and studies in elderly patients with dementia.
Blood and Lymphatic System Disorders: granulocytopenia, neutropenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree,
bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye
swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual
acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling,
cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting
edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort,
generalized edema, drug withdrawal syndrome, peripheral coldness
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis,
tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media,
onychomycosis,
acarodermatitis,
bronchopneumonia,
respiratory
tract
infection,
tracheobronchitis, otitis media chronic
Reference ID: 2960771
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase
increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count
decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body
temperature decreased, blood pressure decreased, transaminases increased
Metabolism and Nutrition Disorders: polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest
pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria,
unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia,
transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss
of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder,
neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep
disorder, listlessness, libido decreased, anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea,
gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation,
ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus
congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion,
rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus,
skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular
Vascular Disorders: flushing
Additional Adverse Reactions Reported with RISPERDAL® CONSTA®
The following is a list of additional adverse reactions that have been reported during the
premarketing evaluation of RISPERDAL® CONSTA®, regardless of frequency of occurrence:
Cardiac Disorders: bradycardia
Ear and Labyrinth Disorders: vertigo
Reference ID: 2960771
25
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Eye Disorders: blepharospasm
Gastrointestinal Disorders: toothache, tongue spasm
General Disorders and Administration Site Conditions: pain
Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis,
subcutaneous abscess
Injury and Poisoning: fall
Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme
increased
Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain
Nervous System Disorders: convulsion, paresthesia
Psychiatric Disorders: depression
Skin and Subcutaneous Tissue Disorders: eczema
Vascular Disorders: hypertension
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®
Treated Adult Patients in Schizophrenia Trials
RISPERDAL®
2-8 mg/day
>8-16 mg/day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Vomiting
0.8%
0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0%
0%
Dystonia
0.5%
0%
0%
Agitation
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Orthostatic hypotension
0.3%
0.5%
0%
Akathisia
0.3%
2.0%
0%
Reference ID: 2960771
26
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54)
placebo-treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy
(1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
Table 8. Adverse Reactions Associated With Discontinuation in 2 or
More RISPERDAL®-Treated Adult Patients in Bipolar Mania
Clinical Trials
RISPERDAL®
1-6 mg/day
Placebo
Adverse Reaction
(N=448)
(N=424)
Parkinsonism
0.4%
0%
Lethargy
0.2%
0%
Dizziness
0.2%
0%
Alanine aminotransferase
0.2%
0.2%
increased
Aspartate aminotransferase
0.2%
0.2%
increased
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
Reference ID: 2960771
27
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For current labeling information, please visit https://www.fda.gov/drugsatfda
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
RISPERDAL®
2 mg
RISPERDAL®
6 mg
RISPERDAL®
10 mg
RISPERDAL®
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
17%
21%
21%
35%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
Dose Groups
RISPERDAL®
RISPERDAL®
RISPERDAL
RISPERDAL®
RISPERDAL®
1 mg
4 mg
® 8 mg
12 mg
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
17%
18%
20%
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing
difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur
at low doses, they occur more frequently and with greater severity with high potency and at
higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is
observed in males and younger age groups.
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
Reference ID: 2960771
28
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palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
Reference ID: 2960771
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The following adverse reactions have been identified during postapproval use of risperidone;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction,
angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased,
diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug
withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate
antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT
prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water
intoxication.
Other adverse events reported since market introduction, which were temporally related to
risperidone but not necessarily causally related, include the following: pituitary adenoma,
pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
Reference ID: 2960771
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7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers
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Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
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Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown.
Non-Teratogenic Effects
Neonates exposed to antipsychotic drugs (including RISPERDAL®) during the third trimester of
pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There
have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress,
and feeding disorder in these neonates. These complications have varied in severity; while in
some cases symptoms have been self-limited, in other cases neonates have required intensive
care unit support and prolonged hospitalization.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
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Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than 1200
pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar
mania who were of similar age and weight, and who received similar dosages of RISPERDAL®
as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In 103
adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of
RISPERDAL® treatment. The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55
and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
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group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated.
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8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
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such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
interval and convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
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There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is: structural formula
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
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RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB®
Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin,
gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL® .
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
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daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
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Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)].
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile
typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
patients receiving quinidine have not been evaluated, but observations in a modest number
(n≅70) of poor metabolizers given RISPERDAL® do not suggest important differences between
poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g.,
carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.17)].
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Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.17)].
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
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Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Highest No-
Effect Level
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
Reference ID: 2960771
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
Reference ID: 2960771
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For current labeling information, please visit https://www.fda.gov/drugsatfda
of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The
most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
Reference ID: 2960771
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For current labeling information, please visit https://www.fda.gov/drugsatfda
significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
Reference ID: 2960771
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Reference ID: 2960771
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this open-
label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of
1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as ≥
25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much
improved’) during the 4-6 month open-label treatment phase for about 140 days, on average,
were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
Reference ID: 2960771
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either
“Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, bottles of 500 NDC
50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01.
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, bottles of 500 NDC
50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, bottles of 500 NDC
50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06 and hospital unit dose
blister packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M
TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30.
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1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature 15°
25°C (59°-77°F). Protect from light and freezing.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
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17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Revised April 2011
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and
RISPERDAL® Oral Solution are manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
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|
custom-source
|
2025-02-12T13:47:21.775534
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020272s064,020588s052,021444s040lbl.pdf', 'application_number': 20272, 'submission_type': 'SUPPL ', 'submission_number': 64}
|
12,409
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NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 3
Dovonex®
(calcipotriene solution)
Rx only
Scalp Solution, 0.005%
FOR TOPICAL DERMATOLOGIC USE ONLY.
Not for Ophthalmic, Oral or Intravaginal Use.
DESCRIPTION
Dovonex
®
(calcipotriene solution) Scalp Solution, 0.005% is a colorless topical solution containing
0.005% calcipotriene in a vehicle of isopropanol (51% v/v), propylene glycol, hydroxypropyl
cellulose, sodium citrate, menthol and water.
The
chemical
name
of
calcipotriene
is
(5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-
5,7,10(19),22tetraene-1α,3β,24-triol, with the empirical formula C27H40O3, a molecular weight of
412.6, and the following structural formula:
CLINICAL PHARMACOLOGY
In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the
sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is
a synthetic analog of vitamin D3.
Although the precise mechanism of calcipotriene’s antipsoriatic action is not fully understood, in vitro
evidence suggests that calcipotriene is roughly equipotent to the natural vitamin in its effects on
proliferation and differentiation of a variety of cell types. Calcipotriene has also been shown, in animal
studies, to be 100-200 times less potent in its effects on calcium utilization than the natural hormone.
Clinical studies with radiolabelled calcipotriene solution indicate that less than 1% of the applied dose
of calcipotriene is absorbed through the scalp when the solution (2.0 mL) is applied topically to normal
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 4
skin or psoriasis plaques (160 cm2) for 12 hours, and that much of the absorbed calcipotriene is
converted to inactive metabolites within 24 hours of application.
Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The
active form of the vitamin, 1,25-dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver
and excreted in the bile. Calcipotriene metabolism following systemic uptake is rapid, and occurs via a
similar pathway to the natural hormone. The primary metabolites are much less potent than the parent
compound.
There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation,
but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is
expected to be similar to that of the naturally occurring vitamin.
CLINICAL STUDIES
Adequate and well-controlled trials of patients treated with Dovonex® Scalp Solution, 0.005%, have
demonstrated improvement usually beginning after 2 weeks of therapy. This improvement continued
with approximately 31% of patients appearing either cleared (14%) or almost cleared (17%) after 8
weeks of therapy.
INDICATIONS AND USAGE
Dovonex® (calcipotriene solution) Scalp Solution, 0.005%, is indicated for the topical treatment of
chronic, moderately severe psoriasis of the scalp. The safety and effectiveness of topical calcipotriene
in dermatoses other than psoriasis have not been established.
CONTRAINDICATIONS
Dovonex® Scalp Solution, 0.005%, is contraindicated in those patients with acute psoriatic eruptions or
a history of hypersensitivity to any of the components of the preparation. It should not be used by
patients with demonstrated hypercalcemia or evidence of vitamin D toxicity.
WARNINGS
Avoid contact with the eyes or mucous membranes. Discontinue use if a sensitivity reaction occurs or
if excessive irritation develops on uninvolved skin areas.
Drug product is flammable. Keep away from open flame.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 5
PRECAUTIONS
General
Use of Dovonex® Scalp Solution, 0.005%, may cause transient irritation of both lesions and
surrounding uninvolved skin. If irritation develops, Dovonex® Scalp Solution, 0.005%, should be
discontinued.
For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.
Reversible elevation of serum calcium has occurred with use of topical calcipotriene. If elevation in
serum calcium outside the normal range should occur, discontinue treatment until normal calcium
levels are restored.
Information for Patients
Patients using Dovonex® Scalp Solution, 0.005%, should receive the following information and
instructions:
1. This medication is to be used only as directed by the physician. It is for external use only. Avoid
contact with the face or eyes. As with any topical medication, patients should wash their hands
after application.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. Patients should report to their physician any signs of adverse reactions.
4. Patients that apply Dovonex® to exposed portions of the body should avoid excessive exposure to
either natural or artificial sunlight (including tanning booths, sun lamps, etc.).
Carcinogenesis, Mutagenesis, Impairment of Fertility
When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30
μg/kg/day (corresponding to 9, 30 and 90 μg/m2/day), no significant changes in tumor incidence were
observed when compared to control.In a study in which albino hairless mice were exposed to both
UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the
formation of skin tumors was observed (statistically significant in males only), suggesting that
calcipotriene may enhance the effect of UVR to induce skin tumors. Patients that apply Dovonex® to
exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight
(including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy
in patients that use Dovonex®.
Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma
TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay
conducted in mice.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 6
Studies in rats at doses up to 54 μg/kg/day (324 μg/m2/day) of calcipotriene indicated no impairment
of fertility or general reproductive performance.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Studies of teratogenicity were done by the oral route where bioavailability is expected to be
approximately 40-60% of the administered dose. Increased rabbit maternal and fetal toxicity was noted
at 12 μg/kg/day (132 μg/m2/day). Rabbits administered 36 μg/kg/day (396 μg/m2/day) resulted in
fetuses with a significant increase in the incidences of pubic bones, forelimb phalanges, and
incomplete bone ossification. In a rat study, oral doses of 54 μg/kg/day (318 μg/m2/day) resulted in a
significantly higher incidence of skeletal abnormalities consisting primarily of enlarged fontanelles and
extra ribs. The enlarged fontanelles are most likely due to calcipotriene's effect upon calcium
metabolism. The maternal and fetal calculated no-effect exposures in the rat (43.2 μg/m2/day) and
rabbit (17.6 μg/m2/day) studies are greater than the expected human systemic exposure level (0.13
μg/m2/day) from dermal application. There are no adequate and well-controlled studies in pregnant
women. Therefore, Dovonex® Scalp Solution, 0.005%, should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers
There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation,
but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is
expected to be similar to that of the naturally occurring vitamin. Because many drugs are excreted in
human milk, caution should be exercised when Dovonex® (calcipotriene solution) Scalp Solution,
0.005%, is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Dovonex® Scalp Solution, 0.005%, in pediatric patients have not been
specifically established. Because of a higher ratio of skin surface area to body mass, pediatric patients
are at greater risk than adults of systemic adverse effects when they are treated with topical medication.
Geriatric Use
Of the total number of patients in clinical studies of calcipotriene solution, approximately 16% were 65
or older, while approximately 4% were 75 and over. The results of an analysis of severity of skin-
related adverse events showed no differences for subjects over 65 years compared to those under 65
years, but greater sensitivity of some older individuals cannot be ruled out.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 7
ADVERSE REACTIONS
In controlled clinical trials, the most frequent adverse reactions reported to be related to Dovonex®
Scalp Solution, 0.005%, use were transient burning, stinging and tingling, which occurred in
approximately 23% of patients. Rash was reported in about 11% of patients. Dry skin, irritation and
worsening of psoriasis were reported in 1-5% of patients. Skin atrophy, hyperpigmentation,
hypercalcemia, and folliculitis were not observed in these studies, but cannot be excluded.
OVERDOSAGE
Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects.
Elevated serum calcium has been observed with excessive use of topical calcipotriene. If elevation in
serum calcium should occur, discontinue treatment until normal calcium levels are restored. (See
PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Comb the hair to remove scaly debris and after suitably parting, apply Dovonex® Scalp Solution,
0.005%, twice daily, only to the lesions, and rub in gently and completely, taking care to prevent the
solution spreading onto the forehead. The safety and efficacy of Dovonex® Scalp Solution, 0.005%,
have been demonstrated in patients treated for eight weeks.
Keep Dovonex® Scalp Solution, 0.005%, well away from the eyes. Avoid application of the solution
to uninvolved scalp margins. Always wash hands thoroughly after use.
HOW SUPPLIED
Dovonex® (calcipotriene solution) Scalp Solution, 0.005% is available in 60 mL plastic bottles N
0430-3030-15
STORAGE
Store at controlled room temperature 15° C - 25° C (59° F - 77° F). Avoid sunlight. Do not freeze.
Manufactured by LEO Pharmaceutical Products, Ltd.
Ballerup, Denmark
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 8
Marketed by:
Warner Chilcott (US), Inc.
Rockaway, NJ 07866 USA
U.S. Patent No. 4,866,048
3030G032 – Trade PI
3030G102 – Sample PI
Revised XXX 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 9
Dovonex®
(calcipotriene cream)
Rx only
Cream, 0.005%
FOR TOPICAL DERMATOLOGIC USE ONLY.
Not for Ophthalmic, Oral or Intravaginal Use.
DESCRIPTION
Dovonex® (calcipotriene cream) Cream, 0.005% contains calcipotriene monohydrate, a synthetic
vitamin D3 derivative, for topical dermatological use.
Chemically,
calcipotriene
monohydrate
is
(5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-
5,7,10(19),22-tetraene-1α,3β,24-triol monohydrate, with the empirical formula C27H40O3•H2O, a
molecular weight of 430.6, and the following structural formula:
OH
H
H
OH
• H2O
HO
Calcipotriene monohydrate is a white or off-white crystalline substance. Dovonex® Cream contains
calcipotriene monohydrate equivalent to 50 μg/g anhydrous calcipotriene in a cream base of cetearyl
alcohol, ceteth-20, diazolidinyl urea, dichlorobenzyl alcohol, dibasic sodium phosphate, edetate
disodium, glycerin, mineral oil, petrolatum, and water.
CLINICAL PHARMACOLOGY
In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the
sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is
a synthetic analog of vitamin D3.
Clinical studies with radiolabelled calcipotriene ointment indicate that approximately 6% (± 3%, SD)
of the applied dose of calcipotriene is absorbed systemically when the ointment is applied topically to
psoriasis plaques, or 5% (± 2.6%, SD) when applied to normal skin, and much of the absorbed active is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 10
converted to inactive metabolites within 24 hours of application. Systemic absorption of the cream has
not been studied.
Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The
active form of the vitamin, 1,25-dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver
and excreted in the bile. Calcipotriene metabolism following systemic uptake is rapid, and occurs via a
similar pathway to the natural hormone.
CLINICAL STUDIES
Adequate and well-controlled trials of patients treated with Dovonex® Cream have demonstrated
improvement usually beginning after 2 weeks of therapy. This improvement continued with
approximately 50% of patients showing at least marked improvement in the signs and symptoms of
psoriasis after 8 weeks of therapy, but only approximately 4% showed complete clearing.
INDICATIONS AND USAGE
Dovonex® (calcipotriene cream) Cream, 0.005%, is indicated for the treatment of plaque psoriasis. The
safety and effectiveness of topical calcipotriene in dermatoses other than psoriasis have not been
established.
CONTRAINDICATIONS
Dovonex® Cream is contraindicated in those patients with a history of hypersensitivity to any of the
components of the preparation. It should not be used by patients with demonstrated hypercalcemia or
evidence of vitamin D toxicity. Dovonex® Cream should not be used on the face.
PRECAUTIONS
General
Use of Dovonex® Cream may cause transient irritation of both lesions and surrounding uninvolved
skin. If irritation develops, Dovonex® Cream should be discontinued.
For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.
Reversible elevation of serum calcium has occurred with use of topical calcipotriene. If elevation in
serum calcium outside the normal range should occur, discontinue treatment until normal calcium
levels are restored.
Information for Patients
Patients using Dovonex® Cream should receive the following information and instructions:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 11
5. This medication is to be used only as directed by the physician. It is for external use only. Avoid
contact with the face or eyes. As with any topical medication, patients should wash their hands
after application.
6. This medication should not be used for any disorder other than that for which it was prescribed.
7. Patients should report to their physician any signs of adverse reactions.
8. Patients that apply Dovonex® to exposed portions of the body should avoid excessive exposure to
either natural or artificial sunlight (including tanning booths, sun lamps, etc.).
Carcinogenesis, Mutagenesis, Impairment of Fertility
When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30
μg/kg/day (corresponding to 9, 30 and 90 μg/m2/day), no significant changes in tumor incidence were
observed when compared to control.In a study in which albino hairless mice were exposed to both
UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the
formation of skin tumors was observed (statistically significant in males only), suggesting that
calcipotriene may enhance the effect of UVR to induce skin tumors. Patients that apply Dovonex® to
exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight
(including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy
in patients that use Dovonex®.
Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma
TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay
conducted in mice.
Studies in rats at doses up to 54 μg/kg/day (324 μg/m2/day) of calcipotriene indicated no impairment
of fertility or general reproductive performance.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Studies of teratogenicity were done by the oral route where bioavailability is expected to be
approximately 40-60% of the administered dose. Increased rabbit maternal and fetal toxicity was noted
at 12 μg/kg/day (132 μg/m2/day). Rabbits administered 36 μg/kg/day (396 μg/m2/day) resulted in
fetuses with a significant increase in the incidences of pubic bones, forelimb phalanges, and
incomplete bone ossification. In a rat study, oral doses of 54 μg/kg/day (318 μg/m2/day) resulted in a
significantly higher incidence of skeletal abnormalities consisting primarily of enlarged fontanelles and
extra ribs. The enlarged fontanelles are most likely due to calcipotriene's effect upon calcium
metabolism. The maternal and fetal calculated no-effect exposures in the rat (43.2 μg/m2/day) and
rabbit (17.6 μg/m2/day) studies are approximately equal to the expected human systemic exposure
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 12
level (18.5 μg/m2/day) from dermal application. There are no adequate and well-controlled studies in
pregnant women. Therefore, Dovonex® Cream should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Nursing Mothers
There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation,
but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is
expected to be similar to that of the naturally occurring vitamin. Because many drugs are excreted in
human milk, caution should be exercised when Dovonex® Cream is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Dovonex® Cream in pediatric patients have not been established. Because
of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of
systemic adverse effects when they are treated with topical medication.
Geriatric Use
Of the total number of patients in clinical studies of calcipotriene cream, approximately 15% were 65
or older, while approximately 3% were 75 and over. There were no significant differences in adverse
events for subjects over 65 years compared to those under 65 years of age. However, the greater
sensitivity of older individuals cannot be ruled out.
ADVERSE REACTIONS
In controlled clinical trials, the most frequent adverse experiences reported for Dovonex®
(calcipotriene cream) Cream, 0.005% were cases of skin irritation, which occurred in approximately
10-15% of patients. Rash, pruritus, dermatitis and worsening of psoriasis were reported in 1 to 10% of
patients.
OVERDOSAGE
Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects.
Elevated serum calcium has been observed with excessive use of topical calcipotriene. If elevation in
serum calcium should occur, discontinue treatment until normal calcium levels are restored. (See
PRECAUTIONS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 13
DOSAGE AND ADMINISTRATION
Apply a thin layer of Dovonex® Cream to the affected skin twice daily and rub in gently and
completely. The safety and efficacy of Dovonex® Cream have been demonstrated in patients treated
for eight weeks.
HOW SUPPLIED
Dovonex® (calcipotriene cream) Cream, 0.005% is available in:
60 gram aluminum tubes N 0430-3020-15
120 gram aluminum tubes N 0430-3020-17
STORAGE
Store at controlled room temperature 15° C-25° C (59° F-77° F). Do not freeze.
Manufactured by LEO Laboratories Ltd.
Dublin, Ireland
Marketed by:
Warner Chilcott (US), Inc.
Rockaway, NJ 07866 USA
U.S. Patent No. 4,866,048
3020G061
Revised XXX 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 14
Dovonex®
(calcipotriene ointment),
0.005%
FOR TOPICAL DERMATOLOGIC USE ONLY.
Not for Ophthalmic, Oral or Intravaginal Use.
DESCRIPTION
Dovonex® (calcipotriene ointment), 0.005% contains the compound calcipotriene, a synthetic vitamin
D3 derivative, for topical dermatological use.
Chemically, calcipotriene is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19), 22-tetraene-
1α,3β,24-triol-, with the empirical formula C27H40O3, a molecular weight of 412.6, and the following
structural formula:
Rx only
Calcipotriene is a white or off-white crystalline substance. Dovonex® ointment contains calcipotriene
50 μg/g in an ointment base of dibasic sodium phosphate, edetate disodium, mineral oil, petrolatum,
propylene glycol, tocopherol, steareth-2 and water.
CLINICAL PHARMACOLOGY
In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the
sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is
a synthetic analog of vitamin D3.
Clinical studies with radiolabelled calcipotriene ointment indicate that approximately 6% (± 3%, SD)
of the applied dose of calcipotriene is absorbed systemically when the ointment is applied topically to
psoriasis plaques or 5% (± 2.6%, SD) when applied to normal skin, and much of the absorbed active is
converted to inactive metabolites within 24 hours of application.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 15
Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The
active form of the vitamin, 1,25-dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver
and excreted in the bile. Calcipotriene metabolism following systemic uptake is rapid, and occurs via a
similar pathway to the natural hormone. The primary metabolites are much less potent than the parent
compound.
There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation,
but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is
expected to be similar to that of the naturally occurring vitamin.
CLINICAL STUDIES
Adequate and well-controlled trials of patients treated with Dovonex® ointment have demonstrated
improvement usually beginning after two weeks of therapy. This improvement continued in patients
using Dovonex® once daily and twice daily. After 8 weeks of once daily Dovonex®, 56.7% of patients
showed at least marked improvements (6.4% showed complete clearing). After 8 weeks of twice daily
Dovonex®, 70.0% of patients showed at least marked improvement (11.3% showed complete clearing).
Subtracting percentages of patients using placebo (vehicle only) from percentages of patients using
Dovonex® who had at least marked improvements after 8 weeks yields 39.9% for once daily and
49.6% for twice daily. This adjustment for placebo effect indicates that what might appear to be
differences between once daily and twice daily use may reflect differences in the studies independent
from the frequency of dosing. Although there was a numerical difference in comparison across studies,
twice daily dosing has not been shown to be superior in efficacy to once daily dosing.
Over 400 patients have been treated in open label clinical studies of Dovonex® for periods of up to one
year. In half of these studies, patients who previously had not responded well to Dovonex® were
excluded. The adverse events in these extended studies included skin irritation in approximately 25%
of patients and worsening of psoriasis in approximately 10% of patients. In one of these open label
studies, half of the patients no longer required Dovonex® by 16 weeks of treatment, because of
satisfactory therapeutic results.
INDICATIONS AND USAGE
Dovonex® (calcipotriene ointment), 0.005%, is indicated for the treatment of plaque psoriasis in adults.
The safety and effectiveness of topical calcipotriene in dermatoses other than psoriasis 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 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 16
CONTRAINDICATIONS
Dovonex® is contraindicated in those patients with a history of hypersensitivity to any of the
components of the preparation. It should not be used by patients with demonstrated hypercalcemia or
evidence of vitamin D toxicity. Dovonex® should not be used on the face.
PRECAUTIONS
General
Use of Dovonex® may cause irritation of lesions and surrounding uninvolved skin. If irritation
develops, Dovonex® should be discontinued.
For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.
Transient, rapidly reversible elevation of serum calcium has occurred with use of Dovonex®. If
elevation in serum calcium outside the normal range should occur, discontinue treatment until normal
calcium levels are restored.
Information for Patients
Patients using Dovonex® should receive the following information and instructions:
9. This medication is to be used as directed by the physician. It is for external use only. Avoid contact
with the face or eyes. As with any topical medication, patients should wash hands after application.
10. This medication should not be used for any disorder other than that for which it was prescribed.
11. Patients should report to their physician any signs of local adverse reactions.
12. Patients that apply Dovonex® to exposed portions of the body should avoid excessive exposure to
either natural or artificial sunlight (including tanning booths, sun lamps, etc.).
Carcinogenesis, Mutagenesis, Impairment of Fertility
When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30
μg/kg/day (corresponding to 9, 30 and 90 μg/m2/day), no significant changes in tumor incidence were
observed when compared to control.In a study in which albino hairless mice were exposed to both
UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the
formation of skin tumors was observed (statistically significant in males only), suggesting that
calcipotriene may enhance the effect of UVR to induce skin tumors. Patients that apply Dovonex® to
exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight
(including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy
in patients that use Dovonex®.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 17
Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma
TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay
conducted in mice.
Studies in rats at doses up to 54 μg/kg/day (324 μg/m2/day) of calcipotriene indicated no impairment
of fertility or general reproductive performance.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Studies of teratogenicity were done by the oral route where bioavailability is expected to be
approximately 40-60% of the administered dose. In rabbits, increased maternal and fetal toxicity were
noted at a dosage of 12 μg/kg/day (132 μg/m2/day); a dosage of 36 μg/kg/day (396 μg/m2/day)
resulted in a significant increase in the incidence of incomplete ossification of the pubic bones and
forelimb phalanges of fetuses. In a rat study, a dosage of 54 μg/kg/day (318 μg/m2/day) resulted in a
significantly increased incidence of skeletal abnormalities (enlarged fontanelles and extra ribs). The
enlarged fontanelles are most likely due to calcipotriene's effect upon calcium metabolism. The
estimated maternal and fetal no-effect exposure levels in the rat (43.2 μg/m2/day) and rabbit (17.6
μg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5
μg/m2/day) from dermal application. There are no adequate and well-controlled studies in pregnant
women. Therefore, Dovonex® ointment should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dovonex® (calcipotriene ointment), 0.005% is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Dovonex® in pediatric patients have not been established. Because of a
higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of
systemic adverse effects when they are treated with topical medication.
Geriatric Use
Of the total number of patients in clinical studies of calcipotriene ointment, approximately 12% were
65 or older, while approximately 4% were 75 and over. The results of an analysis of severity of skin-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 18
related adverse events showed a statistically significant difference for subjects over 65 years (more
severe) compared to those under 65 years (less severe).
ADVERSE REACTIONS
In controlled clinical trials, the most frequent adverse reactions reported for Dovonex® were burning,
itching and skin irritation, which occurred in approximately 10-15% of patients. Erythema, dry skin,
peeling, rash, dermatitis, worsening of psoriasis including development of facial/scalp psoriasis were
reported in 1 to 10% of patients. Other experiences reported in less than 1% of patients included skin
atrophy, hyperpigmentation, hypercalcemia, and folliculitis. Once daily dosing has not been shown to
be superior in safety to twice daily dosing.
OVERDOSAGE
Topically applied Dovonex® can be absorbed in sufficient amounts to produce systemic effects.
Elevated serum calcium has been observed with excessive use of Dovonex® ointment.
DOSAGE AND ADMINISTRATION
Apply a thin layer of Dovonex® ointment once or twice daily and rub in gently and completely.
HOW SUPPLIED
Dovonex® (calcipotriene ointment), 0.005% is available in:
60 gram aluminum tubes N 0430-3010-15.
120 gram aluminum tubes N 0430-3010-17
STORAGE
Store at controlled room temperature 15° C - 25° C (59° F - 77° F). Do not freeze.
Manufactured by LEO Laboratories Ltd.
Dublin, Ireland
Marketed by:
Warner Chilcott (US), Inc.
Rockaway, NJ 07866 USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-611/S-007, NDA 20-554/S-007, NDA 20-273/S-009
Page 19
U.S. Patent No. 4,866,048
3010G061
Revised XXX 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:21.949315
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020611s007,020554s007,020273s009lbl.pdf', 'application_number': 20273, 'submission_type': 'SUPPL ', 'submission_number': 9}
|
12,410
|
DOVONEX®
(calcipotriene) Cream, 0.005%
Rx only
FOR TOPICAL DERMATOLOGIC USE ONLY.
Not for Ophthalmic, Oral or Intravaginal Use.
DESCRIPTION
Dovonex® (calcipotriene) Cream, 0.005% contains calcipotriene monohydrate, a synthetic vitamin D3 derivative, for topical
dermatological use.
Chemically, calcipotriene monohydrate is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1α,3β,24-triol
monohydrate, with the empirical formula C27H40O3•H2O, a molecular weight of 430.6, and the following structural formula: structural formula
Calcipotriene monohydrate is a white or off-white crystalline substance. Dovonex® Cream contains calcipotriene monohydrate
equivalent to 50 μg/g anhydrous calcipotriene in a cream base of cetearyl alcohol, ceteth-20, diazolidinyl urea, dichlorobenzyl alcohol,
dibasic sodium phosphate, edetate disodium, dl-alpha tocopherol, glycerin, mineral oil, petrolatum, and water.
CLINICAL PHARMACOLOGY
In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7
dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D3.
Clinical studies with radiolabelled calcipotriene ointment indicate that approximately 6% (± 3%, SD) of the applied dose of
calcipotriene is absorbed systemically when the ointment is applied topically to psoriasis plaques, or 5% (± 2.6%, SD) when applied to
normal skin, and much of the absorbed active is converted to inactive metabolites within 24 hours of application. Systemic absorption
of the cream has not been studied.
Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The active form of the vitamin, 1,25
dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver and excreted in the bile. Calcipotriene metabolism following
systemic uptake is rapid, and occurs via a similar pathway to the natural hormone.
Reference ID: 3707425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL STUDIES
Adequate and well-controlled trials of patients treated with Dovonex® Cream have demonstrated improvement usually beginning after
2 weeks of therapy. This improvement continued with approximately 50% of patients showing at least marked improvement in the
signs and symptoms of psoriasis after 8 weeks of therapy, but only approximately 4% showed complete clearing.
INDICATIONS AND USAGE
Dovonex® (calcipotriene) Cream, 0.005%, is indicated for the treatment of plaque psoriasis. The safety and effectiveness of topical
calcipotriene in dermatoses other than psoriasis have not been established.
CONTRAINDICATIONS
Dovonex® Cream is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. It
should not be used by patients with demonstrated hypercalcemia or evidence of vitamin D toxicity. Dovonex® Cream should not be
used on the face.
WARNINGS
Contact dermatitis, including allergic contact dermatitis, has been observed with the use of Dovonex®.
PRECAUTIONS
General
Use of Dovonex® Cream may cause transient irritation of both lesions and surrounding uninvolved skin. If irritation develops,
Dovonex® Cream should be discontinued.
For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.
Reversible elevation of serum calcium has occurred with use of topical calcipotriene. If elevation in serum calcium outside the normal
range should occur, discontinue treatment until normal calcium levels are restored.
Information for Patients
Patients using Dovonex® Cream should receive the following information and instructions:
1. This medication is to be used only as directed by the physician. It is for external use only. Avoid contact with the face or eyes. As
with any topical medication, patients should wash their hands after application.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. Patients should report to their physician any signs of adverse reactions.
4. Patients that apply Dovonex® Cream to exposed portions of the body should avoid excessive exposure to either natural or
artificial sunlight (including tanning booths, sun lamps, etc.).
Carcinogenesis, Mutagenesis, Impairment of Fertility
When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 µg/kg/day (corresponding to 9, 30
and 90 µg/m2/day), no significant changes in tumor incidence were observed when compared to control. In a study in which albino
Reference ID: 3707425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the
formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of
UVR to induce skin tumors. Patients that apply Dovonex® Cream to exposed portions of the body should avoid excessive exposure to
either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of
phototherapy in patients that use Dovonex® Cream.
Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma TK locus assay, a human
lymphocyte chromosome aberration assay, or in a micronucleus assay conducted in mice.
Studies in rats at doses up to 54 μg/kg/day (324 μg/m2/day) of calcipotriene indicated no impairment of fertility or general
reproductive performance.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the
administered dose. Increased rabbit maternal and fetal toxicity was noted at 12 μg/kg/day (132 μg/m2/day). Rabbits administered 36
μg/kg/day (396 μg/m2/day) resulted in fetuses with a significant increase in the incidences of pubic bones, forelimb phalanges, and
incomplete bone ossification. In a rat study, oral doses of 54 μg/kg/day (318 μg/m2/day) resulted in a significantly higher incidence
of skeletal abnormalities consisting primarily of enlarged fontanelles and extra ribs. The enlarged fontanelles are most likely due to
calcipotriene's effect upon calcium metabolism. The maternal and fetal calculated no-effect exposures in the rat (43.2 μg/m2/day)
and rabbit (17.6 μg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 μg/m2/day) from
dermal application. There are no adequate and well-controlled studies in pregnant women. Therefore, Dovonex® Cream should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation, but it is not known whether it is
excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin.
Because many drugs are excreted in human milk, caution should be exercised when Dovonex® Cream is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of Dovonex® Cream in pediatric patients have not been established. Because of a higher ratio of skin surface
area to body mass, pediatric patients are at greater risk than adults of systemic adverse effects when they are treated with topical
medication.
Geriatric Use
Of the total number of patients in clinical studies of calcipotriene cream, approximately 15% were 65 or older, while approximately
3% were 75 and over. There were no significant differences in adverse events for subjects over 65 years compared to those under 65
years of age. However, the greater sensitivity of older individuals cannot be ruled out.
Reference ID: 3707425
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Clinical Trials Experience
In controlled clinical trials, the most frequent adverse experiences reported for Dovonex® (calcipotriene) Cream, 0.005% were cases
of skin irritation, which occurred in approximately 10-15% of patients. Rash, pruritus, dermatitis and worsening of psoriasis were
reported in 1 to 10% of patients.
Postmarketing Experience
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 following adverse reactions associated with the use of Dovonex® Cream have been identified post-approval: contact dermatitis,
including allergic contact dermatitis.
OVERDOSAGE
Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been
observed with excessive use of topical calcipotriene. If elevation in serum calcium should occur, discontinue treatment until normal
calcium levels are restored. (See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Apply a thin layer of Dovonex® Cream to the affected skin twice daily and rub in gently and completely. The safety and efficacy of
Dovonex® Cream have been demonstrated in patients treated for eight weeks.
HOW SUPPLIED
Dovonex® (calcipotriene) Cream, 0.005% is available in:
60 gram aluminum tubes (NDC 50222-260-06)
120 gram aluminum tubes (NDC 50222-260-12)
STORAGE
Store at controlled room temperature 15° C - 25° C (59° F - 77° F). Do not freeze. company logo
Manufactured by: LEO Laboratories Ltd.
Dublin, Ireland
Distributed by:
LEO Pharma Inc.
1 Sylvan Way
Reference ID: 3707425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Parsippany, NJ 07054 USA
1-877-494-4536
To report SUSPECT ADVERSE REACTIONS, contact
LEO Pharma Inc at 1-877-494-4536 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch
U.S. Patent No. RE39,706 E
024609-00
Revised 03/2015
Reference ID: 3707425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dovonex® (calcipotriene) Ointment,
0.005%
Rx only
FOR TOPICAL DERMATOLOGIC USE ONLY.
Not for Ophthalmic, Oral or Intravaginal Use.
DESCRIPTION
Dovonex® (calcipotriene) Ointment, 0.005% contains the compound calcipotriene, a synthetic vitamin D3 derivative, for topical
dermatological use.
Chemically, calcipotriene is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19), 22-tetraene-1α,3β,24-triol-, with the
empirical formula C27H40O3, a molecular weight of 412.6, and the following structural formula: structural formula
Calcipotriene is a white or off-white crystalline substance. Dovonex® ointment contains calcipotriene 50 μg/g in an ointment base of
dibasic sodium phosphate, edetate disodium, mineral oil, petrolatum, propylene glycol, tocopherol, steareth-2 and water.
CLINICAL PHARMACOLOGY
In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7
dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D3.
Clinical studies with radiolabelled calcipotriene ointment indicate that approximately 6% (± 3%, SD) of the applied dose of
calcipotriene is absorbed systemically when the ointment is applied topically to psoriasis plaques or 5% (± 2.6%, SD) when applied to
normal skin, and much of the absorbed active is converted to inactive metabolites within 24 hours of application.
Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The active form of the vitamin, 1,25
dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver and excreted in the bile. Calcipotriene metabolism following
systemic uptake is rapid, and occurs via a similar pathway to the natural hormone. The primary metabolites are much less potent than
the parent compound.
There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation, but it is not known whether it is
excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin.
CLINICAL STUDIES
Adequate and well-controlled trials of patients treated with Dovonex® ointment have demonstrated improvement usually beginning
after 2 weeks of therapy. This improvement continued in patients using Dovonex® once daily and twice daily. After 8 weeks of once
Reference ID: 3707425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
daily Dovonex®, 56.7% of patients showed at least marked improvements (6.4% showed complete clearing). After 8 weeks of twice
daily Dovonex®, 70.0% of patients showed at least marked improvement (11.3% showed complete clearing).
Subtracting percentages of patients using placebo (vehicle only) from percentages of patients using Dovonex® who had at least
marked improvements after 8 weeks yields 39.9% for once daily and 49.6% for twice daily. This adjustment for placebo effect
indicates that what might appear to be differences between once daily and twice daily use may reflect differences in the studies
independent from the frequency of dosing. Although there was a numerical difference in comparison across studies, twice daily dosing
has not been shown to be superior in efficacy to once daily dosing.
Over 400 patients have been treated in open label clinical studies of Dovonex® for periods of up to one year. In half of these studies,
patients who previously had not responded well to Dovonex® were excluded. The adverse events in these extended studies included
skin irritation in approximately 25% of patients and worsening of psoriasis in approximately 10% of patients. In one of these open
label studies, half of the patients no longer required Dovonex® by 16 weeks of treatment, because of satisfactory therapeutic results.
INDICATIONS AND USAGE
Dovonex® (calcipotriene) Ointment, 0.005%, is indicated for the treatment of plaque psoriasis in adults. The safety and effectiveness
of topical calcipotriene in dermatoses other than psoriasis have not been established.
CONTRAINDICATIONS
Dovonex® is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. It should
not be used by patients with demonstrated hypercalcemia or evidence of vitamin D toxicity. Dovonex® should not be used on the face.
WARNINGS
Contact dermatitis, including allergic contact dermatitis, has been observed with the use of Dovonex®.
PRECAUTIONS
General
Use of Dovonex® may cause irritation of lesions and surrounding uninvolved skin. If irritation develops, Dovonex® should be
discontinued.
For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.
Transient, rapidly reversible elevation of serum calcium has occurred with use of Dovonex®. If elevation in serum calcium outside the
normal range should occur, discontinue treatment until normal calcium levels are restored.
Information for Patients
Patients using Dovonex® should receive the following information and instructions:
1. This medication is to be used only as directed by the physician. It is for external use only. Avoid contact with the face or eyes. As
with any topical medication, patients should wash their hands after application.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. Patients should report to their physician any signs of local adverse reactions.
4. Patients that apply Dovonex® to exposed portions of the body should avoid excessive exposure to either natural or artificial
sunlight (including tanning booths, sun lamps, etc.).
Reference ID: 3707425
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
When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 µg/kg/day (corresponding to 9, 30
and 90 µg/m2/day), no significant changes in tumor incidence were observed when compared to control. In a study in which albino
hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the
formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of
UVR to induce skin tumors. Patients that apply Dovonex® to exposed portions of the body should avoid excessive exposure to either
natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to avoid use of phototherapy in patients
that use Dovonex®.
Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma TK locus assay, a human
lymphocyte chromosome aberration assay, or in a micronucleus assay conducted in mice.
Studies in rats at doses up to 54 μg/kg/day (324 μg/m2/day) of calcipotriene indicated no impairment of fertility or general
reproductive performance.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the
administered dose. In rabbits, increased maternal and fetal toxicity was noted at 12 μg/kg/day (132 μg/m2/day); a dosage of 36
μg/kg/day (396 μg/m2/day) resulted in a significant increase in the incidences of incomplete ossification of the pubic bones and
forelimb phalanges of fetuses. In a rat study, a dosage of of 54 μg/kg/day (318 μg/m2/day) resulted in a significantly increased
incidence of skeletal abnormalities (enlarged fontanelles and extra ribs). The enlarged fontanelles are most likely due to calcipotriene's
effect upon calcium metabolism. The estimated maternal and fetal no-effect exposure levels in the rat (43.2 μg/m2/day) and rabbit
(17.6 μg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 μg/m2/day) from dermal
application. There are no adequate and well-controlled studies in pregnant women. Therefore, Dovonex® ointment should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in human milk, caution should be
exercised when Dovonex® (calcipotriene ointment), 0.005% is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Dovonex® in pediatric patients have not been established. Because of a higher ratio of skin surface area to
body mass, pediatric patients are at greater risk than adults of systemic adverse effects when they are treated with topical medication.
Geriatric Use
Of the total number of patients in clinical studies of calcipotriene ointment, approximately 12% were 65 or older, while approximately
4% were 75 and over. The results of analysis of severity of skin-related adverse events showed a statistically significant difference for
subjects over 65 years (more severe) compared to those under 65 years (less severe).
ADVERSE REACTIONS
Clinical Trials Experience
Reference ID: 3707425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In controlled clinical trials, the most frequent adverse experiences reported for Dovonex® were burning, itching and skin irritation,
which occurred in approximately 10-15% of patients. Erythema, dry skin, peeling, rash, dermatitis, worsening of psoriasis including
development of facial/scalp psoriasis were reported in 1 to 10% of patients. Other experiences reported in less than 1% of patients
included skin atrophy, hyperpigmentation, hypercalcemia, and folliculitis. Once daily dosing has not been shown to be superior in
safety to twice daily dosing.
Postmarketing Experience
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 following adverse reactions associated with the use of Dovonex® Ointment have been identified post-approval: contact dermatitis,
including allergic contact dermatitis.
OVERDOSAGE
Topically applied Dovonex® can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been
observed with excessive use of Dovonex® ointment.
DOSAGE AND ADMINISTRATION
Apply a thin layer of Dovonex® ointment once or twice daily and rub in gently and completely.
HOW SUPPLIED
Dovonex® (calcipotriene ointment), 0.005% is available in:
60 gram aluminum tubes N 0430-3010-15
120 gram aluminum tubes N 0430-3010-17
STORAGE
Store at controlled room temperature 15° C - 25° C (59° F - 77° F). Do not freeze. company logo
Manufactured by: LEO Laboratories Ltd.
Dublin, Ireland
Revised
03/2015
Reference ID: 3707425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020273s013,020554s012lbl.pdf', 'application_number': 20273, 'submission_type': 'SUPPL ', 'submission_number': 13}
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DERMATOP® Emollient Cream
(prednicarbate emollient cream) 0.1%
FOR DERMATOLOGIC USE ONLY.
NOT FOR USE IN EYES.
DESCRIPTION
DERMATOP® Emollient Cream (prednicarbate emollient cream) 0.1% contains
prednicarbate, a synthetic corticosteroid for topical dermatologic use. The chemical
name of prednicarbate is 11β, 17, 21-trihydroxypregna-1,4-diene- 3,20-dione 17-(ethyl
carbonate) 21-propionate. Prednicarbate has the empirical formula C27H36O8 and a
molecular weight of 488.58. Topical corticosteroids constitute a class of primarily
synthetic steroids used topically as anti-inflammatory and antipruritic agents.
The CAS Registry Number is 73771-04-7. The chemical structure is:
Prednicarbate is a practically odorless white to yellow-white powder insoluble to
practically insoluble in water and freely soluble in ethanol.
Each gram of DERMATOP Emollient Cream 0.1% contains 1.0 mg of prednicarbate in a
base consisting of white petrolatum USP, purified water USP, isopropyl myristate NF,
lanolin alcohols NF, mineral oil USP, cetostearyl alcohol NF, aluminum stearate, edetate
disodium USP, lactic acid USP, and magnesium stearate DAB 9.
CLINICAL PHARMACOLOGY
In common with other topical corticosteroids, prednicarbate has anti-inflammatory,
antipruritic, and vasoconstrictive properties. In general, the mechanism of the anti
inflammatory activity of topical steroids 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. Use of
occlusive dressings with hydrocortisone for up to 24 hours have not been shown to
increase penetration; however, occlusion of hydrocortisone for 96 hours does markedly
Reference ID: 2872757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
enhance penetration. Topical corticosteroids can be absorbed from normal intact skin.
Inflammation and/or other disease processes in the skin increase percutaneous
absorption.
Studies performed with DERMATOP Emollient Cream (prednicarbate emollient cream)
0.1 % indicate that the drug product is in the medium range of potency compared with
other topical corticosteroids.
INDICATIONS AND USAGE
DERMATOP Emollient Cream 0.1% is a medium-potency corticosteroid indicated for
the relief of the inflammatory and pruritic manifestations of corticosteroid responsive
dermatoses. DERMATOP Emollient Cream 0.1% may be used with caution in pediatric
patients 1 year of age or older. The safety and efficacy of drug use for longer than 3
weeks in this population have not been established. Since safety and efficacy of
DERMATOP Emollient Cream 0.1% have not been established in pediatric patients
below 1 year of age, its use in this age group is not recommended.
CONTRAINDICATIONS
DERMATOP Emollient Cream 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 applying a topical steroid 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 Emollient Cream 0.1% did not produce significant HPA-axis suppression
when used at a dose of 30g/day for a week in 10 adult patients with extensive psoriasis
or atopic dermatitis. DERMATOP Emollient Cream 0.1% did not produce HPA-axis
suppression in any of 59 pediatric patients with extensive atopic dermatitis when applied
BID for 3 weeks to > 20% of the body surface (See PRECAUTIONS, Pediatric Use.)
If HPA-axis suppression is noted, an attempt should be made to withdraw the drug, to
reduce the frequency of the 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.)
If irritation develops, DERMATOP Emollient Cream 0.1% should be discontinued and
appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually
Reference ID: 2872757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diagnosed by observing a failure to heal rather than noting a clinical exacerbation, as
observed 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 Emollient Cream
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, 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 this medication in the
treatment of diaper dermatitis. This medication should not be applied in the diaper
area as diapers or plastic pants may constitute occlusive dressing (See DOSAGE
AND ADMINISTRATION).
6. This medication should not be used on the face, underarms, or groin areas.
7. Contact between DERMATOP Emollient Cream 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 Emollient Cream 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.
As with other corticosteroids, therapy should be discontinued when control is achieved.
If no improvement is seen within two weeks, contact the physician.
Laboratory Tests
The following tests may be helpful in evaluating patients for HPA-axis suppression:
ACTH stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
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
Reference ID: 2872757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 1900 times and
45 times 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 higher than the spontaneous rate were noted.
In rabbits, increased liver weights and slight increase in the fetal intrauterine death rate
were observed. The fetuses that were 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. DERMATOP Emollient Cream (prednicarbate emollient cream)
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
Emollient Cream 0.1% is administered to a nursing woman.
Pediatric Use
DERMATOP Emollient Cream 0.1% may be used with caution in pediatric patients 1
year of age or older, although the safety and efficacy of drug use longer than 3 weeks
have not been established. The use of DERMATOP Emollient Cream (prednicarbate
emollient cream) 0.1% is supported by results of a three-week, uncontrolled study in 59
pediatric patients between the ages of 4 months and 12 years of age with atopic
dermatitis. None of the 59 pediatric patients showed evidence of HPA-axis suppression.
Safety and efficacy of DERMATOP Emollient Cream 0.1% in pediatric patients below 1
year of age have not been established, therefore use in this age group is not
recommended. Because of a higher ratio of skin surface area to body mass, pediatric
patients are at a greater risk than adults of HPA-axis suppression and Cushing'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. In an
uncontrolled study in pediatric patients with atopic dermatitis, the incidence of adverse
reactions possibly or probably associated with the use of DERMATOP Emollient Cream
0.1% was limited.
Mild signs of atrophy developed in 5 patients (5/59, 8%) during the clinical trial, with 2
patients exhibiting more than one sign. Two patients (2/59, 3%) developed shininess,
and two patients (2/59, 3%) developed thinness. Three patients (3/59, 5%) were
observed with mild telangiectasia. It is unknown whether prior use of topical
Reference ID: 2872757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
corticosterioids was a contributing factor in the development of telangiectasia in 2 of the
patients. Adverse effects including striae have also been reported with inappropriate use
of topical corticosteroids in infants and children. Pediatric patients applying topical
corticosteroids to greater than 20% of body surface are at higher risk for HPA-axis
suppression.
HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight
gain and intracranial hypertension have been reported in children receiving topical corti-
costeroids. Manifestations of adrenal suppression in children include low plasma
cortisol levels, and absence of response to ACTH stimulation. Manifestations of
intracranial hypertension include bulging fontanelles, headaches, and bilateral
papilledema.
DERMATOP Emollient Cream 0.1% should not be used in the treatment of diaper
dermatitis.
ADVERSE REACTIONS
In controlled adult clinical studies, the incidence of adverse reactions probably or
possibly associated with the use of DERMATOP Emollient Cream 0.1% was
approximately 4%. Reported reactions included mild signs of skin atrophy in 1% of
treated patients, as well as the following reactions which were reported in less than 1% of
patients: pruritis, edema, paresthesia, urticaria, burning, allergic contact dermatitis and
rash.
In an uncontrolled study in pediatric patients with atopic dermatitis, the incidence of
adverse reactions possibly or probably associated with the use of DERMATOP Emollient
Cream 0.1 % was limited. Mild signs of atrophy developed in 5 patients (5/59, 8%)
during the clinical trial, with 2 patients exhibiting more than one sign. Two patients
(2/59, 3%) developed shininess, and 2 patients (2/59, 3%) developed thinness. Three
patients (3/59, 5 %) were observed with mild telangiectasia. It is unknown whether prior
use of topical corticosteroids was a contributing factor in the development of
telangiectasia in 2 of the patients (See PRECAUTIONS, Pediatric Use.)
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:
folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, secondary
infection, 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 Emollient Cream (prednicarbate emollient cream)
0.1% to the affected skin areas twice daily. Rub in gently.
DERMATOP Emollient Cream (prednicarbate emollient cream) 0.1 % may be used in
pediatric patients 1 year of age or older. Safety and efficacy of DERMATOP Emollient
Cream 0.1% in pediatric patients for more than 3 weeks of use have not been
established. Use in pediatric patients under 1 year of age is not recommended.
Reference ID: 2872757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
As with other corticosteroids, therapy should be discontinued when control is achieved.
If no improvement is seen within 2 weeks, reassessment of the diagnosis may be
necessary.
DERMATOP Emollient Cream 0.1% should not be used with occlusive dressings unless
directed by the physician. DERMATOP Emollient Cream 0.1% 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
DERMATOP Emollient Cream (prednicarbate emollient cream) 0.1% is supplied in
15 g (NDC 0066-0507-15) and 60 g (NDC 0066-0507-60) tubes.
Store between 41 and 77°F (5 and 25°C).
Rx Only
Dermik Laboratories
a business of sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Revised October 2010
© 2010 sanofi-aventis U.S. LLC
Reference ID: 2872757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:22.259391
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020279s009lbl.pdf', 'application_number': 20279, 'submission_type': 'SUPPL ', 'submission_number': 9}
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Instructions for Use
Important Note
Please read these instructions completely before using the
GENOTROPIN PEN 5. If there is anything you
do not understand or cannot do, call the toll-free
number listed at the end of these instructions.
If you have any questions about your dose or your treatment
with GENOTROPIN, call your healthcare provider.
GENOTROPIN PEN 5 is a device used to mix and inject doses of GENOTROPIN Lyophilized Powder
(somatropin [rDNA origin] for injection). Use this device only for administration of GENOTROPIN.
What You Will Need
• GENOTROPIN PEN 5
• 5.8 mg two-chamber cartridge of GENOTROPIN
• Alcohol swab
• 29-gauge or 30-gauge Becton Dickinson pen needle
• Proper disposal container for used needles
Components of the GENOTROPIN PEN 5
Before You Begin
To help prevent infection, always wash your hands with soap and water before preparing or using the
GENOTROPIN PEN 5.
1. Attach the Needle
• Remove the front cap from the GENOTROPIN
PEN 5.
• Unscrew the metal front part and detach it from the plastic
body of the pen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Remove the paper covering from the back of a new needle.
• Screw the needle onto the metal front part by gently turning it
clockwise (to the right).
2. Insert the Two-Chamber Cartridge of GENOTROPIN
• Use only the 5.8 mg cartridge.
• Wipe the metal/rubber tip of the cartridge with an alcohol
swab.
• Insert the cartridge into the metal front part of the pen, with
the metal/rubber tip towards the needle end. Push the cartridge
firmly into place.
3. Prepare the Body of the Pen
• Press the red release button to release the black/white
injection knob.
• Turn the black/white injection knob counterclockwise (to
the left) as far as it will go.
• Check that the plunger rod is not visible through the window at
the top of the plastic body of the pen. DO NOT proceed if the
plunger rod is visible, as the medication will not be properly
mixed. Instead, press the red release button again to draw back
the plunger rod. After the rod is no longer visible through the
window, proceed to the next step.
4. Screw the GENOTROPIN PEN 5 Together
• Hold the metal front part upright
• While holding upright, gently screw the metal front part and
the plastic body back together. This mixes the diluent in the rear
chamber of the cartridge with the growth hormone powder in the
front chamber.
• Gently tip the assembled GENOTROPIN PEN 5 from side to
side to help dissolve the powder completely. DO NOT SHAKE
as that might inactivate the growth hormone.
5. Examine Solution and Release Trapped Air
• Look through the cartridge windows in the metal front part of
the pen and make sure the drug solution is clear. If you see
particles or if the solution is discolored, DO NOT INJECT IT.
Instead, call the toll-free number listed at the end of these
instructions.
• Remove the outer needle cap and save it for later.
• Remove and discard the inner needle cap. Be careful not to
touch the exposed needle.
• Remove any trapped air from the solution as follows:
a)
Turn the black/white injection knob clockwise (to the
right) one click. This will line up the white mark on the
injection knob and the black mark on the body of the pen.
b)
Hold the GENOTROPIN PEN 5 upright and gently tap
the metal front part with your finger to move any air
bubbles to the top.
c)
Push the black/white injection knob all the way in. You
will see a drop of liquid appear at the needle point. Any
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
trapped air has now been released.
d)
If no liquid squirts out, press the red release button and
turn the black/white injection knob clockwise (to the
right) until it clicks once. Repeat steps b) and c).
• If desired, attach the reusable needle guard over the needle—
push until it snaps in place. Again, be careful not to touch the
exposed needle. To avoid an accidental needle stick, grip the
sides of the needle guard; never push on the end.
6. Dial Your Prescribed Dose
• Press the red release button to reset the device.
• The black/white injection knob will pop out and the dose
display window will read 0.0.
• With the dose display activated, turn the black/white injection
knob clockwise (to the right) until your prescribed dose is
displayed.
• If you go too far, just turn the knob back the other way until the
correct dose is displayed.
NOTE: If you turn the black/white injection knob backwards
beyond zero after a cartridge has been inserted, the pen display
will show (--). Just turn the injection knob forward (clockwise)
until numbers reappear on the dose display.
• The GENOTROPIN PEN 5 contains a battery for the dose
display. To save the battery’s energy, the dose display is
activated for two minutes and then automatically disappears.
Although the display is no longer visible, the dose remains
available for delivery.
NOTE: Each click of the black/white injection knob equals a
one-tenth-of-a milligram dose (or 0.1 mg). One click—or 0.1
mg—is the minimum possible dose per injection; 20 clicks—or
2.0 mg—is the maximum possible dose per injection. If you
accidentally dial more than the maximum 2.0 mg dose, some
liquid may emerge from the tip. This is normal and will not
affect your injection—simply dial back to the correct dose.
7. Inject your GENOTROPIN
• Select and prepare an appropriate injection site, as directed by
your healthcare provider.
• Pinch a fold of skin at the injection site firmly, and push the
GENOTROPIN PEN 5 into the skinfold at a 90° angle. Push the
pen down as far as possible.
• Push the black/white injection knob until it clicks. Wait at
least 5 seconds and then withdraw the GENOTROPIN PEN 5.
8. Discard the Needle and Store the GENOTROPIN
PEN 5
• Remove and store the needle guard, if you used one.
• Carefully replace the outer protective cap on the needle, as
instructed by your healthcare provider.
• Unscrew the needle and discard it in a proper disposal
container. NEVER REUSE A NEEDLE.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Replace the front cap, then put the GENOTROPIN PEN 5 back
in its protective case. Store it in the refrigerator at 2° to 8°C (36°
to 46°F) until your next injection.
Your Next Injection
If you already have a drug cartridge in your GENOTROPIN PEN 5, prepare the pen and administer your
dose as follows:
• Remove the front cap of the GENOTROPIN PEN 5.
• Remove the paper covering from the back of a new needle.
• Screw the needle onto the metal front part of the pen by turning it clockwise (to the right).
• Remove the outer and inner needle caps.
• Follow the instructions above, starting with step 6.
To Replace the Cartridge
• Press the red release button to reset the GENOTROPIN PEN 5.
• Turn the black/white injection knob counterclockwise (to the left) as far as it will go.
• Unscrew the metal front part and remove the empty cartridge.
• Discard the empty cartridge as instructed by your healthcare provider.
• To insert a new cartridge and prepare the GENOTROPIN PEN 5 for use, follow the instructions above.
Storage
Between uses, store your GENOTROPIN PEN 5 in the refrigerator at 2° to 8°C (36° to 46°F) in its
protective case. Always remove the needle before storing. Do not freeze. Protect from light. Discard the
cartridge in your GENOTROPIN PEN 5 within 28 days after reconstitution (mixing of the growth hormone
powder with the liquid) even if the cartridge is not empty.
When traveling, keep your GENOTROPIN PEN 5 in its protective case and carry it in an insulated bag to
protect it from heat or freezing. Put it back in the refrigerator as soon as possible.
Caring For Your GENOTROPIN PEN 5
No special maintenance is required. To clean the GENOTROPIN PEN 5, wipe the outside surface with a
damp cloth. Do not immerse. Do not use alcohol or any other cleaning agents, as they may damage the
plastic body.
To clean the reusable needle guard, wipe it with a damp cloth or alcohol swab.
COMMON QUESTIONS
How do I tell how much GENOTROPIN is left in the GENOTROPIN PEN 5?
Look at the dose scale imprinted along the side of the window on the metal front part of the pen. The front
edge of the gray rubber plunger lines up with the number of milligrams remaining in the cartridge.
What happens when the battery runs low?
The battery in the GENOTROPIN PEN 5 should run for two years. When it begins to run low due to the
end of the battery’s life, you will see a flashing symbol (≡) in the dose display. This means the battery will
last about another month. When the battery is dead, the dose display will show a steady≡ ≡. A flashing "bt"
means the battery is running very low for some other reason and will last for about another month. When
the battery is dead, the display will then show a steady "bt".
In either case, call the Pfizer Bridge Program at the toll-free number listed below to exchange your
GENOTROPIN PEN 5 for a new one.
If the battery suddenly dies, can the GENOTROPIN PEN 5 still be used?
Yes. Call the Pfizer Bridge Program at the toll-free number listed below for instructions on how to
determine the dose without the electronic dose display.
Questions about how to use the GENOTROPIN PEN 5?
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call the Pfizer Bridge Program toll-free at (800) 645-1280
Manufactured by:
Ypsomed AG
Burgdorf, Switzerland
Caution: Federal law restricts this device to sale by or on the order of a physician
LAB-0225-3.0
Revised September 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Instructions for Use
Important Note
Please read these instructions completely before using the
GENOTROPIN PEN 12. If there is anything you
do not understand or cannot do, call the toll-free
number listed at the end of these instructions.
If you have any questions about your dose or your treatment
with GENOTROPIN, call your healthcare provider.
GENOTROPIN PEN 12 is a device used to mix and inject doses of GENOTROPIN Lyophilized Powder
(somatropin [rDNA origin] for injection). Use this device only for administration of GENOTROPIN.
What You Will Need
•
GENOTROPIN PEN 12
•
13.8 mg two-chamber cartridge of GENOTROPIN
•
Alcohol swab
•
29-gauge or 30-gauge Becton Dickinson pen needle
•
Proper disposal container for used needles
Components of the GENOTROPIN PEN 12
Before You Begin
To help prevent infection, always wash your hands with soap and water before
preparing or using the GENOTROPIN PEN 12.
1. Attach the Needle
•
Remove the front cap from the
GENOTROPIN PEN 12.
•
Unscrew the metal front part and detach it
from the plastic body of the pen.
•
Remove the paper covering from the back of a
new needle.
•
Screw the needle onto the metal front part by
gently turning it clockwise (to the right).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
2. Insert the Two-Chamber Cartridge of
GENOTROPIN
•
Use only the 13.8 mg cartridge.
•
Wipe the metal/rubber tip of the cartridge with
an alcohol swab.
•
Insert the cartridge into the metal front part of
the pen, with the metal/rubber tip towards the
needle end. Push the cartridge firmly into
place.
3. Prepare the Body of the Pen
•
Press the red release button to release the
black/white injection knob.
•
Turn the black/white injection knob
counterclockwise (to the left) as far as it will
go.
•
Check that the plunger rod is not visible
through the window at the top of the plastic
body of the pen. Do NOT proceed if the
plunger rod is visible, as the medication will
not be properly mixed. Instead, press the red
release button again to draw back the plunger
rod. After the rod is no longer visible through
the window, proceed to the next step.
4. Screw the GENOTROPIN PEN 12 Together
•
Hold the metal front part upright.
•
While holding upright, gently screw the metal
front part and the plastic body back together.
This mixes the diluent in the rear chamber of
the cartridge with the growth hormone powder
in the front chamber.
•
Gently tip the assembled GENOTROPIN PEN
12 from side to side to help dissolve the
powder completely. DO NOT SHAKE as that
might inactivate the growth hormone.
5. Examine Solution and Release Trapped Air
•
Look through the cartridge windows in the
metal front part of the pen and make sure the
drug solution is clear. If you see particles or if
the solution is discolored, DO NOT INJECT
IT. Instead, call the toll-free number listed at
the end of these instructions.
•
Remove the outer needle cap and save it for
later.
•
Remove and discard the inner needle cap. Be
careful not to touch the exposed needle.
•
Remove any trapped air from the solution as
follows:
a) Turn the black/white injection knob
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
clockwise (to the right) one click.
This will line up the white mark on
the injection knob and the black mark
on the body of the pen.
b) Hold the GENOTROPIN PEN 12
upright and gently tap the metal front
part with your finger to move any air
bubbles to the top.
c) Push the black/white injection knob
all the way in. You will see a drop of
liquid appear at the needle point. Any
trapped air has now been released.
d) If no liquid squirts out, press the red
release button and turn the
black/white injection knob clockwise
(to the right) until it clicks once.
Repeat steps b) and c).
•
If desired, attach the reusable needle guard
over the needle—push until it snaps in place.
Again, be careful not to touch the exposed
needle. To avoid an accidental needle stick,
grip the sides of the needle guard; never push
on the end.
6. Dial Your Prescribed Dose
•
Press the red release button to reset the device.
•
The black/white injection knob will pop out
and the dose display window will read 0.0.
•
With the dose display activated, turn the
black/white injection knob clockwise (to the
right) until your prescribed dose is displayed.
•
If you go too far, just turn the knob back the
other way until the correct dose is displayed.
NOTE: If you turn the black/white injection
knob backwards beyond zero after a cartridge
has been inserted, the pen display will show (-
-). Just turn the injection knob forward
(clockwise) until numbers reappear on the
dose display.
•
The GENOTROPIN PEN 12 contains a
battery for the dose display. To save the
battery’s energy, the dose display is activated
for two minutes and then automatically
disappears. Although the display is no longer
visible, the dose remains available for
delivery. NOTE: Each click of the black/white
injection knob equals a two-tenth-of-a
milligram dose (or 0.2 mg). One click—or 0.2
mg—is the minimum possible dose per
injection; 20 clicks—or 4.0 mg—is the
maximum possible dose per injection. If you
accidentally dial more than the maximum 4.0
mg dose, some liquid may emerge from the
tip. This is normal and will not affect your
injection—simply dial back to the correct
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
dose.
7. Inject your GENOTROPIN
•
Select and prepare an appropriate injection
site, as directed by your healthcare provider.
•
Pinch a fold of skin at the injection site firmly,
and push the GENOTROPIN PEN 12 into the
skinfold at a 90° angle. Push the pen down as
far as possible.
•
Push the black/white injection knob until it
clicks. Wait at least 5 seconds and then
withdraw the GENOTROPIN PEN 12.
8. Discard the Needle and Store the
GENOTROPIN PEN 12
•
Remove and store the needle guard, if you
used one.
•
Carefully replace the outer protective cap on
the needle, as instructed by your healthcare
provider.
•
Unscrew the needle and discard it in a proper
disposal container. NEVER REUSE A
NEEDLE.
•
Replace the front cap, then put the
GENOTROPIN PEN 12 back in its protective
case. Store it in the refrigerator at 2° to 8°C
(36° to 46°F) until your next injection.
Your Next Injection
If you already have a drug cartridge in your GENOTROPIN PEN 12, prepare the pen and administer your
dose as follows:
•
Remove the front cap of the GENOTROPIN PEN 12.
•
Remove the paper covering from the back of a new needle.
•
Screw the needle onto the metal front part of the pen by turning it clockwise (to the right).
•
Remove the outer and inner needle caps.
•
Follow the instructions above, starting with step 6.
To Replace the Cartridge
•
Press the red release button to reset the GENOTROPIN PEN 12.
•
Turn the black/white injection knob counterclockwise (to the left) as far as it will go.
•
Unscrew the metal front part and remove the empty cartridge.
•
Discard the empty cartridge as instructed by your healthcare provider.
•
To insert a new cartridge and prepare the GENOTROPIN PEN 12 for use, follow the instructions
above.
Storage
Between uses, store your GENOTROPIN PEN 12 in the refrigerator at 2° to 8°C (36° to 46°F) in its
protective case. Always remove the needle before storing. Do not freeze. Protect from light. Discard the
cartridge in your GENOTROPIN PEN 12 within 28 days after reconstitution (mixing of the growth
hormone powder with the diluent) even if the cartridge is not empty.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
When traveling, keep your GENOTROPIN PEN 12 in its protective case and carry it in an insulated bag to
protect it from heat or freezing. Put it back in the refrigerator as soon as possible.
Caring For Your GENOTROPIN PEN 12
No special maintenance is required. To clean the GENOTROPIN PEN 12, wipe the outside surface with a
damp cloth. Do not immerse. Do not use alcohol or any other cleaning agents, as they may damage the
plastic body.
To clean the reusable needle guard, wipe it with a damp cloth or alcohol swab.
COMMON QUESTIONS
How do I tell how much GENOTROPIN is left in the GENOTROPIN PEN 12?
Look at the dose scale imprinted along the side of the window on the metal front part of the pen. The front
edge of the gray rubber plunger lines up with the number of milligrams remaining in the cartridge.
What happens when the battery runs low?
The battery in the GENOTROPIN PEN 12 should run for two years. When it begins to run low due to the
end of the battery´s life, you will see a flashing symbol (
) in the dose display. This means the battery will
last about another month. When the battery is dead, the dose display will show a steady
. A flashing
"bt" means the battery is running very low for some other reason and will last for about another month.
When the battery is dead, the display will then show a steady "bt".
In either case, call the Pfizer Bridge Program at the toll-free number listed below to exchange your
GENOTROPIN PEN 12 for a new one.
If the battery suddenly dies, can the GENOTROPIN PEN 12 still be used?
Yes. Call the Pfizer Bridge Program at the toll-free number listed below for instructions on how to
determine the dose without the electronic dose display.
Questions about how to use the GENOTROPIN PEN 12?
Call the Pfizer Bridge Program toll-free at (800) 645-1280
Caution: Federal law restricts this device to sale by or on the order of a physician.
LAB-0224-4.0
Revised September 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020280s055lbl.pdf', 'application_number': 20280, 'submission_type': 'SUPPL ', 'submission_number': 55}
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ULTRAM®
(tramadol hydrochloride) Tablets
Full Prescribing Information
DESCRIPTION
ULTRAM® (tramadol hydrochloride) tablets is a centrally acting analgesic. The chemical
name
for
tramadol
hydrochloride
is
(±)cis-2-[(dimethylamino)methyl]-1-(3
methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: Structural Formula
The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride is a
white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol
and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH
7. ULTRAM® tablets contain 50 mg of tramadol hydrochloride and are white in color.
Inactive ingredients in the tablet are pregelatinized corn starch, modified starch (corn),
hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and carnauba wax.
CLINICAL PHARMACOLOGY
Pharmacodynamics
ULTRAM® contains tramadol, a centrally acting synthetic opioid analgesic. Although its
mode of action is not completely understood, from animal tests, at least two
complementary mechanisms appear applicable: binding of parent and M1 metabolite to
μ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher
affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal
models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200
times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially
1
antagonized by the opiate antagonist naloxone in several animal tests. The relative
contribution of both tramadol and M1 to human analgesia is dependent upon the plasma
concentrations
of
each
compound
(see
CLINICAL
PHARMACOLOGY,
Pharmacokinetics).
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as
have some other opioid analgesics. These mechanisms may contribute independently to
the overall analgesic profile of ULTRAM®. Analgesia in humans begins approximately
within one hour after administration and reaches a peak in approximately two to three
hours.
Apart from analgesia, ULTRAM® administration may produce a constellation of
symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus)
similar to that of other opioids. In contrast to morphine, tramadol has not been shown to
cause histamine release. At therapeutic doses, ULTRAM® has no effect on heart rate,
left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
Pharmacokinetics
The analgesic activity of ULTRAM® is due to both parent drug and the M1 metabolite
(see
CLINICAL
PHARMACOLOGY,
Pharmacodynamics).
Tramadol
is
administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are
detected in the circulation. Linear pharmacokinetics have been observed following
multiple doses of 50 and 100 mg to steady-state.
Absorption
The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The
mean peak plasma concentration of racemic tramadol and M1 occurs at two and three
hours, respectively, after administration in healthy adults. In general, both enantiomers of
tramadol and M1 follow a parallel time course in the body following single and multiple
doses although small differences (∼ 10%) exist in the absolute amount of each
enantiomer present.
Steady-state plasma concentrations of both tramadol and M1 are achieved within
two days with four times per day dosing. There is no evidence of self-induction
(see Figure 1 and Table 1 below).
2
c
Figure 1:
Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg
Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given
fraph
Table 1
Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1
Metabolite
Population/
Dosage Regimena
Parent Drug/
Metabolite
PeakConc.
(ng/mL)
Time to
Peak (hrs)
Clearance/Fb
(mL/min/Kg)
t1/2 (hrs)
Healthy Adults,
100 mg qid, MD p.o.
Tramadol
M1
592 (30)
110 (29)
2.3 (61)
2.4 (46)
5.90 (25)
c
6.7 (15)
7.0 (14)
Healthy Adults,
100 mg SD p.o.
Tramadol
M1
308 (25)
55.0 (36)
1.6 (63)
3.0 (51)
8.50 (31)
c
5.6 (20)
6.7 (16)
Geriatric, (>75 yrs)
50 mg SD p.o.
Tramadol
M1
208 (31)
d
2.1 (19)
d
6.89 (25)
c
7.0 (23)
d
Hepatic Impaired,
50 mg SD p.o.
Tramadol
M1
217 (11)
19.4 (12)
1.9 (16)
9.8 (20)
4.23 (56)
c
13.3 (11)
18.5 (15)
Renal Impaired,
CLcr10-30 mL/min
100 mg SD i.v.
Tramadol
M1
c
c
c
c
4.23 (54)
c
10.6 (31)
11.5 (40)
Renal Impaired,
CLcr<5 mL/min
100 mg SD i.v.
Tramadol
M1
c
c
c
c
3.73 (17)
c
11.0 (29)
16.9 (18)
a SD = Single dose, MD = Multiple dose, p.o.= Oral administration,
i.v.= Intravenous administration, q.i.d. = Four times daily
b F represents the oral bioavailability of tramadol
Not applicable
d Not measured
Food Effects
Oral administration of ULTRAM® with food does not significantly affect its rate or
extent of absorption, therefore, ULTRAM® can be administered without regard to food.
Distribution
The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female
subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to
3
human plasma proteins is approximately 20% and binding also appears to be independent
of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at
concentrations outside the clinically relevant range.
Metabolism
Tramadol is extensively metabolized after oral administration by a number of pathways,
including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites.
Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60%
of the dose is excreted as metabolites. The remainder is excreted either as unidentified or
as unextractable metabolites. The major metabolic pathways appear to be N- and
O-demethylation and glucuronidation or sulfation in the liver. One metabolite
(O-desmethyltramadol, denoted M1) is pharmacologically active in animal models.
Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which
may affect the therapeutic response (see PRECAUTIONS, Drug Interaction).
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of
cytochrome P-450. These individuals are "poor metabolizers" of debrisoquine,
dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population
PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were
approximately 20% higher in "poor metabolizers" versus "extensive metabolizers", while
M1 concentrations were 40% lower. Concomitant therapy with inhibitors of CYP2D6
such as fluoxetine, paroxetine and quinidine could result in significant drug interactions.
In vitro drug interaction studies in human liver microsomes indicate that inhibitors of
CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine
inhibit the metabolism of tramadol to various degrees, suggesting that concomitant
administration of these compounds could result in increases in tramadol concentrations
and decreased concentrations of M1. The full pharmacological impact of these alterations
in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-
uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events,
including seizure (see WARNINGS) and serotonin syndrome.
Elimination
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are
eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of
racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The
plasma elimination half-life of racemic tramadol increased from approximately six hours
to seven hours upon multiple dosing.
4
Special Populations
Renal
Impaired renal function results in a decreased rate and extent of excretion of tramadol
and its active metabolite, M1. In patients with creatinine clearances of less than
30 mL/min, adjustment of the dosing regimen is recommended (see DOSAGE AND
ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour
dialysis period is less than 7% of the administered dose.
Hepatic
Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the
liver, resulting in both a larger area under the concentration time curve for tramadol and
longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for M1).
In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE
AND ADMINISTRATION).
Geriatric
Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and
elimination half-lives comparable to those observed in healthy subjects less than 65 years
of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs.
162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to
subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients
older than 75 years (see DOSAGE AND ADMINISTRATION).
Gender
The absolute bioavailability of tramadol was 73% in males and 79% in females. The
plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a
100 mg IV dose of tramadol. Following a single oral dose, and after adjusting for body
weight, females had a 12% higher peak tramadol concentration and a 35% higher area
under the concentration-time curve compared to males. The clinical significance of this
difference is unknown.
CLINICAL STUDIES
ULTRAM® has been given in single oral doses of 50, 75 and 100 mg to patients with
pain following surgical procedures and pain following oral surgery (extraction of
impacted molars).
In single-dose models of pain following oral surgery, pain relief was demonstrated in
some patients at doses of 50 mg and 75 mg. A dose of 100 mg ULTRAM® tended to
5
provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the
combination of aspirin 650 mg with codeine phosphate 60 mg.
ULTRAM® has been studied in three long-term controlled trials involving a total of 820
patients, with 530 patients receiving ULTRAM®. Patients with a variety of chronic
painful conditions were studied in double-blind trials of one to three months duration.
Average daily doses of approximately 250 mg of ULTRAM® in divided doses were
generally comparable to five doses of acetaminophen 300 mg with codeine phosphate
30 mg (TYLENOL® with Codeine #3) daily, five doses of aspirin 325 mg with codeine
phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone
hydrochloride 5 mg (TYLOX®) daily.
Titration Trials
In a randomized, blinded clinical study with 129 to 132 patients per group, a
10-day titration to a daily ULTRAM® dose of 200 mg (50 mg four times per day),
attained in 50 mg increments every 3 days, was found to result in fewer discontinuations
due to dizziness or vertigo than titration over only 4 days or no titration. In a second
study with 54 to 59 patients per group, patients who had nausea or vomiting when
titrated over 4 days were randomized to re-initiate ULTRAM® therapy using slower
titration rates.
A 16-day titration schedule, starting with 25 mg qAM and using additional doses in 25
mg increments every third day to 100 mg/day (25 mg four times per day), followed by
50 mg increments in the total daily dose every third day to 200 mg/day (50 mg four times
per day), resulted in fewer discontinuations due to nausea or vomiting and fewer
discontinuations due to any cause than did a 10-day titration schedule.
6
G
r
aph
Figure 2:
INDICATIONS AND USAGE
ULTRAM® is indicated for the management of moderate to moderately severe pain in
adults.
CONTRAINDICATIONS
ULTRAM® should not be administered to patients who have previously demonstrated
hypersensitivity to tramadol, any other component of this product or opioids. ULTRAM®
is contraindicated in any situation where opioids are contraindicated, including acute
intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting
analgesics, opioids or psychotropic drugs. ULTR AM® may worsen central nervous
system and res piratory depression in these patients.
WARNINGS
Seizure Risk
Seizures have been reported in patients receiving ULTRAM® within the
recommended dosage range. Spontaneous post-marketing reports indicate that
seizure risk is increased with doses of ULTRAM® above the recommended range.
Co ncomitant use of ULTRAM® increases the seizure risk in patients taking:
• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g.,
cyclobenzaprine , promethazine, etc.), or
7
• Other opioids.
Administration of ULTRAM ® may enhance the seizure risk in patients taking:
• MAO inhibitors (see also WARNINGS, Use with MAO Inhibitors and Serotonin
Re-Uptake Inhib itors),
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history
of seizures, or in patients with a recognized risk for seizure (such as head trauma,
metabolic disorders, alcohol and drug withdrawal, CNS infections) . In ULTRAM®
overdose, naloxone administration may increase the risk of seizure.
Suicide Risk
• Do not prescribe ULTRAM® for patients who are suicidal or addiction-prone.
• Prescribe ULTRAM® Tablets with caution for patients who are taking
tranquilizers or antidepressant drug and patients who use alcohol in excess and
who suffer from emotional disturbance or depression.
The judicious prescribing of tramadol is essential to the safe use of this drug. With
patients who are depressed or suicidal, consideration should be given to the use of non
narcotic analgesics.
Tramadol-related deaths have occurred in patients with previous histories of emotional
disturbances or suicidal ideation or attempts as well as histories of misuse of
tranquilizers, alcohol, and other CNS-active drugs (see WARNINGS, Risk of
Overdosage).
Serotonin Syndrome Risk
The development of a potentially life-threatening serotonin syndrome may occur
with the use of tramadol products, including ULTRAM®, particularly with
concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and
triptans, with drugs which impair metabolism of serotonin (including MAOIs), and
with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4
inhibitors). This may occur within th e recommended dose (see CLINICAL
PHARMACOLOGY, Pharmacokinetics).
8
Serotonin syndrome may include mental-status changes (e.g., agitation,
hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure,
hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination)
and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Anaphylactoid Reactions
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving
therapy with ULTRAM®. When these events do occur it is often following the first dose.
Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema,
toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of
anaphylactoid reactions to codeine and other opioids may be at increased risk and
therefore should not receive ULTRAM® (see CONTRAINDICATIONS).
Respiratory Depression
Administer ULTRAM® cautiously in patients at risk for respiratory depression. In these
patients alternative non-opioid analgesics should be considered. When large doses of
ULTRAM® are administered with anesthetic medications or alcohol, respiratory
depression may result. Respiratory depression should be treated as an overdose. If
naloxone is to be administered, use cautiously because it may precipitate seizures (see
WARNINGS, Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) Depressants
ULTRAM® should be used with caution and in reduced dosages when administered to
patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics,
phenothiazines, tranquilizers or sedative hypnotics. ULTRAM® increases the risk of
CNS and respiratory depression in these patients.
Interactions with Alcohol and Drugs of Abuse
Tramadol may be expected to have additive effects when used in conjunction with
alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Increased Intracranial Pressure or Head Trauma
ULTRAM® should be used with caution in patients with increased intracranial pressure
or head injury. The respiratory depressant effects of opioids include carbon dioxide
retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly
exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol
may obscure the existence, extent, or course of intracranial pathology. Clinicians should
also maintain a high index of suspicion for adverse drug reaction when evaluating altered
9
mental status in these patients if they are receiving ULTRAM® (see WARNINGS,
Respiratory Depression).
Use in Ambulatory Patients
ULTRAM® may impair the mental and or physical abilities required for the performance
of potentially hazardous tasks such as driving a car or operating machinery. The patient
using this drug should be cautioned accordingly.
Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors
Use ULTRAM® with great caution in patients taking monoamine oxidase inhibitors.
Animal studies have shown increased deaths with combined administration. Concomitant
use of ULTRAM® with MAO inhibitors or SSRI’s increases the risk of adverse events,
including seizure and serotonin syndrome.
Misuse, Abuse and Diversion
Tramadol has mu-opioid agonist activity. ULTRAM® can be sought by drug abusers and
people with addiction disorders and may be subject to criminal diversion.
The possibility of illegal or illicit use should be considered when prescribing or
dispensing ULTRAM® in situations where the physician or pharmacist is concerned
about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses a
significant risk to the abuser that could result in overdose and death (see DRUG ABUSE
AND DEPENDENCE and OVERDOSAGE).
Concerns about abuse, addiction, and diversion should not prevent the proper
management of pain. The development of addiction to opioid analgesics in properly
managed patients with pain has been reported to be rare. However, data are not available
to establish the true incidence of addiction in chronic pain patients.
Risk of Overdosage
Patients taking tramadol should be warned not to exceed the dose recommended by their
physician. Tramadol products in excessive doses, either alone or in combination with
other CNS depressants, including alcohol, are a cause of drug-related deaths. Patients
should be cautioned about the concomitant use of tramadol products and alcohol because
of potentially serious CNS additive effects of these agents. Because of its added
depressant effects, tramadol should be prescribed with caution for those patients whose
medical condition requires the concomitant administration of sedatives, tranquilizers,
muscle relaxants, antidepressants, or other CNS depressant drugs. Patients should be
advised of the additive depressant effects of these combinations.
10
Serious potential consequences of overdosage with ULTRAM® (tramadol hydrochloride)
tablets are central nervous system depression, respiratory depression and death. Some
deaths have occurred as a consequence of the accidental ingestion of excessive quantities
of tramadol alone or in combination with other drugs. In treating an overdose, primary
attention should be given to maintaining adequate ventilation along with general
supportive treatment (see OVERDOSAGE).
Withdrawal
Withdrawal symptoms may occur if ULTRAM® is discontinued abruptly (see also
DRUG ABUSE AND DEPENDENCE). Reported symptoms have included anxiety,
sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms,
piloerection, and rarely hallucinations. Other symptoms that have been reported less
frequently with ULTRAM® discontinuation include panic attacks, severe anxiety, and
paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by
tapering ULTRAM® at the time of discontinuation.
PRECAUTIONS
Acute Abdominal Conditions
The administration of ULTRAM® may complicate the clinical assessment of patients
with acute abdominal conditions.
Use in Renal and Hepatic Disease
Impaired renal function results in a decreased rate and extent of excretion of tramadol
and its active metabolite, M1. In patients with creatinine clearances of less than
30 mL/min,
dosing
reduction
is
recommended
(see
DOSAGE
AND
ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with
advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended
(see DOSAGE AND ADMINISTRATION).
With the prolonged half-life in these conditions, achievement of steady-state is delayed,
so that it may take several days for elevated plasma concentrations to develop.
Information for Patients
• Patients should be informed that ULTRAM® may cause seizures and/or serotonin
syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and
triptans) or drugs that significantly reduce the metabolic clearance of tramadol.
• ULTRAM® may impair mental or physical abilities required for the performance of
potentially hazardous tasks such as driving a car or operating machinery.
11
• ULTRAM® should not be taken with alcohol containing beverages.
• ULTRAM® should be used with caution when taking medications such as
tranquilizers, hypnotics or other opiate containing analgesics.
• The patient should be instructed to inform the physician if they are pregnant, think
they might become pregnant, or are trying to become pregnant (see PRECAUTIONS,
Labor and Delivery).
• The patient should understand the single-dose and 24-hour dose limit and the time
interval between doses, since exceeding these recommendations can result in
respiratory depression, seizures and death.
Drug Interactions
CYP2D6 and CYP3A4 Inhibitors
Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL
PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine and
amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4
inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious
adverse events including seizures and serotonin syndrome.
Serotonergic Drugs
There have been postmarketing reports of serotonin syndrome with use of tramadol and
SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when
ULTRAM® is coadministered with other drugs that may affect the serotonergic
neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which
is a reversible non-selective MAOI), lithium, or St. John’s Wort. If concomitant
treatment of ULTRAM® with a drug affecting the serotonergic neurotransmitter system
is clinically warranted, careful observation of the patient is advised, particularly during
treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).
Triptans
Based on the mechanism of action of tramadol and the potential for serotonin syndrome,
caution is advised when ULTRAM® is coadministered with a triptan. If concomitant
treatment of ULTRAM® with a triptan is clinically warranted, careful observation of the
patient is advised, particularly during treatment initiation and dose increases (see
WARNINGS, Serotonin Syndrome).
12
Use With Carbamazepine
Patients taking carbamazepine may have a significantly reduced analgesic effect of
ULTRAM®. Because carbamazepine increases tramadol metabolism and because of the
seizure risk associated with tramadol, concomitant administration of ULTRAM® and
carbamazepine is not recommended.
Use With Quinidine
Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that
isoenzyme, so that concomitant administration of quinidine and ULTRAM® results in
increased concentrations of tramadol and reduced concentrations of M1. The clinical
consequences of these findings are unknown. In vitro drug interaction studies in human
liver microsomes indicate that tramadol has no effect on quinidine metabolism.
Potential for Other Drugs to Affect Tramadol
In vitro drug interaction studies in human liver microsomes indicate that concomitant
administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and
amitriptyline could result in some inhibition of the metabolism of tramadol.
Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or
inducers, such as rifampin and St. John’s Wort, with Ultram® may affect the metabolism
of tramadol leading to alteted tramadol exposure.
Potential for Tramadol to Affect Other Drugs
In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated
metabolism of other drugs when tramadol is administered concomitantly at therapeutic
doses. Tramadol does not appear to induce its own metabolism in humans, since
observed maximal plasma concentrations after multiple oral doses are higher than
expected based on single-dose data. Tramadol is a mild inducer of selected drug
metabolism pathways measured in animals.
Use With Cimetidine
Concomitant administration of ULTRAM® with cimetidine does not result in clinically
significant changes in tramadol pharmacokinetics. Therefore, no alteration of the
ULTRAM® dosage regimen is recommended.
Use With Digoxin and Warfarin
Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of
warfarin effect, including elevation of prothrombin times.
13
Carcinogenesis, Mutagenesis, Impairment of Fertility
A slight, but statistically significant, increase in two common murine tumors, pulmonary
and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice.
Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.36 times the maximum daily
human dosage of 246 mg/m2) for approximately two years, although the study was not
done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in
humans. No such finding occurred in a rat carcinogenicity study (dosing orally up to 30
mg/kg, 180 mg/m2, or 0.73 times the maximum daily human dosage).
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal
activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the
absence of metabolic activation), dominant lethal mutation tests in mice, chromosome
aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and
Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic
activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the
weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk
to humans.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300
mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.2 and
1.8 times the maximum daily human dosage of 246 mg/m2, respectively.
Pregnancy, Teratogenic Effects: Pregnancy Category C
Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360
mg/m2), rats (≥25 mg/kg or 150 mg/m2) and rabbits (≥75 mg/kg or 900 mg/m2) at
maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on
a mg/m2 basis are 1.4, ≥0.6, and ≥3.6 times the maximum daily human dosage (246
mg/m2) for mouse, rat and rabbit, respectively.
No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg
or 420 mg/m2), rats (up to 80 mg/kg or 480 mg/m2) or rabbits (up to 300 mg/kg or 3600
mg/m2) treated with tramadol by various routes. Embryo and fetal toxicity consisted
primarily of decreased fetal weights, skeletal ossification and increased supernumerary
ribs at maternally toxic dose levels. Transient delays in developmental or behavioral
parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal
lethality were reported only in one rabbit study at 300 mg/kg (3600 mg/m2), a dose that
would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat
14
and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/m2),
respectively.
Non-teratogenic Effects
Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving
oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.2 times the maximum daily
human tramadol dosage) or greater had decreased weights, and pup survival was
decreased early in lactation at 80 mg/kg (480 mg/m2 or 1.9 and higher the maximum
daily human dose).
There are no adequate and well-controlled studies in pregnant women. ULTRAM®
should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth
have been reported during post-marketing.
Labor and Delivery
ULTRAM® should not be used in pregnant women prior to or during labor unless the
potential benefits outweigh the risks. Safe use in pregnancy has not been established.
Chronic use during pregnancy may lead to physical dependence and post-partum
withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE).
Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the
umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol
during labor.
The effect of ULTRAM®, if any, on the later growth, development, and functional
maturation of the child is unknown.
Nursing Mothers
ULTRAM® is not recommended for obstetrical preoperative medication or for post-
delivery analgesia in nursing mothers because its safety in infants and newborns has not
been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion
in breast milk within 16 hours postdose was 100 μg of tramadol (0.1% of the maternal
dose) and 27 μg of M1.
Pediatric Use
The safety and efficacy of ULTRAM® in patients under 16 years of age have not been
established. The use of ULTRAM® in the pediatric population is not recommended.
15
Geriatric Use
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 patients over
75 years of age, daily doses in excess of 300 mg are not recommended (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
A total of 455 elderly (65 years of age or older) subjects were exposed to ULTRAM® in
controlled clinical trials. Of those, 145 subjects were 75 years of age and older.
In studies including geriatric patients, treatment-limiting adverse events were higher in
subjects over 75 years of age compared to those under 65 years of age. Specifically, 30%
of those over 75 years of age had gastrointestinal treatment-limiting adverse events
compared to 17% of those under 65 years of age. Constipation resulted in discontinuation
of treatment in 10% of those over 75.
ADVERSE REACTIONS
ULTRAM® was administered to 550 patients during the double-blind or open-label
extension periods in U.S. studies of chronic nonmalignant pain. Of these patients,
375 were 65 years old or older. Table 2 reports the cumulative incidence rate of adverse
reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days).
The most frequently reported events were in the central nervous system and
gastrointestinal system. Although the reactions listed in the table are felt to be probably
related to ULTRAM® administration, the reported rates also include some events that
may have been due to underlying disease or concomitant medication. The overall
incidence rates of adverse experiences in these trials were similar for ULTRAM® and the
active control groups, TYLENOL® with Codeine #3 (acetaminophen 300 mg with
codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however,
the rates of withdrawals due to adverse events appeared to be higher in the ULTRAM®
groups.
16
Table 2:
Cumulative Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of
Nonmalignant Pain (N=427)
Up to 7 Days
Up to 30 Days
Up to 90 Days
Dizziness/Vertigo
26%
Nausea
24%
Constipation
24%
Headache
18%
Somnolence
16%
Vomiting
9%
Pruritus
8%
" CNS Stimulation"1
7%
Asthenia
6%
Sweating
6%
Dyspepsia
5%
Dry Mouth
5%
Diarrhea
5%
31%
34%
38%
26%
23%
13%
10%
11%
11%
7%
9%
9%
6%
33%
40%
46%
32%
25%
17%
11%
14%
12%
9%
13%
10%
10%
1 "CNS Stimulation " is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria,
emotional lability and hallucinations
Incidence 1% to less than 5% possibly causally related: the following lists adverse
reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for
which the possibility of a causal relationship with ULTRAM® exists.
Body as a Whole: Malaise.
Cardiovascular: Vasodilation.
Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria,
Miosis, Nervousness, Sleep disorder.
Gastrointestinal: Abdominal pain, Anorexia, Flatulence.
Musculoskeletal: Hypertonia.
Skin: Rash.
Special Senses: Visual disturbance.
Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.
Incidence less than 1%, possibly causally related: the following lists adverse reactions
that occurred with an incidence of less than 1% in clinical trials and/or reported in post-
marketing experience.
17
Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal
tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever,
shivering, tremor, agitation, diaphoresis, seizures and coma).
Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.
Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression,
Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS).
Tremor.
Respiratory: Dyspnea.
Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.
Special Senses: Dysgeusia.
Urogenital: Dysuria, Menstrual disorder.
Other adverse experiences, causal relationship unknown: A variety of other adverse
events were reported infrequently in patients taking ULTRAM® during clinical trials
and/or reported in post-marketing experience. A causal relationship between ULTRAM®
and these events has not been determined. However, the most significant events are listed
below as alerting information to the physician.
Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia,
Palpitations, Pulmonary edema, Pulmonary embolism.
Central Nervous System: Migraine, Speech disorders.
Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.
Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin
decrease, Proteinuria.
Sensory: Cataracts, Deafness, Tinnitus.
DRUG ABUSE AND DEPENDENCE
Abuse
Tramadol has mu-opioid agonist activity. ULTRAM can be abused and may be
subject to criminal diversion.
18
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and
environmental factors influencing its development and manifestations. Drug addiction is
characterized by behaviors that include one or more of the following: impaired control
over drug use, compulsive use, use for non-medical purposes, and continued use despite
harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multi
disciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking
tactics include emergency calls or visits near the end of office hours, refusal to undergo
appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering
with prescriptions and reluctance to provide prior medical records or contact information
for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is
common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance.
Physicians should be aware that addiction may not be accompanied by concurrent
tolerance and symptoms of physical dependence in all addicts. In addition, abuse of
ULTRAM® can occur in the absence of true addiction and is characterized by misuse for
non-medical purposes, often in combination with other psychoactive substances.
Concerns about abuse and addiction should not prevent the proper management of pain.
However all patients treated with opioids require careful monitoring for signs of abuse
and addiction, because use of opioid analgesic products carries the risk of addiction even
under appropriate medical use.
Proper assessment of the patient and periodic re-evaluation of therapy are appropriate
measures that help to limit the potential abuse of this product.
ULTRAM® is intended for oral use only.
Dependence
Tolerance is the need for increasing doses of drugs to maintain a defined effect such as
analgesia (in the absence of disease progression or other external factors). Physical
dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug
or upon administration of an antagonist (see also WARNINGS, Withdrawal).
The opioid abstinence or withdrawal syndrome is characterized by some or all of the
following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia,
and mydriasis. Other symptoms also may develop, including irritability, anxiety,
19
backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia,
vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on
continuous therapy with ULTRAM.
OVERDOSAGE
Acute overdosage with tramadol can be manifested by respiratory depression,
somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy
skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol (see
WARNINGS, Misuse, Abuse, and Diversion). Review of case reports has indicated that
the risk of fatal overdose is further increased when tramadol is abused concurrently with
alcohol or other CNS depressants, including other opioids.
In the treatment of tramadol overdosage, primary attention should be given to the re
establishment of a patent airway and institution of assisted or controlled ventilation.
Supportive measures (including oxygen and vasopressors) should be employed in the
management of circulatory shock and pulmonary edema accompanying overdose as
indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by
overdosage with tramadol, the risk of seizures is also increased with
naloxone administration. In animals convulsions following the
administration of toxic doses of ULTRAM® could be suppressed with
barbiturates or benzodiazepines but were increased with naloxone.
Naloxone administration did not change the lethality of an overdose in
mice. Hemodialysis is not expected to be helpful in an overdose because it
removes less than 7% of the administered dose in a 4-hour dialysis period.
DOSAGE AND ADMINISTRATION
Adults (17 years of age and over)
For patients with moderate to moderately severe chronic pain not requiring rapid onset of
analgesic effect, the tolerability of ULTRAM® can be improved by initiating therapy
with the following titration regimen: ULTRAM® should be started at 25 mg/day qAM
and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25
mg q.i.d.). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3
20
days to reach 200 mg/day (50 mg q.i.d.). After titration, ULTRAM® 50 to 100 mg can be
administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day.
For the subset of patients for whom rapid onset of analgesic effect is required and for
whom the benefits outweigh the risk of discontinuation due to adverse events associated
with higher initial doses, ULTRAM® 50 mg to 100 mg can be administered as needed for
pain relief every four to six hours, not to exceed 400 mg per day.
Individualization of Dose
Good pain management practice dictates that the dose be individualized according to
patient need using the lowest beneficial dose. Studies with tramadol in adults have shown
that starting at the lowest possible dose and titrating upward will result in fewer
discontinuations and increased tolerability.
• In all patients with creatinine clearance less than 30 mL/min, it is recommended
that the dosing interval of ULTRAM® be increased to 12 hours, with a maximum
daily dose of 200 mg. Since only 7% of an administered dose is removed by
hemodialysis, dialysis patients can receive their regular dose on the day of dialysis.
• The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.
• In general, dose selection for an elderly patient over 65 years old 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. For elderly patients over 75 years old, total dose should not exceed 300
mg/day.
HOW SUPPLIED
ULTRAM® (tramadol hydrochloride) Tablets - 50 mg are white, capsule-shaped, coated
tablet imprinted “ULTRAM” on one side and “06 59” on the scored side.
Bottles of 100 tablets: NDC 0045-0659-60
Dispense in a tight container. Store at 25°C (77°F); excursions permitted to 15 -30°C (59
– 86°F).
Manufactured by:
Janssen Ortho, LLC
Gurabo, Puerto, Rico 00778
21
Marketed by:
OMP DIVISION
ORTHO-McNEIL PHARMACEUTICAL, INC.
RARITAN, NEW JERSEY 08869
© OMP 2003 Revised March 2008
7517006
22
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custom-source
|
2025-02-12T13:47:23.204027
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033lbl.pdf', 'application_number': 20281, 'submission_type': 'SUPPL ', 'submission_number': 33}
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12,406
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® safely and effectively. See full prescribing information for
RISPERDAL®.
RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral
solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating
tablets
Initial U.S. Approval: 1993
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. RISPERDAL® is
not approved for use in patients with dementia-related psychosis. (5.1)
----------------------------INDICATIONS AND USAGE----------------------------
RISPERDAL® is an atypical antipsychotic agent indicated for:
• Treatment of schizophrenia in adults and adolescents aged 13-17 years
(1.1)
• Alone, or in combination with lithium or valproate, for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I
Disorder in adults, and alone in children and adolescents aged 10-17 years
(1.2)
• Treatment of irritability associated with autistic disorder in children and
adolescents aged 5-16 years (1.3)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Initial
Dose
Titration
Target
Dose
Effective
Dose
Range
Schizophreni
a- adults
(2.1)
2 mg
/day
1-2 mg
daily
4-8 mg
daily
4-16 mg
/day
Schizophreni
a –
adolescents
(2.1)
0.5mg
/day
0.5-1 mg
daily
3mg
/day
1-6 mg
/day
Bipolar
mania –
adults (2.2)
2-3 mg
/day
1mg
daily
1-6mg
/day
1-6 mg
/day
Bipolar
mania in
children/
adolescents
(2.2)
0.5 mg
/day
0.5-1mg
daily
2.5mg
/day
0.5-6 mg
/day
Irritability
associated
with autistic
disorder
(2.3)
0.25 mg
/day
(<20 kg)
0.5 mg
/day
(≥20 kg)
0.25-0.5 mg
at ≥ 2 weeks
0.5 mg
/day
(<20 kg)
1 mg
/day
(≥20 kg)
0.5-3 mg
/day
--------------------DOSAGE FORMS AND STRENGTHS----------------------
• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
• Oral solution: 1 mg/mL (3)
• Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
• Known hypersensitivity to the product (4)
---------------------------WARNINGS AND PRECAUTIONS--------------------
• Cerebrovascular events, including stroke, in elderly patients with dementia-
related psychosis. RISPERDAL® is not approved for use in patients with
dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome (5.3)
• Tardive dyskinesia (5.4)
• Hyperglycemia and diabetes mellitus (5.5)
• Hyperprolactinemia (5.6)
• Orthostatic hypotension (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with
antipsychotics, including RISPERDAL®. Patients with a history of a
clinically significant low white blood cell count (WBC) or a drug-
induced leukopenia/neutropenia should have their complete blood count
(CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign
of a clinically significant decline in WBC in the absence of other
causative factors. (5.8)
• Potential for cognitive and motor impairment (5.9)
• Seizures (5.10)
• Dysphagia (5.11)
• Priapism (5.12)
• Thrombotic Thrombocytopenic Purpura (TTP) (5.13)
• Disruption of body temperature regulation (5.14)
• Antiemetic Effect (5.15)
• Suicide (5.16)
• Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies (5.17)
• Diseases or conditions that could affect metabolism or hemodynamic
responses (5.17)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in clinical trials (≥10%) were
somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism,
akathisia, vomiting, cough, constipation, nasopharyngitis, drooling,
rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety,
headache, nasal congestion, rhinitis, tremor, and rash. (6)
The most common adverse reactions that were associated with discontinuation
from clinical trials were nausea, somnolence, sedation, vomiting, dizziness,
and akathisia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800
JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
---------------------------------DRUG INTERACTIONS----------------------------
• Due to CNS effects, use caution when administering with other centrally-
acting drugs. Avoid alcohol. (7.1)
• Due to hypotensive effects, hypotensive effects of other drugs with this
potential may be enhanced. (7.2)
• Effects of levodopa and dopamine agonists may be antagonized. (7.3)
• Cimetidine and ranitidine increase the bioavailability of risperidone. (7.5)
• Clozapine may decrease clearance of risperidone. (7.6)
• Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10)
• Carbamazepine and other enzyme inducers decrease plasma concentrations
of risperidone. (7.11)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Nursing Mothers: should not breast feed. (8.3)
• Pediatric Use: safety and effectiveness not established for schizophrenia
less than 13 years of age, for bipolar mania less than 10 years of age, and
for autistic disorder less than 5 years of age. (8.4)
• Elderly or debilitated; severe renal or hepatic impairment; predisposition to
hypotension or for whom hypotension poses a risk: Lower initial dose (0.5
mg twice daily), followed by increases in dose in increments of no more
than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should occur at intervals of at least 1 week. (8.5, 2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 09/2010
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
Reference ID: 2870867
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
INDICATIONS AND USAGE
7.2
Drugs with Hypotensive Effects
1.1
Schizophrenia
7.3
Levodopa and Dopamine Agonists
1.2
Bipolar Mania
7.4
Amitriptyline
1.3
Irritability Associated with Autistic Disorder
7.5
Cimetidine and Ranitidine
2
DOSAGE AND ADMINISTRATION
7.6
Clozapine
2.1
Schizophrenia
7.7
Lithium
2.2
Bipolar Mania
7.8
Valproate
2.3
Irritability Associated with Autistic Disorder –
7.9
Digoxin
Pediatrics (Children and Adolescents)
7.10
Drugs That Inhibit CYP 2D6 and Other CYP
2.4
Dosage in Special Populations
Isozymes
2.5
Co-Administration of RISPERDAL® with Certain
7.11
Carbamazepine and Other Enzyme Inducers
Other Medications
7.12
Drugs Metabolized by CYP 2D6
2.6
Administration of RISPERDAL
® Oral Solution
8
USE IN SPECIFIC POPULATIONS
2.7
Directions for Use of RISPERDAL
® M-
8.1
Pregnancy
TAB
® Orally Disintegrating Tablets
Labor and Delive y
8.2
r
3
DOSAGE FORMS AND STRENGTHS
8.3
Nursing Mothers
4
CONTRAINDICATIONS
8.4
Pediatric Use
5
WARNINGS AND PRECAUTIONS
8.5
Geriatric Use
5.1
Increased Mortality in Elderly Patients with
9
DRUG ABUSE AND DEPENDENCE
Dementia-Related Psychosis
9.1
Controlled Substance
5.2
Cerebrovascular Adverse Events, Including
9.2
Abuse
Stroke, in Elderly Patients with Dementia-
9.3
Dependence
Related Psychosis
10
OVERDOSAGE
5.3
Neuroleptic Malignant Syndrome (NMS)
10.1
Human Experience
5.4
Tardive Dyskinesia
10.2
Management of Overdosage
5.5
Hyperglycemia and Diabetes Mellitus
11
DESCRIPTION
5.6
Hyperprolactinemia
12
CLINICAL PHARMACOLOGY
5.7
Orthostatic Hypotension
12.1
Mechanism of Action
5.8
Leukopenia, Neutropenia, and Agranulocytosis
12.2
Pharmacodynamics
5.9
Potential for Cognitive and Motor Impairment
12.3
Pharmacokinetics
5.10
Seizures
13
NONCLINICAL TOXICOLOGY
5.11
Dysphagia
13.1
Carcinogenesis, Mutagenesis, Impairment of
5.12
Priapism
Fertility
5.13
Thrombotic Thrombocytopenic Purpura (TTP)
14
CLINICAL STUDIES
5.14
Body Temperature Regulation
14.1
Schizophrenia
5.15
Antiemetic Effect
14.2
Bipolar Mania - Monotherapy
5.16
Suicide
14.3
Bipolar Mania – Combination Therapy
5.17
Use in Patients with Concomitant Illness
14.4
Irritability Associated with Autistic Disorder
5.18
Monitoring: Laboratory Tests
16
HOW SUPPLIED/STORAGE AND HANDLING
6
ADVERSE REACTIONS
Storage and Handling
6.1
Commonly-Observed Adverse Reactions in
17
PATIENT COUNSELING INFORMATION
Double-Blind, Placebo-Controlled Clinical Trials
17.1
Orthostatic Hypotension
- Schizophrenia
17.2
Interference with Cognitive and Motor
6.2
Commonly-Observed Adverse Reactions in
Performance
Double-Blind, Placebo-Controlled Clinical Trials
17.3
Pregnancy
– Bipolar Mania
17.4
Nursing
6.3
Commonly-Observed Adverse Reactions in
17.5
Concomitant Medication
Double-Blind, Placebo-Controlled Clinical Trials
17.6
Alcohol
- Autistic Disorder
17.7
Phenylketonurics
6.4
Other Adverse Reactions Observed During the
Premarketing Evaluation of RISPERDAL
®
6.5
Discontinuations Due to Adverse Reactions
*Sections or subsections omitted from the full prescribing information are not
6.6
Dose Dependency of Adverse Reactions in
listed
Clinical Trials
6.7
Changes in Body Weight
6.8
Changes in ECG
6.9
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Centrally-Acting Drugs and Alcohol
Reference ID: 2870867
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: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which the findings
of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. RISPERDAL®
(risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)]
1
INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of
schizophrenia [see Clinical Studies (14.1)].
Adolescents
RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years
[see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes
associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years
[see Clinical Studies (14.2)].
Combination Therapy – Adults
The combination of RISPERDAL® with lithium or valproate is indicated for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical
Studies (14.3)].
Reference ID: 2870867
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.3 Irritability Associated with Autistic Disorder
Pediatrics
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in
children and adolescents aged 5–16 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies
(14.4)].
2
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of
1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower
titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see
Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not
demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal
symptoms and other adverse effects, and are generally not recommended. In a single study
supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for
4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the
effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a
controlled trial in patients who had been clinically stable for at least 4 weeks and were then
followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically
reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients
with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above
3 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Reference ID: 2870867
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in
adolescents with schizophrenia. The physician who elects to use RISPERDAL® for extended
periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended
that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic
patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant
antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be
acceptable for some schizophrenic patients, more gradual discontinuation may be most
appropriate for others. The period of overlapping antipsychotic administration should be
minimized. When switching schizophrenic patients from depot antipsychotics, initiate
RISPERDAL® therapy in place of the next scheduled injection. The need for continuing existing
EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per
day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in
dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled
trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible
dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL® doses higher
than 6 mg per day were not studied.
Pediatrics
The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-
daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at
intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended
dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients
with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above
2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than
6 mg/day have not been studied.
Reference ID: 2870867
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients experiencing persistent somnolence may benefit from administering half the daily dose
twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-
term management of a patient who improves during treatment of an acute manic episode with
RISPERDAL®. While it is generally agreed that pharmacological treatment beyond an acute
response in mania is desirable, both for maintenance of the initial response and for prevention of
new manic episodes, there are no systematically obtained data to support the use of
RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to
use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and
benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and
Adolescents)
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less
than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability
of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the
total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for
patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be
increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for
patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not
achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in
increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on
ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL® between 0.5 mg and
2.5 mg per day. The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the
therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or
3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be
given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The
Reference ID: 2870867
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate
the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at
bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated,
patients with severe renal or hepatic impairment, and patients either predisposed to hypotension
or for whom hypotension would pose a risk. Dosage increases in these patients should be in
increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily
should generally occur at intervals of at least 1 week. In some patients, slower titration may be
medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to
eliminate RISPERDAL® than normal adults. Patients with impaired hepatic function may have
increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical
Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk likewise need to be titrated cautiously and carefully
monitored [see Warnings and Precautions (5.2, 5.7, 5.17)]. If a once-daily dosing regimen in the
elderly or debilitated patient is being considered, it is recommended that the patient be titrated on
a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing
regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® treatment. The dose of RISPERDAL® needs to be
titrated accordingly for patients receiving these enzyme inducers, especially during initiation or
discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about
10%. The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine
is co-administered [see Drug Interactions (7.10)].
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2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be
mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the
following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with
either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in
blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the
four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back
foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the
tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a
child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the
blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push
the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire
RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M
TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be
stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets
disintegrate in the mouth within seconds and can be swallowed subsequently with or without
liquid. Patients should not attempt to split or to chew the tablet.
3
DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark
yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All
are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”,
“R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
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RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths,
colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square),
3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been
observed in patients treated with risperidone. Therefore, RISPERDAL® is contraindicated in
patients with a known hypersensitivity to the product.
5
WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. RISPERDAL® (risperidone) is not approved for the treatment of
dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients
with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with risperidone compared to
patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with
dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
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The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely upon prevalence
estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
develop the syndrome. Whether antipsychotic drug products differ in their potential to cause
tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely
to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less
harmful treatments are not available or appropriate. In patients who do require chronic treatment,
the smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug
discontinuation should be considered. However, some patients may require treatment with
RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics
including RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and
glucose abnormalities is complicated by the possibility of an increased background risk of
diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus
in the general population. Given these confounders, the relationship between atypical
antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL®, should be monitored regularly for worsening of
glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history
of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL® ,
should undergo fasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL® ,
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing. In some
cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL® ,
was discontinued; however, some patients required continuation of anti-diabetic treatment
despite discontinuation of RISPERDAL® .
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin
levels and the elevation persists during chronic administration. RISPERDAL® is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
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impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice
and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies
conducted to date have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period, probably reflecting its
alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of
RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of
orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total
(either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and
patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of
concern. A dose reduction should be considered if hypotension occurs. RISPERDAL® should be
used with particular caution in patients with known cardiovascular disease (history of myocardial
infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and
conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
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complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant
decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment,
especially when ascertained by direct questioning of patients. This adverse event is dose-related,
and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct
questioning is more sensitive for detecting adverse events than spontaneous reporting, by which
8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an
adverse event. Since RISPERDAL® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including automobiles,
until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in
0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and
Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9)].
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a
large, open premarketing experience (approximately 1300 patients). She experienced jaundice,
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For current labeling information, please visit https://www.fda.gov/drugsatfda
fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.16 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania,
including children and adolescent patients, and close supervision of high-risk patients should
accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest
quantity of tablets, consistent with good patient management, in order to reduce the risk of
overdose.
5.17 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is
limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive
antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to
antipsychotic medications. Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and
clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could
affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during the product's
premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free
fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose
should be used in such patients [see Dosage and Administration (2.4)].
5.18 Monitoring: Laboratory Tests
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No specific laboratory tests are recommended.
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning
and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
• Antiemetic effect [see Warnings and Precautions (5.15)]
• Suicide [see Warnings and Precautions (5.16)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy
bodies [see Warnings and Precautions (5.17)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.17)]
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The most common adverse reactions in clinical trials (≥ 10%) were somnolence, increased
appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation,
nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea,
anxiety, headache, nasal congestion, rhinitis, tremor, and rash.
The most common adverse reactions that were associated with discontinuation from clinical
trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea,
somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions (6.5)].
The data described in this section are derived from a clinical trial database consisting of 9712
adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of
schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and
elderly patients with dementia. Of these 9712 patients, 2626 were patients who received
RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and
duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 3 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that
were considered to be reasonably associated with the use of RISPERDAL® (adverse drug
reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for RISPERDAL® often cannot be reliably established in individual cases.
Further, 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.
The majority of all adverse reactions were mild to moderate in severity.
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6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult Patients with
Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
2-8 mg per day >8-16 mg per day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Blood and Lymphatic System
Disorders
Anemia
<1
1
0
Cardiac Disorders
Tachycardia
1
3
0
Ear and Labyrinth Disorders
Ear pain
<1
1
0
Eye Disorders
Vision blurred
3
1
1
Gastrointestinal Disorders
Nausea
9
4
4
Constipation
8
9
6
Dyspepsia
8
6
5
Vomiting
7
5
7
Dry mouth
4
0
1
Abdominal discomfort
3
1
1
Salivary hypersecretion
2
1
<1
Diarrhea
2
1
1
Abdominal pain
1
1
0
Abdominal pain upper
1
1
0
Stomach discomfort
1
1
1
General Disorders
Fatigue
3
1
0
Chest pain
2
2
1
Asthenia
2
1
<1
Immune System Disorders
Hypersensitivity
<1
1
0
Infections and Infestations
Nasopharyngitis
3
4
3
Upper respiratory tract infection
2
3
1
Sinusitis
1
2
1
Urinary tract infection
1
3
0
Investigations
Weight increased
1
1
0
Blood creatine phosphokinase
1
2
<1
increased
Heart rate increased
<1
2
0
Metabolism and Nutrition Disorders
Decreased appetite
1
0
<1
Musculoskeletal and Connective
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Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
2-8 mg per day >8-16 mg per day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Tissue Disorders
Back pain
4
1
1
Arthralgia
2
3
<1
Pain in extremity
2
1
1
Joint stiffness
1
1
0
Nervous System Disorders
Parkinsonism*
14
17
8
Akathisia*
10
10
3
Dizziness
7
4
2
Somnolence
7
2
1
Dystonia*
3
4
2
Sedation
3
3
1
Tremor*
2
3
1
Dizziness postural
2
0
0
Dyskinesia*
1
2
2
Syncope
1
1
0
Psychiatric Disorders
Insomnia
32
25
27
Anxiety
16
11
11
Nervousness
1
1
<1
Renal and Urinary Disorders
Urinary incontinence
1
1
0
Reproductive System and Breast
Disorders
Ejaculation failure
<1
1
0
Respiratory, Thoracic and
Mediastinal Disorders
Nasal congestion
4
6
2
Dyspnea
1
2
0
Epistaxis
<1
2
0
Skin and Subcutaneous Tissue
Disorders
Rash
1
4
1
Dry skin
1
3
0
Dandruff
1
1
0
Seborrheic dermatitis
<1
1
0
Hyperkeratosis
0
1
1
Vascular Disorders
Orthostatic hypotension
2
1
0
Hypotension
1
1
0
* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism,
cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity,
and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia
includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture,
oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis.
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Pediatric Patients with Schizophrenia
Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 2.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
RISPERDAL®
System/Organ Class
1-3 mg per day 4-6 mg per day
Placebo
Adverse Reaction
(N=55)
(N=51)
(N=54)
Gastrointestinal Disorders
Salivary hypersecretion
0
10
2
Nervous System Disorders
Parkinsonism*
16
28
11
Sedation
13
8
2
Somnolence
11
4
2
Tremor
11
10
6
Akathisia*
9
10
4
Dizziness
7
14
2
Dystonia*
2
6
0
Psychiatric Disorders
Anxiety
7
6
0
* Parkinsonism includes extrapyramidal disorder, muscle
rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and
restlessness. Dystonia includes dystonia and oculogyration.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult
patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
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Table 3.
Adverse Reactions in ≥1% of RISPERDAL®-Treated Adult
Patients with Bipolar Mania in Double-Blind, Placebo-Controlled
Monotherapy Trials
Percentage of Patients Reporting Event
System/Organ Class
RISPERDAL®
Placebo
Adverse Reaction
1-6 mg per day
(N=424)
(N=448)
Cardiac Disorders
Tachycardia
1
<1
Eye Disorders
Vision blurred
2
1
Gastrointestinal Disorders
Nausea
5
2
Diarrhea
3
2
Salivary hypersecretion
3
1
Dyspepsia
2
2
Stomach discomfort
2
<1
General Disorders
Fatigue
2
1
Asthenia
1
1
Pyrexia
1
1
Infections and Infestations
Nasopharyngitis
1
1
Investigations
Aspartate aminotransferase increased
1
<1
Nervous System Disorders
Parkinsonism*
25
9
Akathisia*
9
3
Tremor*
6
3
Dizziness
6
5
Sedation
6
2
Somnolence
5
2
Dystonia*
5
1
Lethargy
2
1
Dyskinesia*
1
<1
Reproductive System and Breast
Disorders
Galactorrhea
1
0
Skin and Subcutaneous Tissue
Disorders
Acne
1
0
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal
stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel
rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and
parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration,
torticollis. Dyskinesia includes muscle twitching and dyskinesia.
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult
patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy
trials.
Table 4. Adverse Reactions in ≥2% of RISPERDAL®-Treated Adult Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Reference ID: 2870867
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Percentage of Patients Reporting Event
RISPERDAL® + Mood
Placebo +
System/Organ Class
Stabilizer
Mood Stabilizer
Adverse Reaction
(N=127)
(N=126)
Cardiac Disorders
Palpitations
2
0
Gastrointestinal Disorders
Dyspepsia
9
8
Nausea
6
4
Diarrhea
6
4
Dry mouth
4
4
Vomiting
4
6
Constipation
3
3
Salivary hypersecretion
2
0
General Disorders
Chest pain
2
1
Fatigue
2
2
Infections and Infestations
Nasopharyngitis
2
3
Urinary tract infection
2
1
Investigations
Weight increased
2
2
Nervous System Disorders
Parkinsonism*
14
4
Headache
14
15
Akathisia*
8
0
Dizziness
7
2
Sedation
6
3
Tremor
6
2
Somnolence
3
1
Lethargy
2
1
Psychiatric Disorders
Insomnia
4
8
Anxiety
3
2
Respiratory, Thoracic and
Mediastinal Disorders
Pharyngolaryngeal pain
5
2
Cough
2
0
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia.
Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Bipolar Mania
Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Reference ID: 2870867
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Table 5.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric Patients with
Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
RISPERDAL ®
System/Organ Class
0.5-2.5 mg per 3-6 mg per Placebo
Adverse Reaction
day
day
(N=58)
(N=50)
(N=61)
Eye Disorders
Vision blurred
4
7
0
Gastrointestinal Disorders
Abdominal pain upper
16
13
5
Nausea
16
13
7
Vomiting
10
10
5
Diarrhea
8
7
2
Dyspepsia
10
3
2
Stomach discomfort
6
0
2
General Disorders
Fatigue
18
30
3
Metabolism and Nutrition Disorders
Increased appetite
4
7
2
Nervous System Disorders
Somnolence
22
30
12
Sedation
20
23
7
Dizziness
16
13
5
Parkinsonism*
6
12
3
Dystonia*
6
5
0
Akathisia*
0
8
2
Psychiatric Disorders
Anxiety
0
8
3
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain
10
3
5
Skin and Subcutaneous Tissue Disorders
Rash
0
7
2
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity.
Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
Reference ID: 2870867
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6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Autistic Disorder
Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric
patients treated for irritability associated with autistic disorder in two 8-week, double-blind,
placebo-controlled trials.
Table 6.
Adverse Reactions in ≥5% of RISPERDAL®-Treated Pediatric
Patients Treated for Irritability Associated with Autistic Disorder
in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting
Event
System/Organ Class
RISPERDAL®
Placebo
Adverse Reaction
0.5-4.0 mg per day
(N=80)
(N=76)
Cardiac Disorders
Tachycardia
5
0
Gastrointestinal Disorders
Vomiting
25
21
Constipation
21
8
Dry mouth
15
6
Salivary hypersecretion
9
0
Nausea
8
6
General Disorders
Fatigue
42
13
Feeling abnormal
5
0
Infections and Infestations
Nasopharyngitis
21
10
Rhinitis
13
10
Upper respiratory tract infection
8
3
Investigations
Weight increased
5
0
Metabolism and Nutrition Disorders
Increased appetite
47
19
Nervous System Disorders
Somnolence
49
18
Sedation
29
3
Drooling
16
5
Tremor
12
1
Parkinsonism*
11
1
Dizziness
9
3
Dyskinesia
7
3
Lethargy
5
3
Respiratory, Thoracic and
Mediastinal Disorders
Cough
24
18
Rhinorrhea
16
13
Nasal congestion
13
5
Skin and Subcutaneous Tissue
Disorders
Rash
11
8
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder,
muscle rigidity, cogwheel rigidity, and muscle tightness.
Reference ID: 2870867
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6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of
Risperidone
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the
pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled
clinical trial data sets. In addition, the following also includes adverse reactions reported in
RISPERDAL®-treated patients who participated in other studies, including double-blind,
active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric
patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder,
and studies in elderly patients with dementia.
Blood and Lymphatic System Disorders: granulocytopenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree,
bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye
swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual
acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling,
cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting
edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort,
generalized edema, drug withdrawal syndrome, peripheral coldness
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis,
tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media,
onychomycosis,
acarodermatitis,
bronchopneumonia,
respiratory
tract
infection,
tracheobronchitis, otitis media chronic
Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase
increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count
decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body
temperature decreased, blood pressure decreased, transaminases increased
Reference ID: 2870867
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Metabolism and Nutrition Disorders: polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest
pain, posture abormal, myalgia, neck pain, muscular weakness, rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria,
unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia,
transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss
of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder,
neuroleptic malignant syndrome, diabetic coma
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep
disorder, listless, libido decreased, anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea,
gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation,
ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus
congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion,
rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus,
skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular
Vascular Disorders: flushing
Additional Adverse Reactions Reported with RISPERDAL® CONSTA®
The following is a list of additional adverse reactions that have been reported during the
premarketing evaluation of RISPERDAL® CONSTA®, regardless of frequency of occurrence:
Blood and Lymphatic Disorders: neutropenia
Cardiac Disorders: bradycardia
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blepharospasm
Gastrointestinal Disorders: toothache, tongue spasm
Reference ID: 2870867
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General Disorders and Administration Site Conditions: pain
Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis,
subcutaneous abscess
Injury and Poisoning: fall
Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme
increased
Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain
Nervous System Disorders: convulsion, paresthesia
Psychiatric Disorders: depression
Skin and Subcutaneous Tissue Disorders: eczema
Vascular Disorders: hypertension
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-
controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225)
who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more
RISPERDAL®-treated patients were:
Table 7. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated
Adult Patients in Schizophrenia Trials
RISPERDAL®
2-8 mg/day
>8-16 mg/day
Placebo
Adverse Reaction
(N=366)
(N=198)
(N=225)
Dizziness
1.4%
1.0%
0%
Nausea
1.4%
0%
0%
Vomiting
0.8%
0%
0%
Parkinsonism
0.8%
0%
0%
Somnolence
0.8%
0%
0%
Dystonia
0.5%
0%
0%
Agitation
0.5%
0%
0%
Abdominal pain
0.5%
0%
0%
Orthostatic hypotension
0.3%
0.5%
0%
Akathisia
0.3%
2.0%
0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and
tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated
patients in a double-blind, placebo- and active-controlled trial.
Reference ID: 2870867
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Schizophrenia - Pediatrics
Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an
adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54)
placebo-treated patients. The adverse reactions associated with discontinuation for at least one
RISPERDAL®-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy
(1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately
6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event,
compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions
associated with discontinuation in RISPERDAL®-treated patients were:
Table 8. Adverse Reactions Associated With Discontinuation in 2 or More
RISPERDAL®-Treated Adult Patients in Bipolar Mania Clinical
Trials
RISPERDAL®
1-6 mg/day
Placebo
Adverse Reaction
(N=448)
(N=424)
Parkinsonism
0.4%
0%
Lethargy
0.2%
0%
Dizziness
0.2%
0%
Alanine aminotransferase
0.2%
0.2%
increased
Aspartate aminotransferase
0.2%
0.2%
increased
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients
discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The
adverse reactions associated with discontinuation in more than one RISPERDAL®-treated
pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated
with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an
adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse
event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
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Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-
relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including
(1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating
Scale, and (2) incidence of spontaneous complaints of EPS:
Dose Groups
Placebo
RISPERDAL®
RISPERDAL®
RISPERDAL®
RISPERDAL®
2 mg
6 mg
10 mg
16 mg
Parkinsonism
1.2
0.9
1.8
2.4
2.6
EPS Incidence
13%
17%
21%
21%
35%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial
comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
Dose Groups
RISPERDAL®
RISPERDAL®
RISPERDAL
RISPERDAL®
RISPERDAL®
1 mg
4 mg
® 8 mg
12 mg
16 mg
Parkinsonism
0.6
1.7
2.4
2.9
4.1
EPS Incidence
7%
12%
17%
18%
20%
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing
difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur
at low doses, they occur more frequently and with greater severity with high potency and at
higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is
observed in males and younger age groups.
Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed
doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of
adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend
(p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness,
palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function
abnormal, fatigue, and skin discoloration.
6.7 Changes in Body Weight
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The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting
a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week,
placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain
for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week
studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint
was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher
in the active-control group (3.5%).
Changes in body weight were also evaluated in pediatric patients [see Use in Specific
Populations (8.4)]
6.8 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no
statistically significant differences between risperidone and placebo in mean changes from
baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all
RISPERDAL® doses were pooled from randomized controlled trials in several indications, there
was a mean increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were
associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).
In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean
heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged
5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the
RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other
notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there
were no significant changes in ECG parameters, other than the effect of RISPERDAL® to
transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in
adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG
parameters including corrected QT intervals between treatment groups or within treatment
groups over time.
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction,
angioedema, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis in patients with impaired
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glucose metabolism, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion,
intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea
syndrome, thrombocytopenia, urinary retention, and water intoxication.
Other adverse events reported since market introduction, which were temporally related to
risperidone but not necessarily causally related, include the following: pituitary adenoma,
pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7
DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is
taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive
effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and
9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and
26%, respectively. However, cimetidine did not affect the AUC of risperidone and
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and
9-hydroxyrisperidone combined by 20%.
7.6 Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of
risperidone.
7.7 Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
Reference ID: 2870867
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7.8 Valproate
Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and
lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
modest number of poor metabolizers (n≅70) does not suggest that poor and extensive
metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase
the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did
not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of
RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy
on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between RISPERDAL® and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers
Carbamazepine co-administration decreased the steady-state plasma concentrations of
risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine
did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for
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patients receiving carbamazepine, particularly during initiation or discontinuation of
carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined
plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased
efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized
by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-
Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human
dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits
(0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations
was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the
MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a
multigenerational study), there was an increase in pup deaths during the first 4 days of lactation
at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether
these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was
an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a
decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0),
and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was
an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not
the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup
body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the one dose of
risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
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callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL®
therapy is unknown.
Non-Teratogenic Effects
Neonates exposed to antipsychotic drugs (including RISPERDAL®) during the third trimester of
pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There
have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress,
and feeding disorder in these neonates. These complications have varied in severity; while in
some cases symptoms have been self-limited, in other cases neonates have required intensive
care unit support and prolonged hospitalization.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving
RISPERDAL® should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in
417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-
blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical
Studies (14.1)]. Additional safety and efficacy information was also assessed in one long-term
(6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with
schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17
years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications
and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar
disorder have not been established.
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The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic
disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children
and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions
(6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-term studies in more than 1200
pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar
mania who were of similar age and weight, and who received similar dosages of RISPERDAL®
as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with
autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients
were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL®
treatment [see also Warnings and Precautions (5.4)].
Weight Gain
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight
increase was reported as a treatment-emergent adverse event in 14% of patients. In 103
adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of
RISPERDAL® treatment. The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55
and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric
disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed,
which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year
adjusted for age, based on Centers for Disease Control and Prevention normative data). The
majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The
average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and
53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or
mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL®
groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5-2.5 mg
group, 1.44 kg in the RISPERDAL® 3-6 mg group, and 0.65 kg in the placebo group). A similar
trend was observed in the mean change from baseline in body mass index.
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When treating pediatric patients with RISPERDAL® for any indication, weight gain should be
assessed against that expected with normal growth. [See also Adverse Reactions (6.7)]
Somnolence
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients
with autistic disorder. Most cases were mild or moderate in severity. These events were most
often of early onset with peak incidence occurring during the first two weeks of treatment, and
transient with a median duration of 16 days. Somnolence was the most commonly observed
adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the
schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were
most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)]
Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see
Dosage and Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as
in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up
to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or
psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of
patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients
who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged
10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia,
82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to
3-7% of patients on placebo. Increases were dose-dependent and generally greater in females
than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of
RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated
patients.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully
evaluated.
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8.5 Geriatric Use
Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient
numbers of patients aged 65 and over to determine whether or not they respond differently than
younger patients. Other reported clinical experience has not identified differences in responses
between elderly and younger patients. In general, a lower starting dose is recommended for an
elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4,
2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the
elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful
titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be
considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, 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 (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus
RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus
furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of RISPERDAL® regardless of
concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients
with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® has not been systematically studied in animals or humans for its potential for
abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these
observations were not systematic and it is not possible to predict on the basis of this limited
experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
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such patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
Premarketing experience included eight reports of acute RISPERDAL® overdosage with
estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and
symptoms were those resulting from an exaggeration of the drug's known pharmacological
effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal
symptoms. One case, involving an estimated overdose of 240 mg, was associated with
hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an
estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated
doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those
resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness,
sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions
reported since market introduction related to RISPERDAL® overdose include prolonged QT
interval and convulsions. Torsade de pointes has been reported in association with combined
overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of
activated charcoal together with a laxative should be considered. Because of the rapid
disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following
overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,
and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those
of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of
bretylium might be additive to those of risperidone, resulting in problematic hypotension.
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There is no specific antidote to RISPERDAL®. Therefore, appropriate supportive measures
should be instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as
intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be
used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha
blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be
administered. Close medical supervision and monitoring should continue until the patient
recovers.
11 DESCRIPTION
RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)
1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is: structural formula
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble
in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white),
2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the
following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The
0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg
tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C
Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution
contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and
purified water.
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RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg
(light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB®
Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin,
gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric
oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablets contain xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is
unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor
antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM)
for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for
cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® results from the combined concentrations of risperidone
and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism
at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the
other effects of RISPERDAL® .
12.3 Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%).
The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared
to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and
risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg
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daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak
plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of
9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor
metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers.
Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in
extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL®
can be given with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone
is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is
90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor
9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine
(10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and
9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly.
Although
extensive
metabolizers
have
lower
risperidone
and
higher
9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of
risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in
extensive and poor metabolizers.
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Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)].
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile
typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in
patients receiving quinidine have not been evaluated, but observations in a modest number
(n≅70) of poor metabolizers given RISPERDAL® do not suggest important differences between
poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g.,
carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a
decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see
Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism
of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions 7.12)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at
1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and
20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was
about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor
metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after
single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean
elimination half-life of about 20 hours.
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its
active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses
should be reduced in patients with renal disease [see Dosage and Administration (2.4) and
Warnings and Precautions (5.17)].
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Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to
those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by
about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein.
RISPERDAL® doses should be reduced in patients with liver disease [see Dosage and
Administration (2.4) and Warnings and Precautions (5.17)].
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was
decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Dosing should be modified accordingly in the elderly patients [see Dosage and Administration
(2.4)].
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those
in adults after correcting for the difference in body weight.
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether corrected for body weight or not) or race.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice
and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or
0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically
significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary
gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
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Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Highest No-
Effect Level
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6.0 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum
prolactin levels were not measured during the risperidone carcinogenicity studies; however,
measurements during subchronic toxicity studies showed that risperidone elevated serum
prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies.
An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents
after chronic administration of other antipsychotic drugs and is considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine
tumors in rodents is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test,
mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in
mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in
human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in
three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times
the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be
in females, since impaired mating behavior was not noted in the Segment I study in which males
only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at
doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to
10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum
testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat
or dog.
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14 CLINICAL STUDIES
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-
term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for
schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies,
among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general
psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing actively
psychotic schizophrenic patients. A second traditional assessment, the Clinical Global
Impression (CGI), reflects the impression of a skilled observer, fully familiar with the
manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the
Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative
Symptoms (SANS) were employed.
The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses
up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on
the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on
the SANS.
(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL®
(2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all
4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS
psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were
generally superior to placebo on the PANSS negative subscale. The most consistently
positive responses on all measures were seen for the 6 mg dose group, and there was no
suggestion of increased benefit from larger doses.
(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL®
(1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the
four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL®
dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None
Reference ID: 2870867
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of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The
most consistently positive responses were seen for the 4 mg dose group.
(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of
RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups
were generally superior to placebo on several PANSS measures, including a response
measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS
psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg
than for the 4 mg dose group.
Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for
schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic
medication were randomized to RISPERDAL® (2-8 mg/day) or to an active comparator, for
1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a
significantly longer time to relapse over this time period compared to those receiving the active
comparator.
Pediatrics
The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years
was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients
met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at
time of enrollment. In the first trial (study #1), patients were randomized into one of three
treatment groups: RISPERDAL® 1-3 mg/day (n = 55, mean modal dose = 2.6 mg),
RISPERDAL® 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the
second trial (study #2), patients were randomized to either RISPERDAL® 0.15-0.6 mg/day
(n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal
dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of
the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to
the target dosage range by approximately Day 7. Subsequently, dosage was increased to the
maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable
in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from
1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the
4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day
group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically
Reference ID: 2870867
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significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not
reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was
established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV
criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with
or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young
Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the
degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated
mood, speech, increased activity, sexual interest, language/thought disorder, thought content,
appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The
primary outcome in these trials was change from baseline in the YMRS total score. The results
of the trials follow:
(1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes,
which involved a dose range of RISPERDAL® 1-6 mg/day, once daily, starting at 3 mg/day
(mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction
of YMRS total score.
(2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of
1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day),
RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I
disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled,
multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a
manic or mixed episode of bipolar I disorder. Patients were randomized into one of three
treatment groups: RISPERDAL® 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg),
RISPERDAL® 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases,
study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7,
with further increases in dosage to the maximum tolerated dose within the targeted dose range by
Day 10. The primary rating instrument used for assessing efficacy in this study was the mean
change from baseline in the total YMRS score.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with
placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary
parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy
The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute
manic or mixed episodes was established in one controlled trial in adult patients who met the
DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic
features and with or without a rapid-cycling course.
(1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or
valproate therapy with inadequately controlled manic or mixed symptoms were randomized
to receive RISPERDAL®, placebo, or an active comparator, in combination with their
original therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at
2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a
therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively)
was superior to lithium or valproate alone in the reduction of YMRS total score.
(2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium,
valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms
were randomized to receive RISPERDAL® or placebo, in combination with their original
therapy. RISPERDAL®, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day
(mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine
(in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for
valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium,
valproate, or carbamazepine alone in the reduction of YMRS total score. A possible
explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone
clearance by carbamazepine, leading to subtherapeutic levels of risperidone and
9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder
was established in two 8-week, placebo-controlled trials in children and adolescents (aged
5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects
were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
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Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and
the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both
trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including
aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL®
0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL®, starting at 0.25 mg/day or
0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to
clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day),
significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with
placebo.
(2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged
5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at
0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day,
equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared
with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label
study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on
whether they received RISPERDAL® or placebo in the double-blind study). During this open-
label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of
1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as ≥
25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much
improved’) during the 4-6 month open-label treatment phase for about 140 days, on average,
were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind
withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients
who completed the withdrawal study (n=32), undertaken by an independent Data Safety
Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group
compared with the placebo group. Based on the interim analysis results, the study was terminated
due to demonstration of a statistically significant effect on relapse prevention. Relapse was
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For current labeling information, please visit https://www.fda.gov/drugsatfda
defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to
baseline of the randomized withdrawal phase).
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® (risperidone) Tablets
RISPERDAL® (risperidone) Tablets are imprinted "JANSSEN" on one side and either
“Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500
NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC 50458-301-01.
0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500
NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01.
1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458-300-06, bottles of 500 NDC
50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01.
2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458-320-06, bottles of 500 NDC
50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01.
3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458-330-06, bottles of 500 NDC
50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01.
4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-350-06 and hospital unit dose
blister packs of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) Oral Solution
RISPERDAL® (risperidone) 1 mg/mL Oral Solution (NDC 50458-305-03) is supplied in 30 mL
bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume
is 0.25 mL, while the maximum calibrated volume is 3 mL.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with
“R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths. RISPERDAL® M
TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of
4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a child-resistant
pouch containing a blister with 1 tablet.
0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30.
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This label may not be the latest approved by FDA.
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1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30.
2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box,
NDC 50458-325-28.
3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28.
4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28.
Storage and Handling
RISPERDAL® Tablets should be stored at controlled room temperature 15°-25°C (59°-77°F).
Protect from light and moisture.
RISPERDAL® 1 mg/mL Oral Solution should be stored at controlled room temperature 15°
25°C (59°-77°F). Protect from light and freezing.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room
temperature 15°-25°C (59°-77°F).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of
initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that RISPERDAL® therapy does not affect them adversely [see Warnings and
Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during therapy [see Use in Specific Populations (8.1)].
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17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL® [see Use
in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL® [see Drug Interactions
(7.1)].
17.7 Phenylketonurics
Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally
Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB®
Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M
TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL®
M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
Revised December 2010
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
RISPERDAL® Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Oral Solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
Janssen Ortho LLC, Gurabo, Puerto Rico 00778
RISPERDAL® Tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets, and
RISPERDAL® Oral Solution are manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RISPERDAL® CONSTA® safely and effectively. See full prescribing
information for RISPERDAL® CONSTA® .
RISPERDAL® CONSTA® (risperidone) LONG-ACTING INJECTION
Initial U.S. Approval: 2003
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly
patients
with
dementia-related
psychosis
treated
with
antipsychotic drugs are at an increased risk of death. RISPERDAL®
CONSTA® is not approved for use in patients with dementia-related
psychosis. (5.1)
—————————INDICATIONS AND USAGE————————
RISPERDAL® CONSTA® is an atypical antipsychotic indicated:
•
for the treatment of schizophrenia. (1.1)
•
as monotherapy or as adjunctive therapy to lithium or valproate for the
maintenance treatment of Bipolar I Disorder. (1.2)
——————— DOSAGE AND ADMINISTRATION———————
•
For patients who have never taken oral RISPERDAL®, tolerability
should be established with oral RISPERDAL® prior to initiating
treatment with RISPERDAL® CONSTA®.(2)
•
Administer by deep intramuscular (IM) deltoid or gluteal injection.
Each injection should be administered by a health care professional
using the appropriate enclosed safety needle (1-inch for deltoid
administration alternating injections between the two arms and 2-inch
for gluteal administration alternating injections between the two
buttocks). Do not administer intravenously. (2)
•
25 mg intramuscular (IM) every 2 weeks. Patients not responding to
25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The
maximum dose should not exceed 50 mg every 2 weeks. (2)
•
Oral RISPERDAL® (or another antipsychotic medication) should be
given with the first injection of RISPERDAL® CONSTA®, and
continued for 3 weeks (and then discontinued) to ensure adequate
therapeutic plasma concentrations from RISPERDAL® CONSTA®.
(2)
•
Upward dose adjustment of RISPERDAL® CONSTA® should not be
made more frequently than every 4 weeks. Clinical effects of each
upward dose adjustment should not be anticipated earlier than 3 weeks
after injection. (2)
•
Avoid inadvertent administration into a blood vessel. (5.15)
•
See Full Prescribing Information Section 2.8 for instructions for use.
——————— DOSAGE FORMS AND STRENGTHS——————
Vial kits: 12.5 mg, 25 mg, 37.5 mg, and 50 mg (3)
—————————— CONTRAINDICATIONS—————————
•
Known hypersensitivity to the product (4)
——————— WARNINGS AND PRECAUTIONS———————
•
Cerebrovascular events, including stroke, in elderly patients with
dementia-related psychosis. RISPERDAL® CONSTA® is not
approved for use in patients with dementia-related psychosis (5.2)
•
Neuroleptic
Malignant
Syndrome:
Manage
with
immediate
discontinuation and close monitoring (5.3)
•
Tardive Dyskinesia: Discontinue treatment if clinically appropriate
(5.4)
•
Hyperglycemia and Diabetes Mellitus- in some cases extreme and
associated with ketoacidosis or hyperosmolar coma or death, has been
reported in patients taking risperidone. Patients with diabetes mellitus
should have glucose levels monitored regularly. Patients with risk
factors for diabetes mellitus should undergo fasting glucose testing at
the beginning of treatment and periodically during treatment. All
patients taking risperidone should be monitored for symptoms of
hyperglycemia. Symptomatic patients should undergo fasting glucose
testing. (5.5)
•
Hyperprolactinemia: Risperidone treatment may elevate prolactin
levels. Long-standing hyperprolactinemia, when associated with
1
Reference ID: 2870867
hypogonadism, can lead to decreased bone density in men and
women. (5.6)
•
Orthostatic hypotension: associated with dizziness, tachycardia,
bradycardia, and syncope can occur, especially during initial dose
titration with oral risperidone. Use caution in patients with
cardiovascular disease, cerebrovascular disease, and conditions that
could affect hemodynamic responses. (5.7)
•
Leukopenia, Neutropenia, and Agranulocytosis have been reported
with antipsychotics, including RISPERDAL® CONSTA®. Patients
with history of a clinically significant low white blood cell count
(WBC) or a drug-induced leukopenia/neutropenia should have their
complete blood cell count (CBC) monitored frequently during the first
few months of therapy and discontinuation of RISPERDAL®
CONSTA®should be considered at the first sign of a clinically
significant decline in WBC in the absence of other causative
factors.(5.8)
•
Potential for cognitive and motor impairment: has potential to impair
judgment, thinking, and motor skills. Use caution when operating
machinery, including automobiles. (5.9)
•
Seizures: Use cautiously in patients with a history of seizures or with
conditions that potentially lower the seizure threshold. (5.10)
•
Dysphagia: Esophageal dysmotility and aspiration can occur. Use
cautiously in patients at risk for aspiration pneumonia. (5.11)
•
Priapism: has been reported. Severe priapism may require surgical
intervention. (5.12)
•
Thrombotic
Thrombocytopenic
Purpura
(TTP):
has
been
reported.(5.13)
•
Avoid inadvertent administration into a blood vessel (5.15)
•
Suicide: There is increased risk of suicide attempt in patients with
schizophrenia or bipolar disorder, and close supervision of high-risk
patients should accompany drug therapy. (5.17)
•
Increased sensitivity in patients with Parkinson’s disease or those with
dementia with Lewy bodies: has been reported. Manifestations include
mental status changes, motor impairment, extrapyramidal symptoms,
and features consistent with Neuroleptic Malignant Syndrome. (5.18)
•
Diseases or conditions that could affect metabolism or hemodynamic
responses: Use with caution in patients with such medical conditions
(e.g., recent myocardial infarction or unstable cardiac disease) (5.18)
—————————— ADVERSE REACTIONS—————————
The most common adverse reactions in clinical trials in patients with
schizophrenia (≥ 5%) were headache, parkinsonism, dizziness, akathisia,
fatigue, constipation, dyspepsia, sedation, weight increased, pain in
extremity, and dry mouth. The most common adverse reactions in clinical
trials in patients with bipolar disorder were weight increased (5% in
monotherapy trial) and tremor and parkinsonism (≥10% in adjunctive
therapy trial).(6)
The most common adverse reactions that were associated with
discontinuation from clinical trials in patients with schizophrenia were
agitation, depression, anxiety, and akathisia. Adverse reactions that were
associated with discontinuation from bipolar disorder trials were
hyperglycemia (one subject monotherapy trial) and hypokinesia and tardive
dyskinesia (one subject each in adjunctive therapy trial).(6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800
JANSSEN
(1-800-526-7736)
or
FDA
at
1-800-FDA-1088
or
www.fda.gov/medwatch
—————————— DRUG INTERACTIONS—————————
•
Due to CNS effects, use caution when administering with other
centrally-acting drugs. Avoid alcohol. (7.1)
•
Due to hypotensive effects, hypotensive effects of other drugs with
this potential may be enhanced. (7.2)
•
Effects of levodopa and dopamine agonists may be antagonized. (7.3)
•
Cimetidine and ranitidine increase the bioavailability of risperidone.
(7.5)
•
Clozapine may decrease clearance of risperidone. (7.6)
•
Fluoxetine and paroxetine increase plasma concentrations of
risperidone. (7.11)
•
Carbamazepine and other enzyme inducers decrease plasma
concentrations of risperidone. (7.12)
——————— USE IN SPECIFIC POPULATIONS———————
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Renal or Hepatic Impairment: dose appropriately with oral
•
Elderly: dosing for otherwise healthy elderly patients is the same as
RISPERDAL® prior to initiating treatment with RISPERDAL®
for healthy nonelderly. Elderly may be more predisposed to
CONSTA®. A lower starting dose of RISPERDAL® CONSTA® of
orthostatic effects than nonelderly. (8.5)
12.5 mg may be appropriate in some patients. (2.4)
See 17 for PATIENT COUNSELING INFORMATION
•
Nursing Mothers: should not breast feed. (8.3)
•
Pediatric Use: safety and effectiveness not established in patients less
Revised: 098/2010
than 18 years of age. (8.4)
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
1 INDICATIONS AND USAGE
1.1 Schizophrenia
1.2 Bipolar Disorder
2 DOSAGE AND ADMINISTRATION
2.1 Schizophrenia
2.2 Bipolar Disorder
2.3 General Dosing Information
2.4 Dosage in Special Populations
2.5 Reinitiation of Treatment in Patients Previously Discontinued
2.6 Switching from Other Antipsychotics
2.7 Co-Administration of RISPERDAL
® CONSTA
® with Certain
Other Medications
2.8 Instructions for Use
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related
Psychosis
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly
Patients with Dementia-Related Psychosis
5.3 Neuroleptic Malignant Syndrome (NMS)
5.4 Tardive Dyskinesia
5.5 Hyperglycemia and Diabetes Mellitus
5.6 Hyperprolactinemia
5.7 Orthostatic Hypotension
5.8 Leukopenia, Neutropenia, and Agranulocytosis
5.9 Potential for Cognitive and Motor Impairment
5.10 Seizures
5.11 Dysphagia
5.12 Priapism
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
5.14 Body Temperature Regulation
5.15 Administration
5.16 Antiemetic Effect
5.17 Suicide
5.18 Use in Patients with Concomitant Illness
5.19 Osteodystrophy and Tumors in Animals
5.20 Monitoring: Laboratory Tests
6 ADVERSE REACTIONS
6.1 Commonly-Observed Adverse Reactions in Double-Blind,
Placebo-Controlled Clinical Trials - Schizophrenia
6.2 Commonly-Observed Adverse Reactions in Double-Blind,
Placebo-Controlled Clinical Trials – Bipolar Disorder
6.3 Other Adverse Reactions Observed During the Premarketing
Evaluation of RISPERDAL® CONSTA
®
6.4 Discontinuations Due to Adverse Reactions
6.5 Dose Dependency of Adverse Reactions in Clinical Trials
6.6 Changes in Body Weight
6.7 Changes in ECG
6.8 Pain Assessment and Local Injection Site Reactions
6.9 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Centrally-Acting Drugs and Alcohol
7.2 Drugs with Hypotensive Effects
7.3 Levodopa and Dopamine Agonists
7.4 Amitriptyline
7.5 Cimetidine and Ranitidine
7.6 Clozapine
7.7 Lithium
7.8 Valproate
7.9 Digoxin
7.10 Topiramate
7.11 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
7.12 Carbamazepine and Other CYP 3A4 Enzyme Inducers
7.13 Drugs Metabolized by CYP 2D6
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
9.2 Abuse
9.3 Dependence
10 OVERDOSAGE
10.1 Human Experience
10.2 Management of 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 Schizophrenia
14.2 Bipolar Disorder - Monotherapy
14.3 Bipolar Disorder - Adjunctive Therapy
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Orthostatic Hypotension
17.2 Interference with Cognitive and Motor Performance
17.3 Pregnancy
17.4 Nursing
17.5 Concomitant Medication
17.6 Alcohol
* Sections or subsections omitted from the full prescribing information are
not listed
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FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA
RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which the findings
of increased mortality in observational studies may be attributed to the antipsychotic drug
as opposed to some characteristic(s) of the patients is not clear. RISPERDAL® CONSTA®
(risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)]
1 INDICATIONS AND USAGE
1.1 Schizophrenia
RISPERDAL® CONSTA® (risperidone) is indicated for the treatment of schizophrenia [see
Clinical Studies (14.1)].
1.2 Bipolar Disorder
RISPERDAL® CONSTA® is indicated as monotherapy or as adjunctive therapy to lithium or
valproate for the maintenance treatment of Bipolar I Disorder [see Clinical Studies (14.2,
14.3)].
2 DOSAGE AND ADMINISTRATION
For patients who have never taken oral RISPERDAL®, it is recommended to establish
tolerability with oral RISPERDAL® prior to initiating treatment with RISPERDAL®
CONSTA®.
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RISPERDAL® CONSTA® should be administered every 2 weeks by deep intramuscular (IM)
deltoid or gluteal injection. Each injection should be administered by a health care professional
using the appropriate enclosed safety needle [see Dosage and Administration (2.8)]. For
deltoid administration, use the 1-inch needle alternating injections between the two arms. For
gluteal administration, use the 2-inch needle alternating injections between the two buttocks.
Do not administer intravenously.
2.1 Schizophrenia
The recommended dose for the treatment of schizophrenia is 25 mg IM every 2 weeks.
Although dose response for effectiveness has not been established for RISPERDAL®
CONSTA®, some patients not responding to 25 mg may benefit from a higher dose of 37.5 mg
or 50 mg. The maximum dose should not exceed 50 mg RISPERDAL® CONSTA® every 2
weeks. No additional benefit was observed with dosages greater than 50 mg RISPERDAL®
CONSTA®; however, a higher incidence of adverse effects was observed.
The efficacy of RISPERDAL® CONSTA® in the treatment of schizophrenia has not been
evaluated in controlled clinical trials for longer than 12 weeks. Although controlled studies
have not been conducted to answer the question of how long patients with schizophrenia should
be treated with RISPERDAL® CONSTA®, oral risperidone has been shown to be effective in
delaying time to relapse in longer-term use. It is recommended that responding patients be
continued on treatment with RISPERDAL® CONSTA® at the lowest dose needed. The
physician who elects to use RISPERDAL® CONSTA® for extended periods should periodically
re-evaluate the long-term risks and benefits of the drug for the individual patient.
2.2 Bipolar Disorder
The recommended dose for monotherapy or adjunctive therapy to lithium or valproate for the
maintenance treatment of Bipolar I Disorder is 25 mg IM every 2 weeks. Some patients may
benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been studied in
this population. The physician who elects to use RISPERDAL® CONSTA® for extended
periods should periodically re-evaluate the long-term risks and benefits of the drug for the
individual patient.
2.3 General Dosing Information
A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose
adjustment, such as in patients with hepatic or renal impairment, for certain drug interactions
that increase risperidone plasma concentrations [see Drug Interactions (7.11)] or in patients
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who have a history of poor tolerability to psychotropic medications. The efficacy of the 12.5
mg dose has not been investigated in clinical trials.
Oral RISPERDAL® (or another antipsychotic medication) should be given with the first
injection of RISPERDAL® CONSTA® and continued for 3 weeks (and then discontinued) to
ensure that adequate therapeutic plasma concentrations are maintained prior to the main release
phase of risperidone from the injection site [see Clinical Pharmacology (12.3)].
Upward dose adjustment should not be made more frequently than every 4 weeks. The clinical
effects of this dose adjustment should not be anticipated earlier than 3 weeks after the first
injection with the higher dose.
In patients with clinical factors such as hepatic or renal impairment or certain drug interactions
that increase risperidone plasma concentrations [see Drug Interactions (7.11)], dose reduction
as low as 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been
investigated in clinical trials.
Do not combine two different dose strengths of RISPERDAL® CONSTA® in a single
administration.
2.4 Dosage in Special Populations
Elderly
For elderly patients treated with RISPERDAL® CONSTA®, the recommended dosage is 25 mg
IM every 2 weeks. Oral RISPERDAL® (or another antipsychotic medication) should be given
with the first injection of RISPERDAL® CONSTA® and should be continued for 3 weeks to
ensure that adequate therapeutic plasma concentrations are maintained prior to the main release
phase of risperidone from the injection site [see Clinical Pharmacology (12.3)].
Renal or Hepatic Impairment
Patients with renal or hepatic impairment should be treated with titrated doses of oral
RISPERDAL® prior to initiating treatment with RISPERDAL® CONSTA®. The recommended
starting dose is 0.5 mg oral RISPERDAL® twice daily during the first week, which can be
increased to 1 mg twice daily or 2 mg once daily during the second week. If a total daily dose
of at least 2 mg oral RISPERDAL® is well tolerated, an injection of 25 mg RISPERDAL®
CONSTA® can be administered every 2 weeks. Oral supplementation should be continued for 3
weeks after the first injection until the main release of risperidone from the injection site has
begun. In some patients, slower titration may be medically appropriate. Alternatively, a starting
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dose of RISPERDAL® CONSTA® of 12.5 mg may be appropriate. The efficacy of the 12.5 mg
dose has not been investigated in clinical trials.
Patients with renal impairment may have less ability to eliminate risperidone than normal
adults. Patients with impaired hepatic function may have an increase in the free fraction of the
risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)].
Elderly patients and patients with a predisposition to hypotensive reactions or for whom such
reactions would pose a particular risk should be instructed in nonpharmacologic interventions
that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed
for several minutes before attempting to stand in the morning and slowly rising from a seated
position). These patients should avoid sodium depletion or dehydration, and circumstances that
accentuate hypotension (alcohol intake, high ambient temperature, etc.). Monitoring of
orthostatic vital signs should be considered [see Warnings and Precautions (5.7)].
2.5 Reinitiation of Treatment in Patients Previously Discontinued
There are no data to specifically address reinitiation of treatment. When restarting patients who
have had an interval off treatment with RISPERDAL® CONSTA®, supplementation with oral
RISPERDAL® (or another antipsychotic medication) should be administered.
2.6 Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients from other
antipsychotics to RISPERDAL® CONSTA®, or concerning concomitant administration with
other antipsychotics. Previous antipsychotics should be continued for 3 weeks after the first
injection of RISPERDAL® CONSTA® to ensure that therapeutic concentrations are maintained
until the main release phase of risperidone from the injection site has begun [see Clinical
Pharmacology (12.3)]. For patients who have never taken oral RISPERDAL®, it is
recommended to establish tolerability with oral RISPERDAL® prior to initiating treatment with
RISPERDAL® CONSTA®. As recommended with other antipsychotic medications, the need
for continuing existing EPS medication should be re evaluated periodically.
2.7 Co-Administration of RISPERDAL® CONSTA® with Certain Other Medications
Co-administration of carbamazepine and other CYP 3A4 enzyme inducers (e.g., phenytoin,
rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma
concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead
to decreased efficacy of RISPERDAL® CONSTA® treatment. The dose of risperidone needs to
be titrated accordingly for patients receiving these enzyme inducers, especially during initiation
or discontinuation of therapy with these inducers [see Drug Interactions (7.11)]. At the
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initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers,
patients should be closely monitored during the first 4-8 weeks, since the dose of
RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oral
RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP
3A4 hepatic enzyme inducers, the dosage of RISPERDAL® CONSTA® should be re-evaluated
and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL®
CONSTA® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other
CYP 3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone
plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg
RISPERDAL® CONSTA® and discontinuing from carbamazepine or other CYP3A4 enzyme
inducers, it is recommended to continue treatment with the 25-mg dose unless clinical
judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates
interruption of RISPERDAL® CONSTA® treatment. The efficacy of the12.5 mg dose has not
been investigated in clinical trials.
Fluoxetine and paroxetine, CYP 2D6 inhibitors, have been shown to increase the plasma
concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9
hydroxyrisperidone by about 10%. The dose of risperidone needs to be titrated accordingly
when fluoxetine or paroxetine is co-administered. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the dose of
RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is considered, patients
may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the
planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma
concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving
the recommended dose of 25 mg RISPERDAL® CONSTA®, it is recommended to continue
treatment with the 25 mg dose unless clinical judgment necessitates lowering the
RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL®
CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving
fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5
mg dose has not been investigated in clinical trials. The effects of discontinuation of
concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9
hydroxyrisperidone have not been studied. [see Drug Interactions (7.11)]
2.8 Instructions for Use
Dose pack components include:
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usage illustration
RISPERDAL® CONSTA® must be reconstituted only in the diluent supplied in the dose pack, and must be
administered with only the appropriate needle supplied in the dose pack for gluteal (2-inch needle) or deltoid (1-inch
needle) administration. All components are required for administration. Do not substitute any components of the
dose pack. To assure that the intended dose of risperidone is delivered, the full contents from the vial must be
administered. Administration of partial contents may not deliver the intended dose of risperidone.
Remove the dose pack of RISPERDAL® CONSTA® from the refrigerator and allow it to come
to room temperature prior to reconstitution.
1. Flip off the plastic colored cap from the vial. usage illustration
2. Peel back the blister pouch and remove the SmartSite® Needle-Free Vial Access
Device by holding the white luer cap. Do not touch the spike tip of the access device
at any time.
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usage illustration
3. Place vial on a hard surface. Hold the base of the vial. Orient the SmartSite® Access
Device vertically over the vial so that the spike tip is at the center of the vial’s rubber
stopper. With a straight downward push, press the spike tip of the SmartSite® Access
Device through the center of the vial’s rubber stopper until the device securely snaps
onto the vial top. usage illustration
4. Swab the syringe connection point (blue circle) of the SmartSite® Access Device
with preferred antiseptic prior to attaching the syringe to the SmartSite® Access
Device. usage illustration
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5. The prefilled syringe has a white tip consisting of 2 parts: a white collar and a
smooth white cap. To open the syringe, hold the syringe by the white collar and snap
off the smooth white cap (DO NOT TWIST OFF THE WHITE CAP). Remove the
white cap together with the rubber tip cap inside. usage illustration
For all syringe assembly steps, hold the syringe only by the white collar located at the
tip of the syringe. Be careful to not overtighten components when assembling.
Overtightening connections may cause syringe component parts to loosen from the
syringe body.
6. While holding the white collar of the syringe, insert and press the syringe tip into
the blue circle of the SmartSite® Access Device and twist in a clockwise motion to
secure the connection of the syringe to the SmartSite® Access Device (avoid over-
twisting). Hold the skirt of the SmartSite® Access Device during attachment to
prevent it from spinning. Keep the syringe and SmartSite® Access Device aligned. usage illustration
7. Inject the entire contents of the syringe containing the diluent into the vial.
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usage illustration
8. Shake the vial vigorously while holding the plunger rod down with the thumb for a
minimum of 10 seconds to ensure a homogeneous suspension. When properly mixed,
the suspension appears uniform, thick, and milky in color. The microspheres will be
visible in liquid, but no dry microspheres remain. usage illustration
9. Do not store the vial after reconstitution or the suspension may settle. If 2 minutes
pass before injection, re-suspend by shaking vigorously.
10. Invert the vial completely and slowly withdraw the suspension from the vial into
the syringe. Tear section of the vial label at the perforation and apply detached label
to syringe for identification purposes.
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usage illustration
11. While holding the white collar of the syringe, unscrew the syringe from the
SmartSite® Access Device. Discard both the vial and vial access device appropriately. usage illustration
12. Select the appropriate needle:
For GLUTEAL injection, select the 20G TW 2-inch needle (longer needle with
yellow colored hub in blister with yellow print)
For DELTOID injection, select the 21G UTW 1-inch needle (shorter needle with
green colored hub in blister with green print)
13. Peel the blister pouch of the Needle-Pro® safety device open halfway. Grasp the
transparent needle sheath using the plastic peel pouch. To prevent contamination, be
careful not to touch the orange Needle-Pro® safety device’s Luer connector. While
holding the white collar of the syringe, attach the Luer connection of the orange
Needle-Pro® safety device to the syringe with an easy clockwise twisting motion.
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usage illustration
14. While continuing to hold the white collar of the syringe, grasp the transparent
needle sheath and seat the needle firmly on the orange Needle-Pro® safety device with
a push and a clockwise twist. usage illustration
15. If 2 minutes pass before injection, re-suspend by shaking vigorously.
16. While holding the white collar of the syringe, pull the transparent needle sheath
straight away from the needle. DO NOT TWIST the sheath as the Luer connections
may be loosened. usage illustration
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17. Tap the syringe gently to make any air bubbles rise to the top. Remove air in
syringe by depressing the plunger rod while holding the needle in an upright position.
Inject the entire contents of the syringe intramuscularly (IM) into the selected gluteal
or deltoid muscle of the patient within 2 minutes to avoid settling. Gluteal injection
should be made into the upper-outer quadrant of the gluteal area. DO NOT
ADMINISTER INTRAVENOUSLY. usage illustration
WARNING: To avoid a needle stick injury with a contaminated needle:
• Do not use free hand to press the Needle-Pro® safety device over the needle.
• Do not intentionally disengage the Needle-Pro® safety device.
• Do not attempt to straighten the needle or engage Needle-Pro® safety device
if the needle is bent or damaged.
• Do not mishandle the Needle-Pro® safety device as it may cause the needle
to protrude from the Needle-Pro® safety device.
18. After injection is complete, press the needle into the orange Needle-Pro® safety
device using a one-handed technique. Perform a one-handed technique by GENTLY
pressing the orange Needle-Pro® safety device against a table top or other hard, flat
surface. AS THE ORANGE NEEDLE-PRO® SAFETY DEVICE IS PRESSED, THE
NEEDLE WILL FIRMLY ENGAGE INTO THE ORANGE NEEDLE-PRO®
SAFETY DEVICE. Visually confirm that the needle is fully engaged into the orange
Needle-Pro® safety device before discarding. Discard needle appropriately. Also
discard the other (unused) needle provided in the dose pack.
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usage illustration
Upon suspension of the microspheres in the diluent, it is recommended to use
RISPERDAL® CONSTA® immediately. If RISPERDAL® CONSTA® is not
administered within 2 minutes of reconstitution, settling of the microspheres will
occur and resuspension by shaking is necessary prior to administration. Keeping the
vial upright, shake vigorously back and forth for as long as it takes to resuspend the
microspheres. Once in suspension, the product may remain at room temperature (do
not expose to temperatures above 77ºF (25ºC)). RISPERDAL® CONSTA® must be
used within 6 hours of suspension.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
3 DOSAGE FORMS AND STRENGTHS
RISPERDAL® CONSTA® is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and 50
mg risperidone. It is provided as a dose pack, consisting of a vial containing the risperidone
microspheres, a pre-filled syringe containing 2 mL of diluent for RISPERDAL® CONSTA®, a
SmartSite® Needle-Free Vial Access Device, and two Needle-Pro® safety needles for
intramuscular injection (a 21 G UTW 1-inch needle with needle protection device for deltoid
administration and a 20 G TW 2-inch needle with needle protection device for gluteal
administration).
4 CONTRAINDICATIONS
RISPERDAL® CONSTA® (risperidone) is contraindicated in patients with a known
hypersensitivity to the product.
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5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at
an increased risk of death. RISPERDAL®CONSTA®(risperidone) is not approved for the
treatment of dementia-related psychosis (see Boxed Warning).
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with
Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities,
were reported in patients (mean age 85 years; range 73-97) in trials of oral risperidone in
elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a
significantly higher incidence of cerebrovascular adverse events in patients treated with oral
risperidone compared to patients treated with placebo. RISPERDAL® CONSTA® is not
approved for the treatment of patients with dementia-related psychosis [See also Boxed
Warning and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence
of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and
cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase,
myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases in which the clinical presentation includes both
serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately
treated extrapyramidal signs and symptoms (EPS). Other important considerations in the
differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and
primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and
medical monitoring; and (3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for uncomplicated NMS.
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If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in
patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to
be highest among the elderly, especially elderly women, it is impossible to rely upon
prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are
likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to
cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
drugs administered to the patient increase. However, the syndrome can develop, although much
less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® CONSTA® should be prescribed in a manner that is
most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment
should generally be reserved for patients who suffer from a chronic illness that: (1) is known to
respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially
less harmful treatments are not available or appropriate. In patients who do require chronic
treatment, the smallest dose and the shortest duration of treatment producing a satisfactory
clinical response should be sought. The need for continued treatment should be reassessed
periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®
CONSTA®, drug discontinuation should be considered. However, some patients may require
treatment with RISPERDAL® CONSTA® despite the presence of the syndrome.
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5.5 Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis
or hyperosmolar coma or death, have been reported in patients treated with atypical
antipsychotics including RISPERDAL®. Assessment of the relationship between atypical
antipsychotic use and glucose abnormalities is complicated by the possibility of an increased
background risk of diabetes mellitus in patients with schizophrenia and the increasing
incidence of diabetes mellitus in the general population. Given these confounders, the
relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not
completely understood. However, epidemiological studies suggest an increased risk of
treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical
antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients
treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL®, should be monitored regularly for worsening of
glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of
diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL®,
should undergo fasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL®,
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria,
polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment
with atypical antipsychotics, including RISPERDAL®, should undergo fasting blood glucose
testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including
RISPERDAL®, was discontinued; however, some patients required continuation of anti
diabetic treatment despite discontinuation of RISPERDAL®.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin
levels and the elevation persists during chronic administration. Risperidone is associated with
higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary
gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported in patients receiving prolactin-elevating compounds. Long-
standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone
density in both female and male subjects.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tissue culture experiments indicate that approximately one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is
contemplated in a patient with previously detected breast cancer. An increase in pituitary gland,
mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and
pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in
mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic
studies conducted to date have shown an association between chronic administration of this
class of drugs and tumorigenesis in humans; the available evidence is considered too limited to
be conclusive at this time.
5.7 Orthostatic Hypotension
RISPERDAL® CONSTA® may induce orthostatic hypotension associated with dizziness,
tachycardia, and in some patients, syncope, especially during the initial dose-titration period
with oral risperidone, probably reflecting its alpha-adrenergic antagonistic properties. Syncope
was reported in 0.8% (12/1499 patients) of patients treated with RISPERDAL® CONSTA® in
multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that
help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for
several minutes before attempting to stand in the morning and slowly rising from a seated
position).
RISPERDAL® CONSTA® should be used with particular caution in (1) patients with known
cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or
conduction abnormalities), cerebrovascular disease, and conditions which would predispose
patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients
with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in
all such patients, and a dose reduction should be considered if hypotension occurs. Clinically
significant hypotension has been observed with concomitant use of oral RISPERDAL® and
antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class
Effect:
In
clinical
trial
and/or
postmarketing
experience,
events
of
leukopenia/neutropenia have been reported temporally related to antipsychotic agents,
including RISPERDAL® CONSTA®. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count
(WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history of a
clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their
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Reference ID: 2870867
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complete blood count (CBC) monitored frequently during the first few months of therapy and
discontinuation of RISPERDAL® CONSTA® should be considered at the first sign of a
clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients
with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue
RISPERDAL® CONSTA® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was reported by 5% of patients treated with RISPERDAL® CONSTA® in
multiple-dose trials. Since risperidone has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that treatment with RISPERDAL® CONSTA®
does not affect them adversely.
5.10 Seizures
During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated
with RISPERDAL® CONSTA®. Therefore, RISPERDAL® CONSTA® should be used
cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced
Alzheimer’s dementia. RISPERDAL® CONSTA® and other antipsychotic drugs should be used
cautiously in patients at risk for aspiration pneumonia. [see also Boxed Warning and Warnings
and Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9)].
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL®
in a large, open premarketing experience (approximately 1300 patients). She experienced
jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The
relationship to RISPERDAL® therapy is unknown.
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Reference ID: 2870867
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5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral RISPERDAL® or
RISPERDAL® CONSTA® use. Caution is advised when prescribing RISPERDAL® CONSTA®
for patients who will be exposed to temperature extremes.
5.15 Administration
RISPERDAL® CONSTA® should be injected into the deltoid or gluteal muscle, and care must
be taken to avoid inadvertent injection into a blood vessel. [see Dosage and Administration (2)
and Adverse Reactions (6.8)]
5.16 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal
obstruction, Reye’s syndrome, and brain tumor.
5.17 Suicide
There is an increased risk of suicide attempt in patients with schizophrenia or bipolar disorder,
and close supervision of high-risk patients should accompany drug therapy. RISPERDAL®
CONSTA® is to be administered by a health care professional [see Dosage and Administration
(2)]; therefore, suicide due to an overdose is unlikely.
5.18 Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® CONSTA® in patients with certain concomitant
systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies
who receive antipsychotics, including RISPERDAL® CONSTA®, are reported to have an
increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity
have been reported to include confusion, obtundation, postural instability with frequent falls,
extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant
syndrome.
Caution is advisable when using RISPERDAL® CONSTA® in patients with diseases or
conditions that could affect metabolism or hemodynamic responses. RISPERDAL® CONSTA®
has not been evaluated or used to any appreciable extent in patients with a recent history of
myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded
from clinical studies during the product’s premarket testing.
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Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) treated with oral
RISPERDAL®; an increase in the free fraction of risperidone is also seen in patients with
severe hepatic impairment. Patients with renal or hepatic impairment should be carefully
titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a
dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors
warrant dose adjustment, such as in patients with renal or hepatic impairment [see Dosage and
Administration (2.4)].
5.19 Osteodystrophy and Tumors in Animals
RISPERDAL® CONSTA® produced osteodystrophy in male and female rats in a 1-year
toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every
2 weeks.
RISPERDAL® CONSTA® produced renal tubular tumors (adenoma, adenocarcinoma) and
adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40
mg/kg administered IM every 2 weeks. In addition, RISPERDAL® CONSTA® produced an
increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study
and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered
IM every 2 weeks. (Cellular proliferation was not measured at the low dose or in females in
either study.)
The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum
recommended human dose (MRHD) (50 mg) on a mg/m2 basis and is associated with a plasma
exposure (AUC) 2 times the expected plasma exposure (AUC) at the IM MRHD. The no-effect
dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m2 basis). Plasma
exposure (AUC) at the no-effect dose was one third the expected plasma exposure (AUC) at the
IM MRHD.
Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally
administered risperidone. Osteodystrophy was not observed in dogs at doses up to 14 times
(based on AUC) the IM MRHD in a 1-year toxicity study.
The renal tubular and adrenomedullary tumors in male rats and other tumor findings are
described in more detail in Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of
Fertility).
The relevance of these findings to human risk is unknown.
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Reference ID: 2870867
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5.20 Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Increased mortality in elderly patients with dementia-related psychosis [see Boxed
Warning and Warnings and Precautions (5.1)]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-
related psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Tardive dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Orthostatic hypotension [see Warnings and Precautions (5.7)]
• Leukopenia/Neutropenia and Agranulocytosis [see Warnings and Precautions (5.8)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Dysphagia [see Warnings and Precautions (5.11)]
• Priapism [see Warnings and Precautions (5.12)]
• Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions
(5.13)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
• Avoidance of inadvertent injection into a blood vessel [see Warnings and Precautions
(5.15)]
• Antiemetic effect [see Warnings and Precautions (5.16)]
• Suicide [see Warnings and Precautions (5.17)]
• Increased sensitivity in patients with Parkinson’s disease or those with dementia with
Lewy bodies [see Warnings and Precautions (5.18)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.18)]
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•
Osteodystrophy and tumors in animals [see Warnings and Precautions (5.19)]
The most common adverse reactions in clinical trials in patients with schizophrenia (≥5%)
were: headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation,
weight increased, pain in extremity, and dry mouth. The most common adverse reactions in the
double-blind, placebo-controlled periods of the bipolar disorder trials were weight increased
(5% in the monotherapy trial) and tremor and parkinsonism (≥10% in the adjunctive treatment
trial).
The most common adverse reactions that were associated with discontinuation from the 12
week double-blind, placebo-controlled trial in patients with schizophrenia (causing
discontinuation in ≥ 1% of patients) were agitation, depression, anxiety, and akathisia. Adverse
reactions that were associated with discontinuation from the double-blind, placebo-controlled
periods of the bipolar disorder trials were hyperglycemia (one patient in the monotherapy trial)
and hypokinesia and tardive dyskinesia (one patient each in the adjunctive treatment trial).
The data described in this section are derived from a clinical trial database consisting of 2392
patients exposed to one or more doses of RISPERDAL® CONSTA® for the treatment of
schizophrenia. Of these 2392 patients, 332 were patients who received RISPERDAL®
CONSTA® while participating in a 12-week double-blind, placebo-controlled trial. Two
hundred two (202) of the 332 were schizophrenia patients who received 25 mg or 50 mg
RISPERDAL® CONSTA®. The conditions and duration of treatment with RISPERDAL®
CONSTA® in the other clinical trials varied greatly and included (in overlapping categories)
double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label
phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term
(up to 4 years) exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
In addition to the studies in patients with schizophrenia, safety data are presented from a trial
assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as
monotherapy for maintenance treatment in patients with bipolar I disorder. The subjects in this
multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV
criteria for Bipolar Disorder Type I and who were stable on risperidone (oral or long-acting
injection), were stable on other antipsychotics or mood stabilizers, or were experiencing an
acute episode. After a 3-week period of treatment with open-label oral risperidone (n=440),
subjects who demonstrated an initial response to oral risperidone in this period and those who
were stable on risperidone (oral or long-acting injection) at study entry entered into a 26-week
stabilization period of open-label RISPERDAL® CONSTA® (n=501). Subjects who
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demonstrated a maintained response during this period were then randomized into a 24-month
double-blind, placebo-controlled period in which they received RISPERDAL® CONSTA®
(n=154) or placebo (n=149) as monotherapy. Subjects who relapsed or who completed the
double-blind period could choose to enter an 8-week open-label RISPERDAL® CONSTA®
extension period (n=160).
Safety data are also presented from a trial assessing the efficacy and safety of RISPERDAL®
CONSTA® when administered as adjunctive maintenance treatment in patients with bipolar
disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult
patients who met DSM-IV criteria for Bipolar Disorder Type I or Type II and who experienced
at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous
12 months, including at least 2 episodes in the 6 months prior to the start of the study. At the
start of this study, all patients (n=275) entered into a 16-week open-label treatment phase in
which they received RISPERDAL® CONSTA® in addition to continuing their treatment as
usual, which consisted of various mood stabilizers (primarily lithium and valproate),
antidepressants, and/or anxiolytics. Patients who reached remission at the end of this 16-week
open-label treatment phase (n=139) were then randomized into a 52-week double-blind,
placebo-controlled phase in which they received RISPERDAL® CONSTA® (n=72) or placebo
(n = 67) as adjunctive treatment in addition to continuing their treatment as usual. Patients who
did not reach remission at the end of the 16-week open-label treatment phase could choose to
continue to receive RISPERDAL® CONSTA® as adjunctive therapy in an open-label manner,
in addition to continuing their treatment as usual, for up to an additional 36 weeks as clinically
indicated for a total period of up to 52 weeks; these patients (n=70) were also included in the
evaluation of safety.
Adverse events during exposure to study treatment were obtained by general inquiry and
recorded by clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse events, events were
grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events
that were considered to be reasonably associated with the use of RISPERDAL® CONSTA®
(adverse drug reactions) based on the comprehensive assessment of the available adverse event
information. A causal association for RISPERDAL® CONSTA® often cannot be reliably
established in individual cases. Further, 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.
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The majority of all adverse reactions were mild to moderate in severity.
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials - Schizophrenia
Table 1 lists the adverse reactions reported in 2% or more of RISPERDAL® CONSTA®-treated
patients with schizophrenia in one 12-week double-blind, placebo-controlled trial.
Table 1. Adverse Reactions in ≥ 2% of RISPERDAL® CONSTA®-Treated Patients with Schizophrenia in a
12-Week Double-Blind, Placebo-Controlled Trial
System Organ Class
Adverse Reaction
Eye disorders
Vision blurred
Percentage of Patients Reporting Event
RISPERDAL® CONSTA®
Placebo
25 mg
50 mg
(N=99)
(N=103)
(N=98)
2
3
0
Gastrointestinal disorders
Constipation
Dry mouth
Dyspepsia
5
0
6
7
7
6
1
1
0
Nausea
3
4
5
Toothache
1
3
0
Salivary hypersecretion
4
1
0
General disorders and administration site
conditions
Fatigue*
Edema peripheral
Pain
Pyrexia
3
2
4
2
9
3
1
1
0
1
0
0
Infections and infestations
Upper respiratory tract infection
2
0
1
Investigations
Weight increased
Weight decreased
5
4
4
1
2
1
Musculoskeletal and connective tissue
disorders
Pain in extremity
6
2
1
Nervous system disorders
Headache
Parkinsonism*
Dizziness
Akathisia*
Sedation*
Tremor
15
8
7
4
5
0
21
15
11
11
6
3
12
9
6
6
3
0
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Syncope
Hypoesthesia
2
2
1
0
0
0
Respiratory, thoracic and mediastinal
disorders
Cough
Sinus congestion
4
2
2
0
3
0
Skin and subcutaneous tissue disorders
Acne
2
2
0
Dry skin
2
0
0
* Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness,
muscle rigidity, and bradykinesia. Akathisia includes akathisia and restlessness. Sedation includes sedation and
somnolence.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-
Controlled Clinical Trials – Bipolar Disorder
Table 2 lists the treatment-emergent adverse reactions reported in 2% or more of
RISPERDAL® CONSTA®-treated patients in the 24-month double-blind, placebo-controlled
treatment period of the trial assessing the efficacy and safety of RISPERDAL® CONSTA®
when administered as monotherapy for maintenance treatment in patients with Bipolar I
Disorder.
Table 2. Adverse Reactions in ≥ 2% of Patients with Bipolar I Disorder Treated with RISPERDAL®
CONSTA® as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial
Percentage of Patients Reporting Event
System/Organ Class
RISPERDAL® CONSTA®
Placebo
Adverse Reaction
(N=154)
(N=149)
Investigations
Weight increased
5
1
Nervous system disorders
Dizziness
3
1
Vascular disorders
Hypertension
3
1
Table 3 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the
52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and
safety of RISPERDAL® CONSTA® when administered as adjunctive maintenance treatment in
patients with bipolar disorder.
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Table 3. Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with RISPERDAL®
CONSTA® as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial
Percentage of Patients Reporting Event
a Patients received double-blind RISPERDAL® CONSTA® or placebo in addition to continuing their treatment
RISPERDAL®
CONSTA® +
Placebo +
Treatment
Treatment
System/Organ Class
as Usuala
as Usuala
Adverse Reaction
(N=72)
(N=67)
General disorders and administration site conditions
Gait abnormal
4
0
Infections and infestations
Upper respiratory tract infection
6
3
Investigations
Weight increased
7
1
Metabolism and nutrition disorders
Decreased appetite
6
1
Increased appetite
4
0
Musculoskeletal and connective tissue disorders
Arthralgia
4
3
Nervous system disorders
Tremor
24
16
Parkinsonismb
15
6
Dyskinesiab
6
3
Sedationc
7
1
Disturbance in attention
4
0
Reproductive system and breast disorders
Amenorrhea
4
1
Respiratory, thoracic and mediastinal disorders
Cough
4
1
as usual, which included mood stabilizers, antidepressants, and/or anxiolytics.
bParkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes
muscle twitching and dyskinesia.
c Sedation includes sedation and somnolence.
6.3 Other Adverse Reactions Observed During the Premarketing Evaluation of
Risperidone
The following additional adverse reactions occurred in <2% of the RISPERDAL® CONSTA®
treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in
<2% of the RISPERDAL® CONSTA®-treated patients in the above double-blind, placebo-
controlled period of the monotherapy bipolar disorder trial dataset, or in <4% of the
RISPERDAL® CONSTA®-treated patients in the above double-blind, placebo-controlled
period of the adjunctive treatment bipolar disorder trial dataset. The following also includes
additional adverse reactions reported at any frequency in RISPERDAL® CONSTA®-treated
patients who participated in the open-label phases of the above bipolar disorder studies and in
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other studies, including double-blind, active controlled and open-label studies in schizophrenia
and bipolar disorder.
Blood and lymphatic system disorders: anemia, neutropenia
Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus
bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block
right
Ear and labyrinth disorders: ear pain, vertigo
Endocrine disorders: hyperprolactinemia
Eye disorders: conjunctivitis, visual acuity reduced
Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain,
stomach discomfort, gastritis
General disorders and administration site conditions: injection site pain, chest discomfort,
chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration,
injection site swelling, injection site reaction, face edema
Immune system disorders: hypersensitivity
Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection,
rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection,
pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis,
subcutaneous abscess
Injury and poisoning: fall, procedural pain
Investigations:
blood
prolactin
increased,
alanine
aminotransferase
increased,
electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased,
hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT
prolonged, glucose urine present
Metabolism and nutritional disorders: anorexia, hyperglycemia
Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back
pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain
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Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling,
paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria
Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial
insomnia, libido decreased, nervousness
Renal and urinary disorders: urinary incontinence
Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile
dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort,
menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed
Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain,
dyspnea, rhinorrhea
Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, pruritus
Vascular disorders: hypotension, orthostatic hypotension
Additional Adverse Reactions Reported with Oral RISPERDAL®
The following is a list of additional adverse reactions that have been reported during the
premarketing evaluation of oral RISPERDAL®, regardless of frequency of occurrence:
Blood and Lymphatic Disorders: granulocytopenia
Cardiac Disorders: atrioventricular block
Ear and Labyrinth Disorders: tinnitus
Eye Disorders: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling,
eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma
Gastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal
discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism
General Disorders: thirst, feeling abnormal, gait disturbance, pitting edema, edema,
chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness
Immune System Disorders: drug hypersensitivity
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Infections and Infestations: tonsillitis, eye infection, cellulitis, otitis media,
onychomycosis,
acarodermatitis,
bronchopneumonia,
respiratory
tract
infection,
tracheobronchitis, otitis media chronic
Investigations: body temperature increased, heart rate increased, eosinophil count
increased, white blood cell count decreased, hemoglobin decreased, blood creatine
phosphokinase increased, hematocrit decreased, body temperature decreased, blood
pressure decreased, transaminases increased
Metabolism and Nutrition Disorders: polydipsia
Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, joint stiffness,
rhabdomyolysis, torticollis
Nervous System Disorders: hypertonia, balance disorder, dysarthria, unresponsive to
stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian
rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech
disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral
ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma
Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listless,
anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria
Reproductive System and Breast Disorders: vaginal discharge, retrograde ejaculation,
ejaculation disorder, ejaculation failure, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: epistaxis, wheezing, pneumonia
aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract
congestion, rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, skin
disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis,
rash generalised, rash maculopapular
Vascular Disorders: flushing
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6.4 Discontinuations Due to Adverse Reactions
Schizophrenia
Approximately 11% (22/202) of RISPERDAL® CONSTA®-treated patients in the 12-week
double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse
event, compared with 13% (13/98) who received placebo. The adverse reactions associated
with discontinuation in two or more RISPERDAL® CONSTA®-treated patients were: agitation
(3%), depression (2%), anxiety (1%), and akathisia (1%).
Bipolar Disorder
In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the
efficacy and safety of RISPERDAL® CONSTA®when administered as monotherapy for
maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 RISPERDAL®
CONSTA®-treated patients discontinued due to an adverse reaction (hyperglycemia).
In the 52-week double-blind phase of the placebo-controlled trial in which RISPERDAL®
CONSTA® was administered as adjunctive therapy to patients with bipolar disorder in addition
to continuing with their treatment as usual, approximately 4% (3/72) of RISPERDAL®
CONSTA®-treated patients discontinued treatment due to an adverse event, compared with
1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in
RISPERDAL® CONSTA®-treated patients were: hypokinesia (one patient) and tardive
dyskinesia (one patient).
6.5 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms:
Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-
blind, placebo-controlled trial comparing three doses of RISPERDAL® CONSTA® (25 mg, 50
mg, and 75 mg) with placebo in patients with schizophrenia, including: (1) the incidence of
spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the
total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the
Extrapyramidal Symptom Rating Scale (ESRS).
As shown in Table 1, the overall incidence of EPS-related adverse reactions (akathisia,
dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL® CONSTA®
was comparable to that of patients treated with placebo; the incidence of EPS related adverse
reactions was higher in patients treated with 50 mg RISPERDAL® CONSTA®.
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The median change from baseline to endpoint in total ESRS score showed no worsening in
patients treated with RISPERDAL® CONSTA® compared with patients treated with placebo: 0
(placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg
group).
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat,
swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these
symptoms can occur at low doses, they occur more frequently and with greater severity with
high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of
acute dystonia is observed in males and younger age groups.
6.6 Changes in Body Weight
In the 12-week double-blind, placebo-controlled trial in patients with schizophrenia, 9% of
patients treated with RISPERDAL® CONSTA®, compared with 6% of patients treated with
placebo, experienced a weight gain of >7% of body weight at endpoint.
In the 24-month double-blind, placebo-controlled treatment period of a trial assessing the
efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for
maintenance treatment in patients with bipolar I disorder, 11.6% of patients treated with
RISPERDAL® CONSTA® compared with 2.8% of patients treated with placebo experienced a
weight gain of >7% of body weight at endpoint.
In the 52-week double-blind, placebo-controlled trial in patients with bipolar disorder, 26.8%
of patients treated with RISPERDAL® CONSTA® as adjunctive treatment in addition to
continuing their treatment as usual, compared with 27.3% of patients treated with placebo in
addition to continuing their treatment as usual, experienced a weight gain of >7% of body
weight at endpoint.
6.7 Changes in ECG
The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg
RISPERDAL® CONSTA® and 98 schizophrenic patients treated with placebo in the 12-week
double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no
statistically significant differences in QTc intervals (using Fridericia’s and linear correction
factors) during treatment with RISPERDAL® CONSTA®.
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The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month
double-blind, placebo-controlled period. There were no clinically relevant differences in QTc
intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL®
CONSTA® compared to placebo.
The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week
double-blind, placebo-controlled trial. There were no statistically significant differences in QTc
intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL®
CONSTA® 25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition to
continuing treatment as usual compared to placebo.
6.8 Pain Assessment and Local Injection Site Reactions
The mean intensity of injection pain reported by patients with schizophrenia using a visual
analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from
the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8).
After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated
with 25 mg or 50 mg RISPERDAL® CONSTA® experienced redness, swelling, or induration at
the injection site.
In a separate study to observe local-site tolerability in which RISPERDAL® CONSTA® was
administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no patient
discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated
that only mild redness, swelling, or induration at the injection site was observed in subjects
treated with 37.5 mg or 50 mg RISPERDAL® CONSTA® at 2 hours after deltoid injection. All
ratings returned to baseline at the predose assessment of the next injection 2 weeks later. No
moderate or severe reactions were observed in any subject.
6.9 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone;
because these reactions are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction,
angioedema, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis in patients with impaired
glucose metabolism, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion,
intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea
syndrome, thrombocytopenia, urinary retention, and water intoxication. In addition, the
following adverse reactions have been observed during postapproval use of RISPERDAL®
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CONSTA®: cerebrovascular disorders, including cerebrovascular accidents, and diabetes
mellitus aggravated.
Retinal artery occlusion after injection of RISPERDAL® CONSTA® has been reported during
postmarketing surveillance. This has been reported in the presence of abnormal arteriovenous
anastomosis.
Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule,
and ulcer have been reported with RISPERDAL® CONSTA® during postmarketing
surveillance. Isolated cases required surgical intervention.
7 DRUG INTERACTIONS
The interactions of RISPERDAL® CONSTA® with coadministration of other drugs have not
been systematically evaluated. The drug interaction data provided in this section is based on
studies with oral RISPERDAL®.
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL®
CONSTA® is administered in combination with other centrally-acting drugs or alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® CONSTA® may enhance the
hypotensive effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
RISPERDAL® CONSTA® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9
hydroxyrisperidone combined following concomitant administration with oral RISPERDAL®.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%,
respectively. However, cimetidine did not affect the AUC of risperidone and 9
hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9
hydroxyrisperidone combined by 20%.
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7.6 Clozapine
Chronic administration of clozapine with risperidone may decrease the clearance of
risperidone.
7.7 Lithium
Repeated doses of oral RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or
peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated doses of oral RISPERDAL® (4 mg once daily) did not affect the pre-dose or average
plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses)
compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma
concentration (Cmax) after concomitant administration of oral RISPERDAL®.
7.9 Digoxin
Oral RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
7.10 Topiramate
Oral RISPERDAL® administered at doses from 1-6 mg/day concomitantly with topiramate 400
mg/day resulted in a 23% decrease in risperidone Cmax and a 33% decrease in risperidone
AUC0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9
hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This
interaction is unlikely to be of clinical significance. There was no clinically relevant effect of
oral RISPERDAL® on the pharmacokinetics of topiramate.
7.11 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is
polymorphic in the population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone
and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a
70 patients) does not suggest that poor and extensive
؆
modest number of poor metabolizers (n
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metabolizers have different rates of adverse effects. No comparison of effectiveness in the two
groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2,
2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have
been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold
respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.
Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either
concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re
evaluate the dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is
considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to
4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected
increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in
patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it is
recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates
lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of
RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients
already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The
efficacy of the 12.5 mg dose has not been investigated in clinical trials. [see also DOSAGE
AND ADMINISTRATION (2.5)]. The effects of discontinuation of concomitant fluoxetine or
paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not
been studied.
Erythromycin
There were no significant interactions between oral RISPERDAL® and erythromycin.
7.12 Carbamazepine and Other CYP 3A4 Enzyme Inducers
Carbamazepine co-administration with oral RISPERDAL® decreased the steady-state plasma
concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations
of carbamazepine did not appear to be affected. Co-administration of other known CYP 3A4
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause
similar decreases in the combined plasma concentrations of risperidone and 9
hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL® CONSTA®
treatment. At the initiation of therapy with carbamazepine or other known hepatic enzyme
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inducers, patients should be closely monitored during the first 4-8 weeks, since the dose of
RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oral
RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP
3A4 hepatic enzyme inducers, the dosage of RISPERDAL® CONSTA® should be re-evaluated
and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL®
CONSTA® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other
CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of
risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25
mg RISPERDAL® CONSTA® and discontinuing from carbamazepine or other CYP 3A4
enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical
judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates
interruption of RISPERDAL® CONSTA® treatment. The efficacy of the 12.5 mg dose has not
been investigated in clinical trials. [see also DOSAGE AND ADMINSTRATION (2.5)]
7.13 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,
RISPERDAL® CONSTA® is not expected to substantially inhibit the clearance of drugs that
are metabolized by this enzymatic pathway. In drug interaction studies, oral RISPERDAL® did
not significantly affect the pharmacokinetics of donepezil and galantamine, which are
metabolized by CYP 2D6.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of oral risperidone was studied in three embryofetal development
studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the oral maximum
recommended human dose [MRHD] on a mg/m2 basis) and in one embryofetal development
study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the oral MRHD on a mg/m2
basis). The incidence of malformations was not increased compared to control in offspring of
rats or rabbits given 0.4 to 6 times the oral MRHD on a mg/m2 basis. In three reproductive
studies in rats (two peri/post-natal development studies and a multigenerational study), there
was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or
0.1 to 3 times the oral MRHD on a mg/m2 basis. It is not known whether these deaths were due
to a direct effect on the fetuses or pups or to effects on the dams.
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There was no no-effect dose for increased rat pup mortality. In one peri/post-natal development
study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the oral
MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or
pups, as evidenced by a decrease in the number of live pups and an increase in the number of
dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were
observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated
dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to
impair maternal behavior in that pup body weight gain and survival (from Days 1 to 4 of
lactation) were reduced in pups born to control but reared by drug-treated dams. These effects
were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the oral MRHD on
a mg/m2 basis.
No studies were conducted with RISPERDAL® CONSTA®.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis of the corpus
callosum in an infant exposed to risperidone in utero. The causal relationship to oral
RISPERDAL® therapy is unknown.
Non-Teratogenic Effects
Neonates exposed to antipsychotic drugs (including RISPERDAL®) during the third trimester
of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.
There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory
distress, and feeding disorder in these neonates. These complications have varied in severity;
while in some cases symptoms have been self-limited, in other cases neonates have required
intensive care unit support and prolonged hospitalization.
RISPERDAL® CONSTA® should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
8.2 Labor and Delivery
The effect of RISPERDAL® CONSTA® on labor and delivery in humans is unknown.
8.3 Nursing Mothers
Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore,
women should not breast-feed during treatment with RISPERDAL® CONSTA® and for at least
12 weeks after the last injection.
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8.4 Pediatric Use
RISPERDAL® CONSTA® has not been studied in children younger than 18 years old.
8.5 Geriatric Use
In an open-label study, 57 clinically stable, elderly patients (≥65 years old) with schizophrenia
or schizoaffective disorder received RISPERDAL® CONSTA® every 2 weeks for up to 12
months. In general, no differences in the tolerability of RISPERDAL® CONSTA® were
observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing
recommendations for otherwise healthy elderly patients are the same as for nonelderly patients.
Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly
patients, elderly patients should be instructed in nonpharmacologic interventions that help to
reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several
minutes before attempting to stand in the morning and slowly rising from a seated position). In
addition, monitoring of orthostatic vital signs should be considered in elderly patients for
whom orthostatic hypotension is of concern [see Warnings and Precautions (5.7)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related
Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a
higher incidence of mortality was observed in patients treated with furosemide plus oral
risperidone when compared to patients treated with oral risperidone alone or with oral placebo
plus furosemide. No pathological mechanism has been identified to explain this finding, and no
consistent pattern for cause of death was observed. An increase of mortality in elderly patients
with dementia-related psychosis was seen with the use of oral risperidone regardless of
concomitant use with furosemide. RISPERDAL® CONSTA® is not approved for the treatment
of patients with dementia-related psychosis. [see Boxed Warning and Warnings and
Precautions (5.1)]
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
RISPERDAL® CONSTA® (risperidone) is not a controlled substance.
9.2 Abuse
RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its
potential for abuse. Because RISPERDAL® CONSTA® is to be administered by health care
professionals, the potential for misuse or abuse by patients is low.
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9.3 Dependence
RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its
potential for tolerance or physical dependence.
10 OVERDOSAGE
10.1 Human Experience
No cases of overdose were reported in premarketing studies with RISPERDAL® CONSTA®.
Because RISPERDAL® CONSTA® is to be administered by health care professionals, the
potential for overdosage by patients is low.
In premarketing experience with oral RISPERDAL®, there were eight reports of acute
RISPERDAL® overdosage, with estimated doses ranging from 20 to 300 mg and no fatalities.
In general, reported signs and symptoms were those resulting from an exaggeration of the
drug’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and
hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240
mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS.
Another case, involving an estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience with oral RISPERDAL® includes reports of acute overdose, with
estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms
are those resulting from an exaggeration of the drug’s known pharmacological effects, i.e.,
drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse
reactions reported since market introduction related to oral RISPERDAL® overdose include
prolonged QT interval and convulsions. Torsade de pointes has been reported in association
with combined overdose of oral RISPERDAL® and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation
and ventilation. Cardiovascular monitoring should commence immediately and should include
continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic
therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard
of QT prolonging effects that might be additive to those of risperidone. Similarly, it is
reasonable to expect that the alpha-blocking properties of bretylium might be additive to those
of risperidone, resulting in problematic hypotension.
There is no specific antidote to risperidone. Therefore, appropriate supportive measures should
be instituted. The possibility of multiple drug involvement should be considered. Hypotension
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and circulatory collapse should be treated with appropriate measures, such as intravenous fluids
and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta
stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In
cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Close medical supervision and monitoring should continue until the patient recovers.
11 DESCRIPTION
Risperidone is a psychotropic agent belonging to the chemical class of benzisoxazole
derivatives.
The
chemical
designation
is
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1
piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular
formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is: structural formula
Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble
in methanol and 0.1 N HCl.
RISPERDAL® CONSTA® (risperidone) Long-Acting Injection is a combination of extended-
release microspheres for injection and diluent for parenteral use.
The extended-release microspheres formulation is a white to off-white, free-flowing powder
that is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg risperidone per vial.
Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide (PLG) at a concentration
of 381 mg risperidone per gram of microspheres.
The diluent for parenteral use is a clear, colorless solution. Composition of the diluent includes
polysorbate 20, sodium carboxymethyl cellulose, disodium hydrogen phosphate dihydrate,
citric acid anhydrous, sodium chloride, sodium hydroxide, and water for injection. The
microspheres are suspended in the diluent prior to injection.
RISPERDAL® CONSTA® is provided as a dose pack, consisting of a vial containing the
microspheres, a pre-filled syringe containing the diluent, a SmartSite® Needle-Free Vial Access
Device, and two Needle-Pro® safety needles (a 21 G UTW 1-inch needle with needle protection
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device for deltoid administration and a 20 G TW 2-inch needle with needle protection device
for gluteal administration).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of RISPERDAL® CONSTA®, as with other drugs used to treat
schizophrenia, is unknown. However, it has been proposed that the drug’s therapeutic activity
in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin
Type 2 (5HT2) receptor antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3
nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1
histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower
potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin
5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1
and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M)
for cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from RISPERDAL® CONSTA® results from the combined concentrations of
risperidone and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology
(12.3)]. Antagonism at receptors other than D2 and 5HT2[see Clinical Pharmacology (12.1)]
may explain some of the other effects of RISPERDAL® CONSTA®.
12.3 Pharmacokinetics
Absorption
After a single intramuscular (gluteal) injection of RISPERDAL® CONSTA®, there is a small
initial release of the drug (< 1% of the dose), followed by a lag time of 3 weeks. The main
release of the drug starts from 3 weeks onward, is maintained from 4 to 6 weeks, and subsides
by 7 weeks following the intramuscular (IM) injection. Therefore, oral antipsychotic
supplementation should be given during the first 3 weeks of treatment with RISPERDAL®
CONSTA® to maintain therapeutic levels until the main release of risperidone from the
injection site has begun [see Dosage and Administration (2)]. Following single doses of
RISPERDAL® CONSTA®, the pharmacokinetics of risperidone, 9-hydroxyrisperidone (the
major metabolite), and risperidone plus 9-hydroxyrisperidone were linear in the dosing range of
12.5 mg to 50 mg.
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The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of
RISPERDAL® CONSTA® results in sustained therapeutic concentrations. Steady-state plasma
concentrations are reached after 4 injections and are maintained for 4 to 6 weeks after the last
injection. Following multiple doses of 25 mg and 50 mg RISPERDAL® CONSTA®, plasma
concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone
were linear.
Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore,
interchangeable.
Distribution
Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In
plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding
of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is
77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding
sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL),
and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of
risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of unknown
clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through
hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has
similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug
results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of
many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to
genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have
little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and
some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more
slowly. Although extensive metabolizers have lower risperidone and higher 9
hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone
and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive
and poor metabolizers.
44
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The interactions of RISPERDAL® CONSTA® with coadministration of other drugs have not
been systematically evaluated in human subjects. Drug interactions are based primarily on
experience with oral RISPERDAL®. Risperidone could be subject to two kinds of drug-drug
interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9
hydroxyrisperidone [see Drug Interactions (7.11)]. This occurs with quinidine, giving
essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers.
The therapeutic benefits and adverse effects of RISPERDAL® in patients receiving quinidine
70) of poor metabolizers
؆
have not been evaluated, but observations in a modest number (n
given oral RISPERDAL® do not suggest important differences between poor and extensive
metabolizers. Second, co-administration of carbamazepine and other known enzyme inducers
(e.g., phenytoin, rifampin, and phenobarbital) with oral RISPERDAL® cause a decrease in the
combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug
Interactions (7.12)]. It would also be possible for risperidone to interfere with metabolism of
other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme
suggests this is unlikely [see Drug Interactions (7.11)].
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone
administered as solution to three healthy male volunteers, total recovery of radioactivity at 1
week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone plus 9-hydroxyrisperidone following RISPERDAL®
CONSTA®administration is 3 to 6 days, and is associated with a monoexponential decline in
plasma concentrations. This half-life of 3-6 days is related to the erosion of the microspheres
and subsequent absorption of risperidone. The clearance of risperidone and risperidone plus 9
hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP 2D6 metabolizers, and 3.3 L/h
and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. No accumulation of risperidone was
observed during long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg
or 50 mg RISPERDAL® CONSTA®. The elimination phase is complete approximately 7 to 8
weeks after the last injection.
45
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Renal Impairment
In patients with moderate to severe renal disease treated with oral RISPERDAL®, clearance of
the sum of risperidone and its active metabolite decreased by 60% compared with young
healthy subjects. Although patients with renal impairment were not studied with RISPERDAL®
CONSTA®, it is recommended that patients with renal impairment be carefully titrated on oral
RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of 25 mg.
A lower initial dose of 12. 5 mg may be appropriate when clinical factors warrant dose
adjustment, such as in patients with renal impairment [see Dosage and Administration (2.4)].
Hepatic Impairment
While the pharmacokinetics of oral RISPERDAL® in subjects with liver disease were
comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma
was increased by about 35% because of the diminished concentration of both albumin and α1
acid glycoprotein. Although patients with hepatic impairment were not studied with
RISPERDAL® CONSTA®, it is recommended that patients with hepatic impairment be
carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is
initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical
factors warrant dose adjustment, such as in patients with hepatic impairment [see Dosage and
Administration (2.4)].
Elderly
In an open-label trial, steady-state concentrations of risperidone plus 9-hydroxyrisperidone in
otherwise healthy elderly patients (≥65 years old) treated with RISPERDAL® CONSTA® for
up to 12 months fell within the range of values observed in otherwise healthy nonelderly
patients. Dosing recommendations are the same for otherwise healthy elderly patients and
nonelderly patients [see Dosage and Administration (2)].
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a
population pharmacokinetic analysis did not identify important differences in the disposition of
risperidone due to gender (whether or not corrected for body weight) or race.
46
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis - Oral
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25
months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the oral maximum
recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis, or 0.2,
0.75, and 3 times the oral MRHD (mice) or 0.4, 1.5, and 6 times the oral MRHD (rats) on a
mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There was a
significant increase in pituitary gland adenomas in female mice at doses 0.75 and 3 times the
oral MRHD on a mg/m2 basis. There was a significant increase in endocrine pancreatic
adenomas in male rats at doses 1.5 and 6 times the oral MRHD on a mg/m2 basis. Mammary
gland adenocarcinomas were significantly increased in female mice at all doses tested (0.2,
0.75, and 3 times the oral MRHD on a mg/m2 basis), in female rats at all doses tested (0.4, 1.5,
and 6 times the oral MRHD on a mg/m2 basis), and in male rats at a dose 6 times the oral
MRHD on a mg/m2 basis.
Carcinogenesis - Intramuscular
RISPERDAL® CONSTA® was evaluated in a 24-month carcinogenicity study in which SPF
Wistar rats were treated every 2 weeks with intramuscular (IM) injections of either 5 mg/kg or
40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/m2 basis.
A control group received injections of 0.9% NaCl, and a vehicle control group was injected
with placebo microspheres. There was a significant increase in pituitary gland adenomas,
endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM
MRHD on a mg/m2 basis. The incidence of mammary gland adenocarcinomas was significantly
increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m2 basis). A
significant increase in renal tubular tumors (adenoma, adenocarcinomas) was observed in male
rats at 8 times the IM MRHD on a mg/m2 basis. Plasma exposures (AUC) in rats were 0.3 and
2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure (AUC) at the IM
MRHD.
Dopamine D2 receptor antagonists have been shown to chronically elevate prolactin levels in
rodents. Serum prolactin levels were not measured during the carcinogenicity studies of oral
risperidone; however, measurements taken during subchronic toxicity studies showed that oral
risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used
in the oral carcinogenicity studies. Serum prolactin levels increased in a dose-dependent
47
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
manner up to 6- and 1.5-fold in male and female rats, respectively, at the end of the 24-month
treatment with RISPERDAL® CONSTA® every 2 weeks. Increases in the incidence of pituitary
gland, endocrine pancreas, and mammary gland neoplasms have been found in rodents after
chronic administration of other antipsychotic drugs and may be prolactin-mediated.
The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents
is unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for oral risperidone was found in the in vitro Ames reverse
mutation test, in vitro mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in
vivo oral micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the in
vitro chromosomal aberration test in human lymphocytes or in Chinese hamster cells.
In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse
mutation test for RISPERDAL® CONSTA®.
Impairment of Fertility
Oral risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats
in three reproductive studies (two mating and fertility studies and a multigenerational study) at
doses 0.1 to 3 times the oral maximum recommended human dose (MRHD) (16 mg/day) on a
mg/m2 basis. The effect appeared to be in females, since impaired mating behavior was not
noted in the mating and fertility study in which males only were treated. In a subchronic study
in Beagle dogs in which oral risperidone was administered at doses of 0.31 to 5 mg/kg, sperm
motility and concentration were decreased at doses 0.6 to 10 times the oral MRHD on a mg/m2
basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum
testosterone and sperm values partially recovered, but remained decreased after treatment was
discontinued. No no-effect doses were noted in either rat or dog.
No mating and fertility studies were conducted with RISPERDAL® CONSTA®.
14 CLINICAL STUDIES
14.1 Schizophrenia
The effectiveness of RISPERDAL® CONSTA® in the treatment of schizophrenia was
established, in part, on the basis of extrapolation from the established effectiveness of the oral
formulation of risperidone. In addition, the effectiveness of RISPERDAL® CONSTA® in the
48
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
treatment of schizophrenia was established in a 12-week, placebo-controlled trial in adult
psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia.
Efficacy data were obtained from 400 patients with schizophrenia who were randomized to
receive injections of 25 mg, 50 mg, or 75 mg RISPERDAL® CONSTA® or placebo every 2
weeks. During a 1-week run-in period, patients were discontinued from other antipsychotics
and were titrated to a dose of 4 mg oral RISPERDAL®. Patients who received RISPERDAL®
CONSTA® were given doses of oral RISPERDAL® (2 mg for patients in the 25-mg group, 4
mg for patients in the 50-mg group, and 6 mg for patients in the 75-mg group) for the 3 weeks
after the first injection to provide therapeutic plasma concentrations until the main release
phase of risperidone from the injection site had begun. Patients who received placebo injections
were given placebo tablets.
Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated,
multi-item inventory, composed of five subscales to evaluate positive symptoms, negative
symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.
The primary efficacy variable in this trial was change from baseline to endpoint in the total
PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this study
was 81.5.
Total PANSS scores showed significant improvement in the change from baseline to endpoint
in schizophrenic patients treated with each dose of RISPERDAL® CONSTA® (25 mg, 50 mg,
or 75 mg) compared with patients treated with placebo. While there were no statistically
significant differences between the treatment effects for the three dose groups, the effect size
for the 75 mg dose group was actually numerically less than that observed for the 50 mg dose
group.
Subgroup analyses did not indicate any differences in treatment outcome as a function of age,
race, or gender.
14.2 Bipolar Disorder - Monotherapy
The effectiveness of RISPERDAL® CONSTA® for the maintenance treatment of Bipolar I
Disorder was established in a multicenter, double-blind, placebo-controlled study of adult
patients who met DSM-IV criteria for Bipolar Disorder Type I, who were stable on medications
or experiencing an acute manic or mixed episode.
A total of 501 patients were treated during a 26-week open-label period with RISPERDAL®
CONSTA® (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or
49
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
50 mg; in patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg). In the
open-label phase, 303 (60%) patients were judged to be stable and were randomized to double-
blind treatment with either the same dose of RISPERDAL® CONSTA® or placebo and
monitored for relapse. The primary endpoint was time to relapse to any mood episode
(depression, mania, hypomania, or mixed).
Time to relapse was delayed in patients receiving RISPERDAL® CONSTA® monotherapy as
compared to placebo. The majority of relapses were due to manic rather than depressive
symptoms. Based on their bipolar disorder history, subjects entering this study had had, on
average, more manic episodes than depressive episodes.
14.3 Bipolar Disorder - Adjunctive Therapy
The effectiveness of RISPERDAL® CONSTA® as an adjunct to treatment with lithium or
valproate for the maintenance treatment of Bipolar Disorder was established in a multi-center,
randomized, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria
for Bipolar Disorder Type I and who experienced at least 4 episodes of mood disorder requiring
psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6
months prior to the start of the study.
A total of 240 patients were treated during a 16-week open-label period with RISPERDAL®
CONSTA® (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or
50 mg), as adjunctive therapy in addition to continuing their treatment as usual for their bipolar
disorder, which consisted of mood stabilizers (primarily lithium and valproate),
antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first
three weeks of the initial RISPERDAL® CONSTA® injection. In the open-label phase, 124
(51.7%) were judged to be stable for at least the last 4 weeks and were randomized to double-
blind treatment with either the same dose of RISPERDAL® CONSTA® or placebo in addition
to continuing their treatment as usual and monitored for relapse during a 52-week period. The
primary endpoint was time to relapse to any new mood episode (depression, mania, hypomania,
or mixed).
Time to relapse was delayed in patients receiving adjunctive therapy with RISPERDAL®
CONSTA® as compared to placebo. The relapse types were about half depressive and half
manic or mixed episodes.
16 HOW SUPPLIED/STORAGE AND HANDLING
RISPERDAL® CONSTA® (risperidone) is available in dosage strengths of 12.5 mg, 25 mg,
37.5 mg, or 50 mg risperidone. It is provided as a dose pack, consisting of a vial containing the
50
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for RISPERDAL®
CONSTA®, a SmartSite® Needle-Free Vial Access Device, and two Needle-Pro® safety needles
for intramuscular injection (a 21 G UTW 1-inch needle with needle protection device for
deltoid administration and a 20 G TW 2-inch needle with needle protection device for gluteal
administration).
12.5-mg vial/kit (NDC 50458-309-11): 41 mg (equivalent to 12.5 mg of risperidone) of a white
to off-white powder provided in a vial with a violet flip-off cap (NDC 50458-309-01).
25-mg vial/kit (NDC 50458-306-11): 78 mg (equivalent to 25 mg of risperidone) of a white to
off-white powder provided in a vial with a pink flip-off cap (NDC 50458-306-01).
37.5-mg vial/kit (NDC 50458-307-11): 116 mg (equivalent to 37.5 mg of risperidone) of a
white to off-white powder provided in a vial with a green flip-off cap (NDC 50458-307-01).
50-mg vial/kit (NDC 50458-308-11): 152 mg (equivalent to 50 mg of risperidone) of a white to
off-white powder provided in a vial with a blue flip-off cap (NDC 50458-308-01).
Storage and Handling
The entire dose pack should be stored in the refrigerator (36°- 46°F; 2°- 8°C) and protected
from light.
If refrigeration is unavailable, RISPERDAL® CONSTA® can be stored at temperatures not
exceeding 77°F (25°C) for no more than 7 days prior to administration. Do not expose
unrefrigerated product to temperatures above 77°F (25°C).
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL® CONSTA®.
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension and instructed in
nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension
(e.g., sitting on the edge of the bed for several minutes before attempting to stand in the
morning and slowly rising from a seated position) [see Warnings and Precautions (5.7)].
51
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
17.2 Interference with Cognitive and Motor Performance
Because RISPERDAL® CONSTA® has the potential to impair judgment, thinking, or motor
skills, patients should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that treatment with RISPERDAL® CONSTA®
does not affect them adversely [see Warnings and Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy and for at least 12 weeks after the last injection of
RISPERDAL® CONSTA®[see Use in Specific Populations (8.1)].
17.4 Nursing
Patients should be advised not to breast-feed an infant during treatment and for at least 12
weeks after the last injection of RISPERDAL® CONSTA®[see Use in Specific Populations
(8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for interactions [see Drug
Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol during treatment with RISPERDAL®
CONSTA®[see Drug Interactions (7.1)].
Revised December 2010
©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007
Risperidone is manufactured by:
Janssen Pharmaceutical Ltd.
Wallingstown, Little Island, County Cork, Ireland
Microspheres are manufactured by:
Alkermes, Inc.
Wilmington, Ohio
52
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Diluent is manufactured by:
Vetter Pharma Fertigung GmbH & Co. KG
Ravensburg or Langenargen, Germany
or
Cilag AG
Schaffhausen, Switzerland
or
Ortho Biotech Products, L.P.
Raritan, NJ
RISPERDAL® CONSTA® is manufactured for:
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
53
Reference ID: 2870867
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:23.212135
|
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|
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___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
• Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy (4.4)
These highlights do not include all the information needed to use Genotropin
• Children with closed epiphyses (4.5)
safely and effectively. See full prescribing information for Genotropin.
• Known hypersensitivity to somatropin or m-cresol (4.6)
GENOTROPIN (somatropin [rDNA origin] for injection)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Initial U.S. Approval: 1987
Acute Critical Illness: Potential benefit of treatment continuation should be
weighed against the potential risk (5.1).
----------------------------RECENT MAJOR CHANGES--------------------------
• Prader-Willi syndrome in Children: Evaluate for signs of upper airway
Warnings and Precautions, Neoplasms (5.3)
9/2014
obstruction and sleep apnea before initiation of treatment.
Discontinue treatment if these signs occur (5.2).
----------------------------INDICATIONS AND USAGE--------------------------
• Neoplasm: Monitor patients with preexisting tumors for progression or
GENOTROPIN is a recombinant human growth hormone indicated for:
recurrence. Increased risk of a second neoplasm in childhood cancer
• Pediatric: Treatment of children with growth failure due to growth hormone
survivors treated with somatropin in particular meningiomas in patients
deficiency (GHD), Prader-Willi syndrome, Small for Gestational Age, Turner
treated with radiation to the head for their first neoplasm (5.3).
syndrome, and Idiopathic Short Stature (1.1)
• Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked.
• Adult: Treatment of adults with either adult onset or childhood onset GHD (1.2)
Periodically monitor glucose levels in all patients. Doses of concurrent
antihyperglycemic drugs in diabetics may require adjustment (5.4).
----------------------DOSAGE AND ADMINISTRATION----------------------
• Intracranial Hypertension: Exclude preexisting papilledema. May develop
GENOTROPIN should be administered subcutaneously (2)
and is usually reversible after discontinuation or dose reduction (5.5).
• Pediatric GHD: 0.16 to 0.24 mg/kg/week (2.1)
• Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome – especially
• Prader-Willi Syndrome: 0.24 mg/kg/week (2.1)
in adults): May occur frequently. Reduce dose as necessary (5.6).
• Small for Gestational Age: Up to 0.48 mg/kg/week (2.1)
• Hypopituitarism: Closely monitor other hormone replacement therapies
• Turner Syndrome: 0.33 mg/kg/week (2.1)
(5.7)
• Idiopathic Short Stature: up to 0.47 mg/kg/week (2.1)
• Hypothyroidism: May first become evident or worsen (5.8).
• Adult GHD: Either a non-weight based or a weight based dosing regimen may be
• Slipped Capital Femoral Epiphysis: May develop. Evaluate children with
followed, with doses adjusted based on treatment response and IGF-I
the onset of a limp or hip/knee pain (5.9).
concentrations (2.2)
• Progression of Preexisting Scoliosis: May develop (5.10)
• Non-weight based dosing: A starting dose of approximately 0.2mg/day (range,
• Pancreatitis: Consider pancreatitis in patients with persistent severe
0.15-0.30 mg/day) may be used without consideration of body weight, and
abdominal pain (5.14).
increased gradually every 1-2 months by increments of approximately 0.1-0.2
mg/day. (2.2)
------------------------------ADVERSE REACTIONS------------------------------
• Weight based dosing: The recommended initial dose is not more than 0.04
Other common somatropin-related adverse reactions include injection site
mg/kg/week; the dose may be increased as tolerated to not more than 0.08
reactions/rashes and lipoatrophy (6.1) and headaches (6.3).
mg/kg/week at 4–8 week intervals. (2.2)
• GENOTROPIN cartridges are color-coded to correspond to a specific
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
GENOTROPIN PEN delivery device (2.3)
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
• Injection sites should always be rotated to avoid lipoatrophy (2.3)
------------------------------DRUG INTERACTIONS------------------------------
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1: May require the
GENOTROPIN lyophilized powder in a two-chamber color-coded cartridge (3):
initiation of glucocorticoid replacement therapy. Patients treated with
• 5 mg (green tip) and 12 mg (purple tip) (with preservative)
glucocorticoid replacement for previously diagnosed hypoadrenalism may
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-
require an increase in their maintenance doses (7.1, 7.2).
chamber cartridge (without preservative):
• Glucocorticoid Replacement: Should be carefully adjusted (7.2)
• 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0
• Cytochrome P450-Metabolized Drugs: Monitor carefully if used with
mg
somatropin (7.3)
• Oral Estrogen: Larger doses of somatropin may be required in women (7.4)
-------------------------------CONTRAINDICATIONS-----------------------------
• Insulin and/or Oral/Injectable Hypoglycemic Agents: May require
• Acute Critical Illness (4.1, 5.1)
adjustment (7.5)
• Children with Prader-Willi syndrome who are severely obese or have severe
respiratory impairment – reports of sudden death (4.2, 5.2)
See 17 for PATIENT COUNSELING INFORMATION
• Active Malignancy (4.3)
Revised: 9/2014
5.9 Slipped Capital Femoral Epiphysis in Pediatric Patients
FULL PRESCRIBING INFORMATION: CONTENTS*
5.10 Progression of Preexisting Scoliosis in Pediatric Patients
5.11 Otitis Media and Cardiovascular Disorders in Turner Syndrome
1
INDICATIONS AND USAGE
5.12 Local and Systemic Reactions
1.1 Pediatric Patients
5.13 Laboratory Tests
1.2 Adult Patients
5.14 Pancreatitis
2
DOSAGE AND ADMINISTRATION
2.1 Dosing of Pediatric Patients
6
ADVERSE REACTIONS
2.2 Dosing of Adult Patients
6.1 Most Serious and/or Most Frequently Observed Adverse Reactions
2.3 Preparation and Administration
6.2 Clinical Trials Experience
3
DOSAGE FORMS AND STRENGTHS
6.3 Post-Marketing Experience
4
CONTRAINDICATIONS
7
DRUG INTERACTIONS
4.1 Acute Critical Illness
7.1 11 β-Hydroxysteroid Dehydrogenase Type 1
4.2 Prader-Willi Syndrome in Children
7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic
4.3 Active Malignancy
Glucocortioid Treatment
4.4 Diabetic Retinopathy
7.3 Cytochrome P450- Metabolized Drugs
4.5 Closed Epiphyses
7.4 Oral Estrogen
4.6 Hypersensitivity
7.5 Insulin and/or Oral/Injectable Hypoglycemic Agents
5
WARNINGS AND PRECAUTIONS
8
USE IN SPECIFIC POPULATIONS
5.1 Acute Critical Illness
8.1 Pregnancy
5.2 Prader-Willi Syndrome in Children
8.3 Nursing Mothers
5.3 Neoplasms
8.5 Geriatric Use
5.4 Impaired Glucose Tolerance and Diabetes Mellitus
10 OVERDOSAGE
5.5 Intracranial Hypertension
11 DESCRIPTION
5.6 Fluid Retention
12 CLINICAL PHARMACOLOGY
5.7 Hypopituitarism
12.1 Mechanism of Action
5.8 Hypothyroidism
12.2 Pharmacodynamics
1
Reference ID: 3634596
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12.3 Pharmacokinetics
14.3 SGA
13 NONCLINICAL TOXICOLOGY
14.4 Turner Syndrome
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14.5 Idiopathic Short Stature
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
14.1 Adult Growth Hormone Deficiency
17 PATIENT COUNSELING INFORMATION
14.2 Prader-Willi Syndrome
*Sections or subsections omitted from the full prescribing information are not listed.
Reference ID: 3634596
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
1
INDICATIONS AND USAGE
1.1
Pediatric Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of
endogenous growth hormone.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome
(PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing (see CONTRAINDICATIONS).
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to
manifest catch-up growth by age 2 years.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure associated with Turner syndrome.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short
stature, defined by height standard deviation score (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.
1.2
Adult Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who
meet either of the following two criteria:
Adult Onset (AO): Patients who have growth hormone 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 growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of
somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. According to current standards, confirmation of the diagnosis of adult
growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary
hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.
2
DOSAGE AND ADMINISTRATION
The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN must not be injected intravenously.
Therapy with GENOTROPIN should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure
associated with growth hormone deficiency (GHD), Prader-Willi syndrome (PWS), Turner syndrome (TS), those who were born small for gestational age (SGA) or
Idiopathic Short Stature (ISS), and adult patients with either childhood onset or adult onset GHD.
2.1
Dosing of Pediatric Patients
General Pediatric Dosing Information
The GENOTROPIN dosage and administration schedule should be individualized based on the growth response of each patient.
Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during
the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism,
undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH).
Treatment with GENOTROPIN for short stature should be discontinued when the epiphyses are fused.
Pediatric Growth Hormone Deficiency (GHD)
Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.
Prader-Willi Syndrome
Generally, a dose of 0.24 mg/kg body weight/week is recommended.
Turner Syndrome
Generally, a dose of 0.33 mg/kg body weight/week is recommended.
Idiopathic Short Stature
Generally, a dose up to 0.47 mg/kg body weight/week is recommended.
Small for Gestational Agea
Generally, a dose of up to 0.48 mg/kg body weight/week is recommended.
a Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.48 mg/kg/week), 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 0.24 mg/kg/week) 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., 0.24 mg/kg/week),
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.
Reference ID: 3634596
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2
Dosing of Adult Patients
Adult Growth Hormone Deficiency (GHD)
Either of two approaches to GENOTROPIN dosing may be followed: a non-weight based regimen or a weight based regimen.
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 GHD registration trials, the recommended dosage at the start of treatment is not more than 0.04
mg/kg/week. The dose may be increased according to individual patient requirements to not more than 0.08 mg/kg/week at 4–8 week intervals. 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. In order to reach the defined treatment
goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
2.3
Preparation and Administration
The GENOTROPIN 5 and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN Pen delivery device. The 5 mg cartridge has a green tip
to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.
Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
GENOTROPIN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless.
GENOTROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.
3
DOSAGE FORMS AND STRENGTHS
GENOTROPIN lyophilized powder:
•
5 mg two-chamber cartridge (green tip, with preservative)
concentration of 5 mg/mL
•
12 mg two-chamber cartridge (purple tip, with preservative)
concentration of 12 mg/mL
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)
•
0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg
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-growth hormone 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 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 [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 growth hormone 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
GENOTROPIN is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. The 5 mg and 12 mg presentations of
GENOTROPIN lyophilized powder contain m-cresol as a preservative. These products should not be used by patients with a known sensitivity to this preservative. The
GENOTROPIN MINIQUICK presentations are preservative-free (see HOW SUPPLIED). 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 amounts 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 having acute critical illnesses should be weighed against the potential risk.
Reference ID: 3634596
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 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)].
5.3
Neoplasms
5.3
Neoplasms
In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with
somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, 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 [see Contraindications (4.3)].
Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor.
Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks
and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of
neoplasms.
Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi.
5.4
Impaired Glucose Tolerance and Diabetes Mellitus
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. New-onset Type 2 diabetes mellitus has been reported. 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 (i.e., insulin or oral/injectable 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 and Prader-Willi syndrome may be at increased risk for the development of IH.
5.6
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may 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 growth hormone deficiency, central
(secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid
function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
5.9
Slipped Capital Femoral Epiphyses in Pediatric Patients
Slipped capital femoral epiphyses may occur more frequently in patients with endocrine disorders (including GHD 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 Turner syndrome patients. 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 Turner Syndrome
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since 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., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.
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. (2.3) ].
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 (PTH) and IGF-I may increase during somatropin therapy.
5
Reference ID: 3634596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.14
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 persistent severe abdominal pain.
6
ADVERSE REACTIONS
6.1
Most Serious and/or Most Frequently Observed Adverse Reactions
This list presents the most seriousb and/or most frequently observeda adverse reactions during treatment with somatropin:
• b Sudden death in pediatric patients with Prader-Willi syndrome with 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)]
• b Intracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a
first neoplasm and somatropin [see Contraindications (4.3) and Warnings and Precautions (5.3)]
• a , b Glucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see
Warnings and Precautions (5.4)]
• b Intracranial hypertension [see Warnings and Precautions (5.5)]
• b Significant diabetic retinopathy [see Contraindications (4.4)]
• b Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.8)]
• b Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.9)]
• aFluid 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 (5.7)]
• aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings and Precautions (5.11)]
• b Pancreatitis [see Warnings and Precautions (5.14)]
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.
Clinical Trials in children with GHD
In clinical studies with GENOTROPIN in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning
associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild
hyperglycemia.
Clinical Trials in PWS
In two clinical studies with GENOTROPIN in pediatric patients with Prader-Willi syndrome, the following drug-related events were reported: edema, aggressiveness,
arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia.
Clinical Trials in children with SGA
In clinical studies of 273 pediatric patients born small for gestational age treated with GENOTROPIN, the following clinically significant events were reported: mild
transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several
patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Anti-hGH antibodies were not detected in any
of the patients treated with GENOTROPIN.
Clinical Trials in children with Turner Syndrome
In two clinical studies with GENOTROPIN in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses
(influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint
pain.
Clinical Trials in children with Idiopathic Short Stature
In two open-label clinical studies with GENOTROPIN in pediatric patients with ISS, the most commonly encountered adverse events include upper respiratory tract
infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies,
during Genotropin treatment, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as
follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0. 23 and the 0.47 mg/kg/week groups, respectively, had at least one
measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD.
Clinical Trials in adults with GHD
In clinical trials with GENOTROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including
peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during
therapy, and tended to be transient and/or responsive to dosage reduction.
Table 1 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN. Also
presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials.
Reference ID: 3634596
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of
GENOTROPIN and Placebo, Grouped by Duration of Treatment
Double Blind Phase
Open Label Phase
GENOTROPIN
Adverse Event
Placebo
0–6 mo.
n = 572
% Patients
GENOTROPIN
0–6 mo.
n = 573
% Patients
6–12 mo.
n = 504
% Patients
12–18 mo.
n = 63
% Patients
18–24 mo.
n = 60
% Patients
Swelling, peripheral
Arthralgia
Upper respiratory infection
5.1
4.2
14.5
17.5*
17.3*
15.5
5.6
6.9
13.1
0
6.3
15.9
1.7
3.3
13.3
Pain, extremities
5.9
14.7*
6.7
1.6
3.3
Edema, peripheral
Paresthesia
2.6
1.9
10.8*
9.6*
3.0
2.2
0
3.2
0
0
Headache
7.7
9.9
6.2
0
0
Stiffness of extremities
1.6
7.9*
2.4
1.6
0
Fatigue
Myalgia
Back pain
3.8
1.6
4.4
5.8
4.9*
2.8
4.6
2.0
3.4
6.3
4.8
4.8
1.7
6.7
5.0
*
Increased significantly when compared to placebo, P≤.025: Fisher´s Exact Test (one-sided)
n
= number of patients receiving treatment during the indicated period.
% = percentage of patients who reported the event during the indicated period.
Post-Trial Extension Studies in Adults
In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN. All 12 patients had
predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN. Of the 3,031 patients receiving
GENOTROPIN, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other
adverse events that have been reported include generalized edema and hypoesthesia.
Anti-hGH Antibodies
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the
assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of
antibodies to GENOTROPIN with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities
lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater
than 2 mg/mL, interference with the growth response was observed.
In 419 pediatric patients evaluated in clinical studies with GENOTROPIN lyophilized powder, 244 had been treated previously with GENOTROPIN or other growth
hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously
treated patients at baseline. Three of the six became negative for anti-hGH antibodies during 6 to 12 months of treatment with GENOTROPIN. Of the remaining
413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There
was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients.
Periplasmic Escherichia coli Peptides
Preparations of GENOTROPIN contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients
treated with GENOTROPIN, but these appear to be of no clinical significance.
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.
Leukemia has been reported in a small number of GHD 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 GHD 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 GHD, if any, remains to
be established [see Contraindications (4.3) and Warnings and Precautions (5.3)].
The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and
pancreatitis (children and adults, see Warnings and Precautions [5.14]).
New-onset type 2 diabetes mellitus has been reported.
7
DRUG INTERACTIONS
7.1 11 β-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
7
Reference ID: 3634596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 Glucocortioid 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 (CYP450)-mediated antipyrine clearance in man. These data suggest that
somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids,
anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450
liver enzymes. However, formal drug interaction studies have not been conducted.
7.4
Oral Estrogen
In patients on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal [see Dosage and Administration (2.2)].
7.5
Insulin and/or Oral/Injectable Hypoglycemic Agents
In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable agent may require adjustment when somatropin therapy is initiated
[see Warnings and Precautions (5.4)]).
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. Reproduction studies carried out with GENOTROPIN at doses of 0.3, 1, and 3.3 mg/kg/day administered SC in the rat and 0.08, 0.3, and 1.3
mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively,
based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic. In rats receiving SC doses during gametogenesis and up to 7
days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in
males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day
(approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted.
In perinatal and postnatal studies in rats, GENOTROPIN doses of 0.3, 1, and 3.3 mg/kg/day produced growth-promoting effects in the dams but not in the fetuses.
Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on
gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offsprings due to GENOTROPIN. 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.
8.3
Nursing Mothers
There have been no studies conducted with GENOTROPIN 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 GENOTROPIN is administered to a nursing woman.
8.5
Geriatric Use
The safety and effectiveness of GENOTROPIN in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the
action of GENOTROPIN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for
older patients [see Dosage and Administration (2.2)].
10
OVERDOSAGE
Short-Term
Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid
retention.
Long-Term
Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone [see Dosage
and Administration (2)].
11
DESCRIPTION
GENOTROPIN lyophilized powder contains somatropin [rDNA origin], which is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues
and a molecular weight of 22,124 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin).
GENOTROPIN is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone. GENOTROPIN is a sterile
white lyophilized powder intended for subcutaneous injection.
GENOTROPIN 5 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 5.8 mg, glycine 2.2 mg, mannitol 1.8 mg, sodium
dihydrogen phosphate anhydrous 0.32 mg, and disodium phosphate anhydrous 0.31 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and mannitol 45
mg in 1.14 mL water for injection. The GENOTROPIN 5 mg two-chambered cartridge contains 5.8 mg of somatropin. The reconstituted concentration is 5mg/ml. The
cartridge contains overfill to allow for delivery of 1ml containing the stated amount of GENOTROPIN – 5 mg.
GENOTROPIN 12mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 13.8 mg, glycine 2.3 mg, mannitol 14.0 mg,
sodium dihydrogen phosphate anhydrous 0.47 mg, and disodium phosphate anhydrous 0.46 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and
mannitol 32 mg in 1.13 mL water for injection. The GENOTROPIN 12 mg two-chambered cartridge contains 13.8 mg of somatropin. The reconstituted concentration is
12 mg/ml . The cartridge contains overfill to allow for delivery of 1ml containing the stated amount of GENOTROPIN – 12 mg.
GENOTROPIN MINIQUICK is dispensed as a single-use syringe device containing a two-chamber cartridge. GENOTROPIN MINIQUICK is available as individual
doses of 0.2 mg to 2.0 mg in 0.2 mg increments. The front chamber contains recombinant somatropin 0.22 to 2.2 mg, glycine 0.23 mg, mannitol 1.14 mg, sodium
8
Reference ID: 3634596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dihydrogen phosphate 0.05 mg, and disodium phosphate anhydrous 0.027 mg; the rear chamber contains mannitol 12.6 mg in water for injection 0.275 mL. The
reconstituted GENOTROPIN MINIQUICK two-chamber cartridge contains overfill to allow for delivery of 0.25 ml containing the stated amount of GENOTROPIN.
GENOTROPIN is a highly purified preparation. The reconstituted recombinant somatropin solution has an osmolality of approximately 300 mOsm/kg, and a pH of
approximately 6.7. The concentration of the reconstituted solution varies by strength and presentation (see HOW SUPPLIED).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
In vitro, preclinical, and clinical tests have demonstrated that GENOTROPIN lyophilized powder is therapeutically equivalent to human growth hormone of pituitary
origin and achieves similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD), have Prader-Willi syndrome
(PWS), were born small for gestational age (SGA), have Turner syndrome (TS), or have Idiopathic short stature (ISS), treatment with GENOTROPIN stimulates linear
growth. In patients with GHD or PWS, treatment with GENOTROPIN also normalizes concentrations of IGF-I (Insulin-like Growth Factor-I/Somatomedin C). In
adults with GHD, treatment with GENOTROPIN results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid
metabolism, and normalization of IGF-I concentrations.
In addition, the following actions have been demonstrated for GENOTROPIN and/or somatropin.
12.2
Pharmacodynamics
Tissue Growth
A. Skeletal Growth: GENOTROPIN stimulates skeletal growth in pediatric patients with GHD, PWS, SGA, TS, or ISS. The measurable increase in body
length after administration of GENOTROPIN results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role
in skeletal growth, are generally low in the serum of pediatric patients with GHD, PWS, or SGA, but tend to increase during treatment with GENOTROPIN.
Elevations in mean serum alkaline phosphatase concentration are also seen.
B.
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 the normal pediatric population. Treatment with somatropin results in an increase in both the number and size of muscle cells.
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 GENOTROPIN.
Carbohydrate Metabolism
Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with GENOTROPIN. Large doses of growth
hormone may impair glucose tolerance.
Lipid Metabolism
In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.
Mineral Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after
therapy with GENOTROPIN. Serum calcium is not significantly altered by GENOTROPIN. Growth hormone could increase calciuria.
Body Composition
Adult GHD patients treated with GENOTROPIN at the recommended adult dose (see DOSAGE AND ADMINISTRATION) demonstrate a decrease in fat mass
and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of GENOTROPIN is to modify body
composition, an effect that is maintained with continued treatment.
12.3
Pharmacokinetics
Absorption
Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN to adult GHD patients, approximately 80% of the dose was systemically
available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been
observed in healthy adult male subjects.
In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN was 35%
greater than that for 1.3 mg/mL GENOTROPIN. The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL,
respectively.
In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN.
The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.
Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN at a concentration of 1.3 mg/mL, with a one- to four-week washout period between
injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.
There are no data on the bioequivalence between the 12 mg/mL formulation and either the 1.3 mg/mL or the 5.3 mg/mL formulations.
Distribution
The mean volume of distribution of GENOTROPIN following administration to GHD adults was estimated to be 1.3 (± 0.8) L/kg.
Metabolism
The metabolic fate of GENOTROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are
returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN in normal adults is 0.4 hours, whereas subcutaneously administered
GENOTROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.
Reference ID: 3634596
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Excretion
The mean clearance of subcutaneously administered GENOTROPIN in 16 GHD adult patients was 0.3 (± 0.11) L/hrs/kg.
Special Populations
Pediatric: The pharmacokinetics of GENOTROPIN are similar in GHD pediatric and adult patients.
Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of GENOTROPIN was similar in males and
females.
Race: No studies have been conducted with GENOTROPIN to assess pharmacokinetic differences among races.
Renal or hepatic insufficiency: No studies have been conducted with GENOTROPIN in these patient populations.
Table 2
Mean SC Pharmacokinetic Parameters in Adult GHD Patients
Bioavaila
bility
(%)
(N=15)
Tmax
(hours)
(N=16)
CL/F
(L/hr x
kg)
(N=16)
Vss/F
(L/kg)
(N=16)
T1/2
(hours)
(N=16)
Mean
(± SD)
80.5
*
5.9
(± 1.65)
0.3
(± 0.11)
1.3
(± 0.80)
3.0
(± 1.44)
95% CI
70.5 –
92.1
5.0 – 6.7
0.2 – 0.4
0.9 – 1.8
2.2 – 3.7
Tmax = time of maximum plasma concentration T 1/2 = terminal half-life
CL/F = plasma clearance
SD = standard deviation
Vss/F = volume of distribution
CI = confidence interval
* The absolute bioavailability was estimated under the assumption that the
log-transformed data follow a normal distribution. The mean and standard
deviation of the log-transformed data were mean = 0.22 (± 0.241).
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with GENOTROPIN. No potential mutagenicity of GENOTROPIN was revealed in a battery of tests including
induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (mouse L5178Y cells), and chromosomal damage in intact
animals (bone marrow cells in rats). See PREGNANCY section for effect on fertility.
14
CLINICAL STUDIES
14.1
Adult Growth Hormone Deficiency (GHD)
GENOTROPIN lyophilized powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6
month double-blind treatment period, during which 85 patients received GENOTROPIN and 87 patients received placebo, followed by an open-label treatment period
in which participating patients received GENOTROPIN for up to a total of 24 months. GENOTROPIN was administered as a daily SC injection at a dose of 0.04
mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months.
Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving GENOTROPIN as compared with the
placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body
composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline
values after 12 months of treatment.
14.2
Prader-Willi Syndrome (PWS)
The safety and efficacy of GENOTROPIN in the treatment of pediatric patients with Prader-Willi syndrome (PWS) were evaluated in two randomized, open-label,
controlled clinical trials. Patients received either GENOTROPIN or no treatment for the first year of the studies, while all patients received GENOTROPIN during the
second year. GENOTROPIN was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group
received GENOTROPIN at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN at a dose of 0.48
mg/kg/week. In Study 2, the treatment group received GENOTROPIN at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group
received GENOTROPIN at a dose of 0.36 mg/kg/week.
Patients who received GENOTROPIN showed significant increases in linear growth during the first year of study, compared with patients who received no treatment
(see Table 3). Linear growth continued to increase in the second year, when both groups received treatment with GENOTROPIN.
Reference ID: 3634596
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Table 3
Efficacy of GENOTROPIN in Pediatric Patients with Prader-Willi
Syndrome (Mean ± SD)
Study 1
Study 2
GENOTR
OPIN
(0.24
mg/kg/we
ek)
n=15
Untreated
Control
n=12
GENOTR
OPIN
(0.36
mg/kg/we
ek)
n=7
Untreated
Control
n=9
Linear growth
(cm)
Baseline height
112.7 ±
14.9
109.5 ±
12.0
120.3 ±
17.5
120.5 ±
11.2
Growth from
months 0 to 12
11.6* ± 2.3
5.0 ± 1.2
10.7* ± 2.3
4.3 ± 1.5
Height
Standard
Deviation Score
(SDS) for age
Baseline SDS
-1.6 ± 1.3
-1.8 ± 1.5
-2.6 ± 1.7
-2.1 ± 1.4
SDS at 12
months
-0.5† ± 1.3
-1.9 ± 1.4
-1.4† ± 1.5
-2.2 ± 1.4
*
p ≤ 0.001
†
p ≤ 0.002 (when comparing SDS change at 12 months)
Changes in body composition were also observed in the patients receiving GENOTROPIN (see Table 4). These changes included a decrease in the amount of fat mass,
and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while changes in body weight were similar to those seen in patients who received no
treatment. Treatment with GENOTROPIN did not accelerate bone age, compared with patients who received no treatment.
Table 4
Effect of GENOTROPIN on Body Composition
in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
GENOTROPIN
n=14
Untreated Control
n=10
Fat mass (kg)
Baseline
12.3 ± 6.8
9.4 ± 4.9
Change from
months 0 to 12
-0.9* ± 2.2
2.3 ± 2.4
Lean body mass
(kg)
Baseline
15.6 ± 5.7
14.3 ± 4.0
Change from
months 0 to 12
4.7* ± 1.9
0.7 ± 2.4
Lean body
mass/Fat mass
Baseline
1.4 ± 0.4
1.8 ± 0.8
Change from
months 0 to 12
1.0* ± 1.4
-0.1 ± 0.6
Body weight (kg) †
Baseline
27.2 ± 12.0
23.2 ± 7.0
Change from
months 0 to 12
3.7‡ ± 2.0
3.5 ± 1.9
*
p < 0.005
†
n=15 for the group receiving GENOTROPIN; n=12 for the
Control group
‡
n.s.
Reference ID: 3634596
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14.3
SGA
Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2
The safety and efficacy of GENOTROPIN in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled
clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either GENOTROPIN (two doses per study, most
often 0.24 and 0.48 mg/kg/week) as a daily SC injection or no treatment for the first 24 months of the studies. After 24 months in the studies, all patients received
GENOTROPIN.
Patients who received any dose of GENOTROPIN showed significant increases in growth during the first 24 months of study, compared with patients who received no
treatment (see Table 5). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children
treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth between months 24 to 72 (data not shown).
Table 5
Efficacy of GENOTROPIN in Children Born Small for Gestational Age
(Mean ± SD)
GENOTRO
PIN
(0.24
mg/kg/week)
n=76
GENOTRO
PIN
(0.48
mg/kg/week)
n=93
Untreated
Control
n=40
Height Standard
Deviation Score (SDS)
Baseline SDS
-3.2 ± 0.8
-3.4 ± 1.0
-3.1 ± 0.9
SDS at 24 months
-2.0 ± 0.8
-1.7 ± 1.0
-2.9 ± 0.9
Change in SDS from
baseline to month 24
1.2* ± 0.5
1.7*† ± 0.6
0.1 ± 0.3
*
p = 0.0001 vs Untreated Control group
†
p = 0.0001 vs group treated with GENOTROPIN 0.24 mg/kg/week
14.4
Turner Syndrome
Two randomized, open-label, clinical trials were conducted that evaluated the efficacy and safety of GENOTROPIN in Turner syndrome patients with short stature.
Turner syndrome patients were treated with GENOTROPIN alone or GENOTROPIN plus adjunctive hormonal therapy (ethinylestradiol or oxandrolone). A total of 38
patients were treated with GENOTROPIN alone in the two studies. In Study 055, 22 patients were treated for 12 months, and in Study 092, 16 patients were treated for
12 months. Patients received GENOTROPIN at a dose between 0.13 to 0.33 mg/kg/week.
SDS for height velocity and height are expressed using either the Tanner (Study 055) or Sempé (Study 092) standards for age-matched normal children as well as the
Ranke standard (both studies) for age-matched, untreated Turner syndrome patients. As seen in Table 5, height velocity SDS and height SDS values were smaller at
baseline and after treatment with GENOTROPIN when the normative standards were utilized as opposed to the Turner syndrome standard.
Both studies demonstrated statistically significant increases from baseline in all of the linear growth variables (i.e., mean height velocity, height velocity SDS, and
height SDS) after treatment with GENOTROPIN (see Table 6). The linear growth response was greater in Study 055 wherein patients were treated with a larger dose of
GENOTROPIN.
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Table 6
Growth Parameters (mean ± SD) after 12 Months of Treatment with
GENOTROPIN
in Pediatric Patients with Turner Syndrome in Two Open Label Studies
GENOTROPIN
0.33 mg/kg/week
Study 055^ n=22
GENOTROPIN
0.13–0.23 mg/kg/week
Study 092# n=16
Height Velocity (cm/yr)
Baseline
4.1 ± 1.5
3.9 ± 1.0
Month 12
7.8 ± 1.6
6.1 ± 0.9
Change from baseline
(95% CI)
3.7 (3.0, 4.3)
2.2 (1.5, 2.9)
Height Velocity SDS
(Tanner^/Sempé#
Standards)
(n=20)
Baseline
-2.3 ± 1.4
-1.6 ± 0.6
Month 12
2.2 ± 2.3
0.7 ± 1.3
Change from baseline
(95% CI)
4.6 (3.5, 5.6)
2.2 (1.4, 3.0)
Height Velocity SDS
(Ranke Standard)
Baseline
-0.1 ± 1.2
-0.4 ± 0.6
Month 12
4.2 ± 1.2
2.3 ± 1.2
Change from baseline
(95% CI)
4.3 (3.5, 5.0)
2.7 (1.8, 3.5)
Height SDS
(Tanner^/Sempé#
Standards)
Baseline
-3.1 ± 1.0
-3.2 ± 1.0
Month 12
-2.7 ± 1.1
-2.9 ± 1.0
Change from baseline
(95% CI)
0.4 (0.3, 0.6)
0.3 (0.1, 0.4)
Height SDS
(Ranke Standard)
Baseline
-0.2 ± 0.8
-0.3 ± 0.8
Month 12
0.6 ± 0.9
0.1 ± 0.8
Change from baseline
(95% CI)
0.8 (0.7, 0.9)
0.5 (0.4, 0.5)
SDS = Standard Deviation Score
Ranke standard based on age-matched, untreated Turner syndrome patients
Tanner^/Sempé# standards based on age-matched normal children
p<0.05, for all changes from baseline
14.5
Idiopathic Short Stature
The long-term efficacy and safety of GENOTROPIN in patients with idiopathic short stature (ISS) were evaluated in one randomized, open-label, clinical trial that
enrolled 177 children. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status (criteria for idiopathic short
stature were retrospectively applied and included 126 patients). All patients were observed for height progression for 12 months and were subsequently randomized to
Genotropin or observation only and followed to final height. Two Genotropin doses were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47
mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD):
chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were
treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 7. GENOTROPIN therapy improved final height in ISS
children relative to untreated controls. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to
untreated control subjects. A height gain of 1 SDS was observed in 10 % of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects
receiving 0.47 mg/kg/week
Table 7. Final height SDS results for pre-pubertal patients with ISS*
Untreated
(n=30)
GEN 0.033
(n=30)
GEN 0.067
(n=42)
GEN 0.033 vs.
Untreated
(95% CI)
GEN 0.067 vs.
Untreated
(95% CI)
Baseline height SDS
Final height SDS minus
baseline
Baseline predicted ht
Final height SDS minus
baseline predicted final
height SDS
0.41 (0.58)
0.23 (0.66)
0.95 (0.75)
0.73 (0.63)
1.36 (0.64)
1.05 (0.83)
+0.53 (0.20, 0.87)
p=0.0022
+0.60 (0.09, 1.11)
p=0.0217
+0.94 (0.63, 1.26)
p<0.0001
+0.90 (0.42, 1.39)
p=0.0004
*Mean (SD) are observed values.
**Least square means based on ANCOVA (final height SDS and final height SDS minus baseline predicted height SDS were adjusted for baseline height SDS)
.
Reference ID: 3634596
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16
HOW SUPPLIED/STORAGE AND HANDLING
GENOTROPIN lyophilized powder is available in the following packages:
5 mg two-chamber cartridge (with preservative)
Concentration of 5 mg/mL
For use with the GENOTROPIN PEN 5 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER™ Growth Hormone Reconstitution Device.
Package of 1 NDC 0013-2626-81
12 mg two-chamber cartridge (with preservative)
Concentration of 12 mg/mL
For use with the GENOTROPIN PEN 12 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER Growth Hormone Reconstitution Device.
Package of 1 NDC 0013-2646-81
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)
After reconstitution, each GENOTROPIN MINIQUICK delivers 0.25 mL, regardless of strength. Available in the following strengths, each in a package of 7:
0.2 mg
NDC 0013-2649-02
0.4 mg
NDC 0013-2650-02
0.6 mg
NDC 0013-2651-02
0.8 mg
NDC 0013-2652-02
1.0 mg
NDC 0013-2653-02
1.2 mg
NDC 0013-2654-02
1.4 mg
NDC 0013-2655-02
1.6 mg
NDC 0013-2656-02
1.8 mg
NDC 0013-2657-02
2.0 mg
NDC 0013-2658-02
Storage and Handling
Except as noted below, store GENOTROPIN lyophilized powder under refrigeration at 36°F to 46°F (2°C to 8°C).Do not freeze. Protect from light.
The 5 mg and 12 mg cartridges of GENOTROPIN contain a diluent with a preservative. Thus, after reconstitution, they may be stored under refrigeration for up to 28
days.
The GENOTROPIN MINIQUICK Growth Hormone Delivery Device should be refrigerated prior to dispensing, but may be stored at or below 77°F (25°C) for up to
three months after dispensing. The diluent has no preservative. After reconstitution, the GENOTROPIN MINIQUICK may be stored under refrigeration for up to 24
hours before use. The GENOTROPIN MINIQUICK should be used only once and then discarded.
17
PATIENT COUNSELING INFORMATION
Patients being treated with GENOTROPIN (and/or their parents) should be informed about the potential benefits and risks associated with GENOTROPIN treatment [in
particular, see Adverse Reactions (6.1) for a listing of the most serious and/or most frequently observed adverse reactions associated with somatropin treatment in
children and adults]. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects.
Patients and caregivers who will administer GENOTROPIN should receive appropriate training and instruction on the proper use of GENOTROPIN from the physician
or other suitably qualified health care professional. A puncture-resistant container for the disposal of used syringes and needles 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.
GENOTROPIN is supplied in a two-chamber cartridge, with the lyophilized powder in the front chamber and a diluent in the rear chamber. A reconstitution device is
used to mix the diluent and powder. The two-chamber cartridge contains overfill in order to deliver the stated amount of GENOTROPIN
The GENOTROPIN 5 mg and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN Pen delivery device. The 5 mg cartridge has a green
tip to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.
Follow the directions for reconstitution provided with each device. Do not shake; shaking may cause denaturation of the active ingredient.
Please see accompanying directions for use of the reconstitution and/or delivery device.
Manufactured by:
Vetter Pharma-Fertigung GmbH & Co. KG
Ravensburg, Germany
Or
Vetter Pharma-Fertigung GmbH & Co. KG
14
Reference ID: 3634596
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Langenargen, Germany
Rx only company logo
LAB-0222-18.2
Reference ID: 3634596
15
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020280s077lbl.pdf', 'application_number': 20280, 'submission_type': 'SUPPL ', 'submission_number': 77}
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CO:LX
PRESCRIBING INFORMATION
COREG®
(carvedilol)
Tablets
DESCRIPTION
Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is (±)-1-
(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. It is a racemic mixture with
the following structure:
Tablets for Oral Administration: COREG (carvedilol) is a white, oval, film-coated tablet containing
3.125 mg, 6.25 mg, 12.5 mg, or 25 mg of carvedilol. The 6.25 mg, 12.5 mg, and 25 mg tablets are
TILTAB® tablets. Inactive ingredients consist of colloidal silicon dioxide, crospovidone,
hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sucrose,
and titanium dioxide.
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular
formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and
methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and
practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS
without pancreatin, pH 7.5).
CLINICAL PHARMACOLOGY
COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is
present in the S(-) enantiomer and α-adrenergic blocking activity is present in both R(+) and S(-)
enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.
Pharmacokinetics: COREG is rapidly and extensively absorbed following oral administration, with
absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass
metabolism. Following oral administration, the apparent mean terminal elimination half-life of
carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the
oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by
a delay in the time to reach peak plasma levels, with no significant difference in extent of
bioavailability. Taking COREG with food should minimize the risk of orthostatic hypotension.
Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol
to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as
measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the
urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The
oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The
metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and
hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based
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Page 4
on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than
carvedilol for β-blockade.
Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma
concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have
pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of
R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in
healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to
9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in
human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and
2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a
potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation
pathway of S(-)-carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of
debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations
of R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are
increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a
lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not
appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450
2C19).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The
plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a
basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L,
indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to
700 mL/min.
Congestive Heart Failure: Steady-state plasma concentrations of carvedilol and its
enantiomers increased proportionally over the 6.25 to 50 mg dose range in patients with congestive
heart failure. Compared to healthy subjects, congestive heart failure patients had increased mean AUC
and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in
6 patients with NYHA class IV heart failure. The mean apparent terminal elimination half-life for
carvedilol was similar to that observed in healthy subjects.
Pharmacokinetic Drug-Drug Interactions: Since carvedilol undergoes substantial
oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by
induction or inhibition of cytochrome P450 enzymes.
Rifampin: In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin
(600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70%.
Cimetidine: In a pharmacokinetic study conducted in 10 healthy male subjects,
cimetidine (1000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change in
Cmax.
Glyburide: In 12 healthy subjects, combined administration of carvedilol (25 mg once
daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction
for either compound.
Hydrochlorothiazide: A single oral dose of carvedilol 25 mg did not alter the
pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 patients with hypertension.
Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.
Digoxin: Following concomitant administration of carvedilol (25 mg once daily) and
digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were
increased by 14% and 16%, respectively, in 12 hypertensive patients.
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Torsemide: In a study of 12 healthy subjects, combined oral administration of
carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant
differences in their pharmacokinetics compared with administration of the drugs alone.
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state
prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following
concomitant administration with warfarin in 9 healthy volunteers.
Special Populations: Elderly: Plasma levels of carvedilol average about 50% higher in the elderly
compared to young subjects.
Hepatic Impairment: Compared to healthy subjects, patients with cirrhotic liver disease
exhibit significantly higher concentrations of carvedilol (approximately 4- to 7-fold) following
single-dose therapy.
Renal Insufficiency: Although carvedilol is metabolized primarily by the liver, plasma
concentrations of carvedilol have been reported to be increased in patients with renal impairment.
Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were
observed in hypertensive patients with moderate to severe renal impairment compared to a control
group of hypertensive patients with normal renal function. However, the ranges of AUC values were
similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately
12% to 26% higher in patients with impaired renal function.
Consistent with its high degree of plasma protein-binding, carvedilol does not appear to be
cleared significantly by hemodialysis.
Pharmacodynamics: Congestive Heart Failure: The basis for the beneficial effects of COREG
in congestive heart failure is not established.
Two placebo-controlled studies compared the acute hemodynamic effects of COREG to
baseline measurements in 59 and 49 patients with NYHA class II-IV heart failure receiving diuretics,
ACE inhibitors, and digitalis. There were significant reductions in systemic blood pressure, pulmonary
artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output,
stroke volume index, and systemic vascular resistance were small and variable.
These studies measured hemodynamic effects again at 12 to 14 weeks. COREG significantly
reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular
resistance, and heart rate, while stroke volume index was increased.
Among 839 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 US
placebo-controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide
ventriculography increased by 9 EF units (%) in COREG patients and by 2 EF units in placebo patients
at a target dose of 25-50 mg twice daily. The effects of carvedilol on ejection fraction were related to
dose. Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily were associated with
placebo-corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these
effects were nominally statistically significant.
Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the
beneficial effects of COREG in patients with left ventricular dysfunction following an acute
myocardial infarction is not established.
Hypertension: The mechanism by which β-blockade produces an antihypertensive effect has
not been established.
β-adrenoreceptor blocking activity has been demonstrated in animal and human studies
showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or
isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant
β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies,
showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and
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Page 6
(3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure
and usually are seen within 30 minutes of drug administration.
Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the
standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare
instances of syncope, can occur. Following oral administration, when postural hypotension has
occurred, it has been transient and is uncommon when COREG is administered with food at the
recommended starting dose and titration increments are closely followed (see DOSAGE AND
ADMINISTRATION).
In hypertensive patients with normal renal function, therapeutic doses of COREG decreased
renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in
excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal
function were similar after COREG and placebo.
COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels,
but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases
levels of atrial natriuretic peptide.
CLINICAL TRIALS
Congestive Heart Failure: A total of 6,975 patients with mild to severe heart failure were evaluated
in placebo-controlled and active-controlled studies of carvedilol.
Trials in Mild-to-Moderate Heart Failure: Carvedilol was studied in 5 multicenter,
placebo-controlled studies, and in 1 active-controlled study (COMET study) involving patients with
mild-to-moderate heart failure.
Four US multicenter, double-blind, placebo-controlled studies enrolled 1,094 patients
(696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction <0.35. The
vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were assigned
to the studies based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled
study enrolled 415 patients (half randomized to carvedilol) with less severe heart failure. All protocols
excluded patients expected to undergo cardiac transplantation during the 7.5 to 15 months of
double-blind follow-up. All randomized patients had tolerated a 2-week course on carvedilol 6.25 mg
twice daily.
In each study, there was a primary end point, either progression of heart failure (1 US study) or
exercise tolerance (2 US studies meeting enrollment goals and the Australia-New Zealand study).
There were many secondary end points specified in these studies, including NYHA classification,
patient and physician global assessments, and cardiovascular hospitalization. Other analyses not
prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In
situations where the primary end points of a trial do not show a significant benefit of treatment,
assignment of significance values to the other results is complex, and such values need to be
interpreted cautiously.
The results of the US and Australia-New Zealand trials were as follows:
Slowing Progression of Heart Failure: One US multicenter study (366 subjects) had as its
primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained
increase in heart failure medications. Heart failure progression was reduced, during an average
follow-up of 7 months, by 48% (p = 0.008).
In the Australia-New Zealand study, death and total hospitalizations were reduced by about
25% over 18 to 24 months. In the 3 largest US studies, death and total hospitalizations were reduced by
19%, 39%, and 49%, nominally statistically significant in the last 2 studies. The Australia-New
Zealand results were statistically borderline.
Functional Measures: None of the multicenter studies had NYHA classification as a primary
end point, but all such studies had it as a secondary end point. There was at least a trend toward
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Page 7
improvement in NYHA class in all studies. Exercise tolerance was the primary end point in 3 studies;
in none was a statistically significant effect found.
Subjective Measures: Quality of life, as measured with a standard questionnaire (a primary end
point in 1 study), was unaffected by carvedilol. However, patients’ and investigators’ global
assessments showed significant improvement in most studies.
Mortality: Death was not a pre-specified end-point in any study, but was analyzed in all
studies. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 studies.
The COMET Trial: In this double-blind trial, 3,029 patients with NYHA class II-IV heart failure (left
ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg
twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of
the patients was approximately 62 years, 80% were males, and the mean left ventricular ejection
fraction at baseline was 26%. Approximately 96% of the patients had NYHA class II or III heart
failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%),
aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-
up was 4.8 years. The mean dose of carvedilol was 42 mg per day.
The study had 2 primary endpoints: all-cause mortality and the composite of death plus
hospitalization for any reason. All-cause mortality carried most of the statistical weight and was the
primary determinant of the study size. All-cause mortality was 34% in the patients treated with
carvedilol and was 40% in the immediate-release metoprolol group (p=0.0017; hazard ratio=0.83, 95%
CI 0.74-0.93). The difference between the 2 groups with respect to the composite endpoint was not
significant (p=0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with
immediate-release metoprolol.
It is not known whether this formulation of metoprolol at any dose or this low dose of
metoprolol in any formulation has any effect on survival or hospitalization in patients with heart
failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart
failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol
(Toprol XL) with benefits in heart failure.
Trials in Severe Heart Failure: In a double-blind study (COPERNICUS), 2,289 patients with heart
failure at rest or with minimal exertion and left ventricular ejection fraction <25% (mean 20%), despite
digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol.
Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or
up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg.
The study was conducted in Eastern and Western Europe, the United States, Israel, and Canada.
Similar numbers of subjects per group (about 100) withdrew during the titration period.
The primary end point of the trial was all-cause mortality, but cause-specific mortality and the
risk of death or hospitalization (total, cardiovascular [CV], or congestive heart failure [CHF]) were
also examined. The developing trial data were followed by a data monitoring committee, and mortality
analyses were adjusted for these multiple looks. The trial was stopped after a median follow-up of
10 months because of an observed 35% reduction in mortality (from 19.7% per patient year on placebo
to 12.8% on carvedilol, hazard ratio 0.65, 95% CI 0.52 – 0.81, p = 0.0014, adjusted) (see Figure 1).
The results of COPERNICUS are shown in Table 1.
Table 1. Results of COPERNICUS
End point
Placebo
N = 1,133
Carvedilol
N = 1,156
Hazard ratio
(95% CI)
%
Reduction
Nominal p
value
Mortality
190
130
0.65
(0.52 – 0.81)
35
0.00013
Mortality + all
hospitalization
507
425
0.76
(0.67 – 0.87)
24
0.00004
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End point
Placebo
N = 1,133
Carvedilol
N = 1,156
Hazard ratio
(95% CI)
%
Reduction
Nominal p
value
Mortality + CV
hospitalization
395
314
0.73
(0.63 – 0.84)
27
0.00002
Mortality + CHF
hospitalization
357
271
0.69
(0.59 – 0.81)
31
0.000004
Figure 1. Survival Analysis for COPERNICUS (intent-to-treat)
The effect on mortality was principally the result of a reduction in the rate of sudden death
among patients without worsening heart failure.
Patients' global assessments, in which carvedilol-treated patients were compared to placebo,
were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-
treatment showed improvement, worsening or no change compared to baseline. Patients treated with
carvedilol showed significant improvements in global assessments compared with those treated with
placebo in COPERNICUS.
The protocol also specified that hospitalizations would be assessed. Fewer patients on COREG
than on placebo were hospitalized for any reason (372 vs. 432, p = 0.0029), for cardiovascular reasons
(246 vs. 314, p = 0.0003), or for worsening heart failure (198 vs. 268, p = 0.0001).
COREG had a consistent and beneficial effect on all-cause mortality as well as the combined
end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall study
population and in all subgroups examined, including men and women, elderly and non-elderly, blacks
and non-blacks, and diabetics and non-diabetics (see Figure 2).
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Figure 2. Effects on Mortality for Subgroups in COPERNICUS
Left Ventricular Dysfunction Following Myocardial Infarction: CAPRICORN was a
double-blind study comparing carvedilol and placebo in 1,959 patients with a recent myocardial
infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without
symptoms of heart failure. Patients given carvedilol received 6.25 mg twice daily, titrated as tolerated
to 25 mg twice daily. Patients had to have a systolic blood pressure >90 mm Hg, a sitting heart rate
>60 beats/minute, and no contraindication to β-blocker use. Treatment of the index infarction included
aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and
acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor
blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline
population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood
pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage
achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a
23% risk reduction in patients treated with carvedilol (95% CI 2-40%, p = 0.03), as shown in Figure 3.
The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were
cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or
related to pump failure (both types of death were reduced by carvedilol). Another study endpoint, total
mortality and all-cause hospitalization, did not show a significant improvement.
There was also a significant 40% reduction in fatal and non-fatal myocardial infarction
observed in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar reduction in
the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of
carvedilol in heart failure.
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Figure 3. Survival Analysis for CAPRICORN (intent-to-treat)
Figure 4. Effects on Mortality for Subgroups in CAPRICORN
Hypertension: COREG was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at
total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed 12.5 mg.
At 50 mg/day, COREG reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at
25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed
a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about
7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers, responses were smaller in
black than non-black patients. There were no age- or gender-related differences in response.
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related blood
pressure response was accompanied by a dose-related increase in adverse effects (see ADVERSE
REACTIONS).
INDICATIONS AND USAGE
Congestive Heart Failure: COREG is indicated for the treatment of mild-to-severe heart failure of
ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to
increase survival and, also, reduce the risk of hospitalization. (see CLINICAL TRIALS).
Left Ventricular Dysfunction Following Myocardial Infarction: COREG is indicated to
reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a
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myocardial infarction and have a left ventricular ejection fraction of ≤40% (with or without
symptomatic heart failure) (see CLINICAL TRIALS).
Hypertension: COREG is also indicated for the management of essential hypertension. It can be
used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics (see
PRECAUTIONS, Drug Interactions).
CONTRAINDICATIONS
COREG is contraindicated in patients with bronchial asthma (2 cases of death from status
asthmaticus have been reported in patients receiving single doses of COREG) or related
bronchospastic conditions, second- or third-degree AV block, sick sinus syndrome or severe
bradycardia (unless a permanent pacemaker is in place), or in patients with cardiogenic shock or who
have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients
should first be weaned from intravenous therapy before initiating COREG.
Use of COREG in patients with clinically manifest hepatic impairment is not recommended.
COREG is contraindicated in patients with hypersensitivity to any component of the product.
WARNINGS
Cessation of Therapy with COREG: Patients with coronary artery disease, who are being
treated with COREG, should be advised against abrupt discontinuation of therapy. Severe
exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias
have been reported in angina patients following the abrupt discontinuation of therapy with
β-blockers. The last 2 complications may occur with or without preceding exacerbation of the
angina pectoris. As with other β-blockers, when discontinuation of COREG is planned, the
patients should be carefully observed and advised to limit physical activity to a minimum.
COREG should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or
acute coronary insufficiency develops, it is recommended that COREG be promptly reinstituted,
at least temporarily. Because coronary artery disease is common and may be unrecognized, it
may be prudent not to discontinue COREG therapy abruptly even in patients treated only for
hypertension or heart failure (See DOSAGE AND ADMINISTRATION.)
Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial
insufficiency in patients with peripheral vascular disease. Caution should be exercised in such
individuals.
Anesthesia and Major Surgery: If treatment with COREG is to be continued perioperatively,
particular care should be taken when anesthetic agents which depress myocardial function, such as
ether, cyclopropane, and trichloroethylene, are used. See OVERDOSAGE for information on treatment
of bradycardia and hypertension.
Diabetes and Hypoglycemia: In general, β-blockers may mask some of the manifestations of
hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced
hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous
hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned
about these possibilities. In congestive heart failure patients, there is a risk of worsening
hyperglycemia (see PRECAUTIONS).
Thyrotoxicosis: β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as
tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of
hyperthyroidism or may precipitate thyroid storm.
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PRECAUTIONS
General: In clinical trials, COREG caused bradycardia in about 2% of hypertensive patients, 9% of
congestive heart failure patients, and 6.5% of myocardial infarction patients with left ventricular
dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural
hypotension occurred in 9.7% and syncope in 3.4% of patients receiving COREG compared to 3.6%
and 2.5% of placebo patients, respectively. The risk for these events was highest during the first
30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of
therapy in 0.7% of COREG patients, compared to 0.4% of placebo patients. In a long-term,
placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension
occurred in 15.1% and syncope in 2.9% of heart failure patients receiving COREG compared to 8.7%
and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in
1.1% of COREG patients, compared to 0.8% of placebo patients.
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily
following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy
in 1% of patients.
In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or
postural hypotension occurred in 20.2% of patients receiving COREG compared to 12.6% of placebo
patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause
for discontinuation of therapy in 2.5% of patients receiving COREG, compared to 0.2% of placebo
patients.
To decrease the likelihood of syncope or excessive hypotension, treatment should be initiated
with 3.125 mg twice daily for congestive heart failure patients, and at 6.25 mg twice daily for
hypertensive patients and survivors of an acute myocardial infarction with left ventricular dysfunction.
Dosage should then be increased slowly, according to recommendations in the DOSAGE AND
ADMINISTRATION section, and the drug should be taken with food. During initiation of therapy, the
patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could
result should syncope occur.
Rarely, use of carvedilol in patients with congestive heart failure has resulted in deterioration of
renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure
<100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal
insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with
these risk factors it is recommended that renal function be monitored during up-titration of carvedilol
and the drug discontinued or dosage reduced if worsening of renal function occurs.
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such
symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until
clinical stability resumes (see DOSAGE AND ADMINISTRATION). Occasionally it is necessary to
lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent
successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of patients
with severe heart failure, worsening heart failure during the first 3 months was reported to a similar
degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening
heart failure was reported less frequently in patients treated with carvedilol than with placebo.
Worsening heart failure observed during long-term therapy is more likely to be related to the patients’
underlying disease than to treatment with carvedilol.
In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of
any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there
has been no experience with its use in this condition. Therefore, caution should be taken in the
administration of carvedilol to patients suspected of having pheochromocytoma.
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NDA 20-297/S-013
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Agents with non-selective β-blocking activity may provoke chest pain in patients with
Prinzmetal’s variant angina. There has been no clinical experience with carvedilol in these patients
although the α-blocking activity may prevent such symptoms. However, caution should be taken in the
administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.
In congestive heart failure patients with diabetes, carvedilol therapy may lead to worsening
hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that
blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued.
Risk of Anaphylactic Reaction: While taking β-blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
Nonallergic Bronchospasm (e.g., chronic bronchitis and emphysema): Patients with
bronchospastic disease should, in general, not receive β-blockers. COREG may be used with caution,
however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is
prudent, if COREG is used, to use the smallest effective dose, so that inhibition of endogenous or
exogenous β-agonists is minimized.
In clinical trials of patients with congestive heart failure, patients with bronchospastic disease
were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In
such patients, it is recommended that carvedilol be used with caution. The dosing recommendations
should be followed closely and the dose should be lowered if any evidence of bronchospasm is
observed during up-titration.
Information for Patients: Patients taking COREG should be advised of the following:
• they should not interrupt or discontinue using COREG without a physician’s advice.
• congestive heart failure patients should consult their physician if they experience signs or symptoms
of worsening heart failure such as weight gain or increasing shortness of breath.
• they may experience a drop in blood pressure when standing, resulting in dizziness and, rarely,
fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur.
• if patients experience dizziness or fatigue, they should avoid driving or hazardous tasks.
• they should consult a physician if they experience dizziness or faintness, in case the dosage should
be adjusted.
• they should take COREG with food.
• diabetic patients should report any changes in blood sugar levels to their physician.
• contact lens wearers may experience decreased lacrimation.
Drug Interactions: (Also see CLINICAL PHARMACOLOGY, Pharmacokinetic Drug-Drug
Interactions.)
Inhibitors of CYP2D6; poor metabolizers of debrisoquin: Interactions of carvedilol with
strong inhibitors of CYP2D6 (such as quinidine, fluoxetine, paroxetine, and propafenone) have not
been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of
carvedilol (see CLINICAL PHARMACOLOGY). Retrospective analysis of side effects in clinical
trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably
resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.
Catecholamine-depleting Agents: Patients taking both agents with β-blocking properties
and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should
be observed closely for signs of hypotension and/or severe bradycardia.
Clonidine: Concomitant administration of clonidine with agents with β-blocking properties
may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with
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NDA 20-297/S-013
Page 14
agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should be
discontinued first. Clonidine therapy can then be discontinued several days later by gradually
decreasing the dosage.
Cyclosporine: Modest increases in mean trough cyclosporine concentrations were observed
following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic
vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to
maintain cyclosporine concentrations within the therapeutic range, while in the remainder no
adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20%
in these patients. Due to wide interindividual variability in the dose adjustment required, it is
recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol
therapy and that the dose of cyclosporine be adjusted as appropriate.
Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are
administered concomitantly. Both digoxin and COREG slow AV conduction. Therefore, increased
monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG.
Inducers and Inhibitors of Hepatic Metabolism: Rifampin reduced plasma
concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no
change in Cmax.
Calcium Channel Blockers: Isolated cases of conduction disturbance (rarely with
hemodynamic compromise) have been observed when COREG is co-administered with diltiazem. As
with other agents with β-blocking properties, if COREG is to be administered orally with calcium
channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure
be monitored.
Insulin or Oral Hypoglycemics: Agents with β-blocking properties may enhance the
blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or
oral hypoglycemics, regular monitoring of blood glucose is recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In 2-year studies conducted in rats
given carvedilol at doses up to 75 mg/kg/day (12 times the maximum recommended human dose
[MRHD] when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the
MRHD on a mg/m2 basis), carvedilol had no carcinogenic effect.
Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames
and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo
human lymphocyte cell tests for clastogenicity.
At doses ≥200 mg/kg/day (≥32 times the MRHD as mg/m2) carvedilol was toxic to adult rats
(sedation, reduced weight gain) and was associated with a reduced number of successful matings,
prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete
resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of
fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
Pregnancy: Teratogenic Effects: Pregnancy Category C. Studies performed in pregnant rats and
rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day
(50 times the MRHD as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as
mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of
300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the
frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the
no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as
mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and
well-controlled studies in pregnant women. COREG should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
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Nursing Mothers: It is not known whether this drug is excreted in human milk. Studies in rats have
shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and
are excreted in breast milk. There was increased mortality at 1 week post-partum in neonates from rats
treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through
day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from β-blockers, especially bradycardia, 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. The effects of other α- and β-blocking agents have included perinatal and
neonatal distress.
Pediatric Use: Safety and efficacy in patients younger than 18 years have not been established.
Geriatric Use: Of the 765 patients with congestive heart failure randomized to COREG in US
clinical trials, 31% (235) were 65 years or older, and 7.3% (56) were 75 years or older. Of the
1,156 patients randomized to COREG in a long-term, placebo-controlled trial in severe heart failure,
47% (547) were 65 years or older, and 15% (174) were 75 years or older. Of 3,025 patients receiving
COREG in congestive heart failure trials worldwide, 42% were 65 years or older.
Of the 975 myocardial infarction patients randomized to COREG in the CAPRICORN trial,
48% (468) were 65 years or older, and 11% (111) were 75 years or older.
Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were treated
with COREG, 21% (436) were 65 years or older. Of 3,722 patients receiving COREG in hypertension
clinical trials conducted worldwide, 24% were 65 years or older.
With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly vs. 6%
in younger patients), no overall differences in the safety or effectiveness (See Figures 2 and 4.) were
observed between the older subjects and younger subjects in each of these populations. Similarly, other
reported clinical experience has not identified differences in responses between the elderly and
younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
COREG has been evaluated for safety in patients with congestive heart failure (mild, moderate, and
severe heart failure), in patients with left ventricular dysfunction following myocardial infarction and
in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of
the drug and the health status of the patients in the clinical trials. Adverse events reported for each of
these patient populations are provided below. Excluded are adverse events considered too general to be
informative, and those not reasonably associated with the use of the drug because they were associated
with the condition being treated or are very common in the treated population. Rates of adverse events
were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks
and non-blacks).
Congestive Heart Failure: COREG has been evaluated for safety in congestive heart failure in
more than 4,500 patients worldwide of whom more than 2,100 participated in placebo-controlled
clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials
received COREG for at least 6 months and 30% received COREG for at least 12 months. In the
COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with COREG for up to
5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared
COREG in daily doses up to 100 mg (n = 765) to placebo (n = 437), and in a multinational clinical trial
in severe heart failure (COPERNICUS) that compared COREG in daily doses up to 50 mg (n = 1,156)
with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and
placebo patients. In placebo-controlled clinical trials, the only cause of discontinuation >1%, and
occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the
COPERNICUS trial).
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Page 16
Table 2 shows adverse events reported in patients with mild-to-moderate heart failure enrolled
in US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS
trial. Shown are adverse events that occurred more frequently in drug-treated patients than
placebo-treated patients with an incidence of >3% in patients treated with carvedilol regardless of
causality. Median study medication exposure was 6.3 months for both carvedilol and placebo patients
in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure
patients. The adverse event profile of COREG observed in the long-term COMET study was generally
similar to that observed in the US Heart Failure Trials.
Table 2. Adverse Events (% Occurrence ) Occurring More Frequently with COREG Than With
Placebo in Patients With Mild-to-Moderate Heart Failure Enrolled in US Heart Failure Trials or
in Patients With Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Patients
Treated with Carvedilol, Regardless of Causality)
Mild-to-Moderate HF
Severe Heart Failure
COREG
Placebo
COREG
Placebo
(n = 765)
(n = 437)
(n = 1,156)
(n = 1,133)
Body as a Whole
Asthenia
7
7
11
9
Fatigue
24
22
-
-
Digoxin Level
Increased
5
4
2
1
Edema Generalized
5
3
6
5
Edema Dependent
4
2
-
-
Cardiovascular
Bradycardia
9
1
10
3
Hypotension
9
3
14
8
Syncope
3
3
8
5
Angina Pectoris
2
3
6
4
Central Nervous System
Dizziness
32
19
24
17
Headache
8
7
5
3
Gastrointestinal
Diarrhea
12
6
5
3
Nausea
9
5
4
3
Vomiting
6
4
1
2
Metabolic
Hyperglycemia
12
8
5
3
Weight Increase
10
7
12
11
BUN Increased
6
5
-
-
NPN Increased
6
5
-
-
Hypercholesterolemia
4
3
1
1
Edema Peripheral
2
1
7
6
Musculoskeletal
Arthralgia
6
5
1
1
Respiratory
Cough Increased
8
9
5
4
Rales
4
4
4
2
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Mild-to-Moderate HF
Severe Heart Failure
COREG
Placebo
COREG
Placebo
(n = 765)
(n = 437)
(n = 1,156)
(n = 1,133)
Vision
Vision Abnormal
5
2
-
-
Cardiac failure and dyspnea were also reported in these studies, but the rates were equal or
greater in patients who received placebo.
The following adverse events were reported with a frequency of >1% but ≤3% and more
frequently with COREG in either the US placebo-controlled trials in patients with mild-to-moderate
heart failure, or in patients with severe heart failure in the COPERNICUS trial.
Incidence >1% to ≤3%
Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block,
palpitation, hypertension.
Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.
Gastrointestinal: Melena, periodontitis.
Liver and Biliary System: SGPT increased, SGOT increased.
Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline
phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia,
creatinine increased.
Musculoskeletal: Muscle cramps.
Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocytopenia.
Psychiatric: Somnolence.
Reproductive, male: Impotence.
Special Senses: Blurred vision.
Urinary System: Renal insufficiency, albuminuria, hematuria.
Left Ventricular Dysfunction Following Myocardial Infarction: COREG has been evaluated
for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the
CAPRICORN trial which involved 969 patients who received COREG and 980 who received placebo.
Approximately 75% of the patients received COREG for at least 6 months and 53% received COREG
for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with
COREG and placebo, respectively.
The most common adverse events reported with COREG in the CAPRICORN trial were
consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The
only additional adverse events reported in CAPRICORN in >3% of the patients and more commonly
on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with
a frequency of >1% but ≤3% and more frequently with COREG: Flu syndrome, cerebrovascular
accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis and gout .
The overall rates of discontinuations due to adverse events were similar in both groups of patients. In
this database, the only cause of discontinuation >1%, and occurring more often on carvedilol was
hypotension (1.5% on carvedilol, 0.2% on placebo).
Hypertension: COREG has been evaluated for safety in hypertension in more than 2,193 patients in
US clinical trials and in 2,976 patients in international clinical trials. Approximately 36% of the total
treated population received COREG for at least 6 months. In general, COREG was well tolerated at
doses up to 50 mg daily. Most adverse events reported during COREG therapy were of mild to
moderate severity. In US controlled clinical trials directly comparing COREG monotherapy in doses
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up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of COREG patients discontinued for adverse
events vs. 5.2% of placebo patients. Although there was no overall difference in discontinuation rates,
discontinuations were more common in the carvedilol group for postural hypotension (1% vs. 0). The
overall incidence of adverse events in US placebo-controlled trials was found to increase with
increasing dose of COREG. For individual adverse events this could only be distinguished for
dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to
50 mg.
Table 3 shows adverse events in US placebo-controlled clinical trials for hypertension that
occurred with an incidence of >1% regardless of causality, and that were more frequent in drug-treated
patients than placebo-treated patients.
Table 3. Adverse Events in US Placebo-Controlled Hypertension Trials Incidence >1%,
Regardless of Causality*
Adverse Reactions
COREG
Placebo
(n = 1,142)
(n = 462)
% occurrence
% occurrence
Cardiovascular
Bradycardia
2
—
Postural Hypotension
2
—
Peripheral Edema
1
—
Central Nervous System
Dizziness
6
5
Insomnia
2
1
Gastrointestinal
Diarrhea
2
1
Hematologic
Thrombocytopenia
1
—
Metabolic
Hypertriglyceridemia
1
—
*Shown are events with rate >1% rounded to nearest integer.
Dyspnea and fatigue were also reported in these studies, but the rates were equal or greater in
patients who received placebo.
The following adverse events not described above were reported as possibly or probably related
to COREG in worldwide open or controlled trials with COREG in patients with hypertension or
congestive heart failure.
Incidence >0.1% to ≤1%
Cardiovascular: Peripheral ischemia, tachycardia.
Central and Peripheral Nervous System: Hypokinesia.
Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients
and 0.4% of congestive heart failure patients were discontinued from therapy because of increases in
hepatic enzymes; see Laboratory Abnormalities.
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration,
abnormal thinking, paroniria, emotional lability.
Respiratory System: Asthma (see CONTRAINDICATIONS).
Reproductive: Male: decreased libido.
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Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform,
photosensitivity reaction.
Special Senses: Tinnitus.
Urinary System: Micturition frequency increased.
Autonomic Nervous System: Dry mouth, sweating increased.
Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.
Hematologic: Anemia, leukopenia.
The following events were reported in ≤0.1% of patients and are potentially important:
Complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder,
convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis,
amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis,
increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
Laboratory Abnormalities: Reversible elevations in serum transaminases (ALT or AST) have been
observed during treatment with COREG. Rates of transaminase elevations (2- to 3-times the upper
limit of normal) observed during controlled clinical trials have generally been similar between patients
treated with COREG and those treated with placebo. However, transaminase elevations, confirmed by
rechallenge, have been observed with COREG. In a long-term, placebo-controlled trial in severe heart
failure, patients treated with COREG had lower values for hepatic transaminases than patients treated
with placebo, possibly because COREG-induced improvements in cardiac function led to less hepatic
congestion and/or improved hepatic blood flow.
COREG therapy has not been associated with clinically significant changes in serum
potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or
creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients;
fasting serum glucose was not evaluated in the congestive heart failure clinical trials.
Postmarketing Experience: The following adverse reaction has been reported in
postmarketing experience: Reports of aplastic anemia have been rare and received only when
carvedilol was administered concomitantly with other medications associated with the event.
OVERDOSAGE
The acute oral LD50 doses in male and female mice and male and female rats are over
8000 mg/kg. Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency,
cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of
consciousness, and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept under observation
and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may
be used shortly after ingestion. The following agents may be administered:
for excessive bradycardia: atropine, 2 mg IV.
to support cardiovascular function: glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed
by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at
doses according to body weight and effect.
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or
noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia,
pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics (as aerosol or IV) or
aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or
clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with
antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour
half-life of carvedilol.
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Cases of overdosage with COREG alone or in combination with other drugs have been
reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced
included low blood pressure and heart rate. Standard supportive treatment was provided and
individuals recovered.
DOSAGE AND ADMINISTRATION
Congestive Heart Failure: DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY
MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG, it is
recommended that fluid retention be minimized. The recommended starting dose of COREG is
3.125 mg, twice daily for 2 weeks. Patients who tolerate a dose of 3.125 mg twice daily may have their
dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks.
Patients should be maintained on lower doses if higher doses are not tolerated. A maximum dose of
50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over
85 kg (187 lbs).
Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases
may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within
the first hour after dosing. Thus during these periods they should avoid situations such as driving or
hazardous tasks, where symptoms could result in injury. In addition, COREG should be taken with
food to slow the rate of absorption. Vasodilatory symptoms often do not require treatment, but it may
be useful to separate the time of dosing of COREG from that of the ACE inhibitor or to reduce
temporarily the dose of the ACE inhibitor. The dose of COREG should not be increased until
symptoms of worsening heart failure or vasodilation have been stabilized.
Fluid retention (with or without transient worsening heart failure symptoms) should be treated
by an increase in the dose of diuretics.
The dose of COREG should be reduced if patients experience bradycardia (heart rate
<55 beats/minute).
Episodes of dizziness or fluid retention during initiation of COREG can generally be managed
without discontinuation of treatment and do not preclude subsequent successful titration of, or a
favorable response to, carvedilol.
Left Ventricular Dysfunction Following Myocardial Infarction: DOSAGE MUST BE
INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with COREG may
be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable
and fluid retention has been minimized. It is recommended that COREG be started at 6.25 mg twice
daily and increased after 3 to 10 days, based on tolerability to 12.5 mg twice daily, then again to the
target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or, the
rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate,
or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The
recommended dosing regimen need not be altered in patients who received treatment with an IV or oral
β-blocker during the acute phase of the myocardial infarction.
Hypertension: DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of
COREG is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured
about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased
to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic
pressure 1 hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to
14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full
antihypertensive effect of COREG is seen within 7 to 14 days. Total daily dose should not exceed
50 mg. COREG should be taken with food to slow the rate of absorption and reduce the incidence of
orthostatic effects.
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Addition of a diuretic to COREG, or COREG to a diuretic can be expected to produce additive
effects and exaggerate the orthostatic component of COREG action.
Use in Patients With Hepatic Impairment: COREG should not be given to patients with severe
hepatic impairment (see CONTRAINDICATIONS).
HOW SUPPLIED
Tablets: White, oval, film-coated tablets: 3.125 mg–engraved with 39 and SB, in bottles of 100;
6.25 mg–engraved with 4140 and SB, in bottles of 100; 12.5 mg–engraved with 4141 and SB, in
bottles of 100; 25 mg–engraved with 4142 and SB, in bottles of 100. The 6.25 mg, 12.5 mg, and 25 mg
tablets are TILTAB tablets.
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.
3.125 mg 100’s: NDC 0007-4139-20
6.25 mg 100’s: NDC 0007-4140-20
12.5 mg 100’s: NDC 0007-4141-20
25 mg 100’s: NDC 0007-4142-20
COREG and TILTAB are registered trademarks of GlaxoSmithKline.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2005, GlaxoSmithKline. All rights reserved.
February, 2005
CO:LX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:47:23.765876
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020297s013lbl.pdf', 'application_number': 20297, 'submission_type': 'SUPPL ', 'submission_number': 13}
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NDA 20-297/S-018
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CO:LXX
PRESCRIBING INFORMATION
COREG®
(carvedilol)
Tablets
DESCRIPTION
Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is (±)-1-
(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. It is a racemic mixture with
the following structure:
Carvedilol
Tablets for Oral Administration: COREG (carvedilol) is a white, oval, film-coated tablet containing
3.125 mg, 6.25 mg, 12.5 mg, or 25 mg of carvedilol. The 6.25 mg, 12.5 mg, and 25 mg tablets are
TILTAB® tablets. Inactive ingredients consist of colloidal silicon dioxide, crospovidone,
hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sucrose,
and titanium dioxide.
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular
formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and
methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and
practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS
without pancreatin, pH 7.5).
CLINICAL PHARMACOLOGY
COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is
present in the S(-) enantiomer and α-adrenergic blocking activity is present in both R(+) and S(-)
enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.
Pharmacokinetics: COREG is rapidly and extensively absorbed following oral administration, with
absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass
metabolism. Following oral administration, the apparent mean terminal elimination half-life of
carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the
oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by
a delay in the time to reach peak plasma levels, with no significant difference in extent of
bioavailability. Taking COREG with food should minimize the risk of orthostatic hypotension.
Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol
to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as
measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the
urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The
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NDA 20-297/S-018
Page 4
oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The
metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and
hydroxylation at the phenol ring produce three active metabolites with β-receptor blocking activity.
Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent
than carvedilol for β-blockade.
Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. Plasma
concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have
pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of
R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in
healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to
9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in
human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and
2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a
potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation
pathway of S(-)-carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of
debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations
of R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are
increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a
lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not
appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450
2C19).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The
plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a
basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L,
indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to
700 mL/min.
Congestive Heart Failure: Steady-state plasma concentrations of carvedilol and its
enantiomers increased proportionally over the 6.25 to 50 mg dose range in patients with congestive
heart failure. Compared to healthy subjects, congestive heart failure patients had increased mean AUC
and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in
6 patients with NYHA class IV heart failure. The mean apparent terminal elimination half-life for
carvedilol was similar to that observed in healthy subjects.
Pharmacokinetic Drug-Drug Interactions: Since carvedilol undergoes substantial
oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by
induction or inhibition of cytochrome P450 enzymes.
Rifampin: In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin
(600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70%.
Cimetidine: In a pharmacokinetic study conducted in 10 healthy male subjects,
cimetidine (1000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change in
Cmax.
Glyburide: In 12 healthy subjects, combined administration of carvedilol (25 mg once
daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction
for either compound.
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Page 5
Hydrochlorothiazide: A single oral dose of carvedilol 25 mg did not alter the
pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 patients with hypertension.
Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.
Digoxin: Following concomitant administration of carvedilol (25 mg once daily) and
digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were
increased by 14% and 16%, respectively, in 12 hypertensive patients.
Torsemide: In a study of 12 healthy subjects, combined oral administration of
carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant
differences in their pharmacokinetics compared with administration of the drugs alone.
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state
prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following
concomitant administration with warfarin in 9 healthy volunteers.
Special Populations: Elderly: Plasma levels of carvedilol average about 50% higher in the elderly
compared to young subjects.
Hepatic Impairment: Compared to healthy subjects, patients with cirrhotic liver disease
exhibit significantly higher concentrations of carvedilol (approximately 4- to 7-fold) following
single-dose therapy.
Renal Insufficiency: Although carvedilol is metabolized primarily by the liver, plasma
concentrations of carvedilol have been reported to be increased in patients with renal impairment.
Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were
observed in hypertensive patients with moderate to severe renal impairment compared to a control
group of hypertensive patients with normal renal function. However, the ranges of AUC values were
similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately
12% to 26% higher in patients with impaired renal function.
Consistent with its high degree of plasma protein-binding, carvedilol does not appear to be
cleared significantly by hemodialysis.
Pharmacodynamics: Congestive Heart Failure: The basis for the beneficial effects of COREG
in congestive heart failure is not established.
Two placebo-controlled studies compared the acute hemodynamic effects of COREG to
baseline measurements in 59 and 49 patients with NYHA class II-IV heart failure receiving diuretics,
ACE inhibitors, and digitalis. There were significant reductions in systemic blood pressure, pulmonary
artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output,
stroke volume index, and systemic vascular resistance were small and variable.
These studies measured hemodynamic effects again at 12 to 14 weeks. COREG significantly
reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular
resistance, and heart rate, while stroke volume index was increased.
Among 839 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 US
placebo-controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide
ventriculography increased by 9 EF units (%) in COREG patients and by 2 EF units in placebo patients
at a target dose of 25-50 mg twice daily. The effects of carvedilol on ejection fraction were related to
dose. Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily were associated with
placebo-corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these
effects were nominally statistically significant.
Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the
beneficial effects of COREG in patients with left ventricular dysfunction following an acute
myocardial infarction is not established.
Hypertension: The mechanism by which β-blockade produces an antihypertensive effect has
not been established.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-297/S-018
Page 6
β-adrenoreceptor blocking activity has been demonstrated in animal and human studies
showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or
isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant
β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies,
showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and
(3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure
and usually are seen within 30 minutes of drug administration.
Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the
standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare
instances of syncope, can occur. Following oral administration, when postural hypotension has
occurred, it has been transient and is uncommon when COREG is administered with food at the
recommended starting dose and titration increments are closely followed (see DOSAGE AND
ADMINISTRATION).
In hypertensive patients with normal renal function, therapeutic doses of COREG decreased
renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in
excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal
function were similar after COREG and placebo.
COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels,
but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases
levels of atrial natriuretic peptide.
CLINICAL TRIALS
Congestive Heart Failure: A total of 6,975 patients with mild to severe heart failure were evaluated
in placebo-controlled studies of carvedilol.
Trials in Mild-to-Moderate Heart Failure: Carvedilol was studied in 5 multicenter,
placebo-controlled studies, and in 1 active-controlled study (COMET study) involving patients with
mild-to-moderate heart failure.
Four US multicenter, double-blind, placebo-controlled studies enrolled 1,094 patients
(696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction ≤0.35. The
vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were assigned
to the studies based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled
study enrolled 415 patients (half randomized to carvedilol) with less severe heart failure. All protocols
excluded patients expected to undergo cardiac transplantation during the 7.5 to 15 months of
double-blind follow-up. All randomized patients had tolerated a 2-week course on carvedilol 6.25 mg
twice daily.
In each study, there was a primary end point, either progression of heart failure (1 US study) or
exercise tolerance (2 US studies meeting enrollment goals and the Australia-New Zealand study).
There were many secondary end points specified in these studies, including NYHA classification,
patient and physician global assessments, and cardiovascular hospitalization. Other analyses not
prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In
situations where the primary end points of a trial do not show a significant benefit of treatment,
assignment of significance values to the other results is complex, and such values need to be
interpreted cautiously.
The results of the US and Australia-New Zealand trials were as follows:
Slowing Progression of Heart Failure: One US multicenter study (366 subjects) had as its
primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained
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Page 7
increase in heart failure medications. Heart failure progression was reduced, during an average
follow-up of 7 months, by 48% (p = 0.008).
In the Australia-New Zealand study, death and total hospitalizations were reduced by about
25% over 18 to 24 months. In the 3 largest US studies, death and total hospitalizations were reduced by
19%, 39%, and 49%, nominally statistically significant in the last 2 studies. The Australia-New
Zealand results were statistically borderline.
Functional Measures: None of the multicenter studies had NYHA classification as a primary
end point, but all such studies had it as a secondary end point. There was at least a trend toward
improvement in NYHA class in all studies. Exercise tolerance was the primary end point in 3 studies;
in none was a statistically significant effect found.
Subjective Measures: Quality of life, as measured with a standard questionnaire (a primary end
point in 1 study), was unaffected by carvedilol. However, patients’ and investigators’ global
assessments showed significant improvement in most studies.
Mortality: Death was not a pre-specified end-point in any study, but was analyzed in all
studies. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 studies.
The COMET Trial: In this double-blind trial, 3,029 patients with NYHA class II-IV heart failure (left
ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg
twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of
the patients was approximately 62 years, 80% were males, and the mean left ventricular ejection
fraction at baseline was 26%. Approximately 96% of the patients had NYHA class II or III heart
failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%),
aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-
up was 4.8 years. The mean dose of carvedilol was 42 mg per day.
The study had 2 primary endpoints: all-cause mortality and the composite of death plus
hospitalization for any reason. All-cause mortality carried most of the statistical weight and was the
primary determinant of the study size. All-cause mortality was 34% in the patients treated with
carvedilol and was 40% in the immediate-release metoprolol group (p=0.0017; hazard ratio=0.83,
95%CI 0.74-0.93). The difference between the 2 groups with respect to the composite endpoint was
not significant (p=0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years
with immediate-release metoprolol.
It is not known whether this formulation of metoprolol at any dose or this low dose of
metoprolol in any formulation has any effect on survival or hospitalization in patients with heart
failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart
failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol
(Toprol XL) with benefits in heart failure.
Trials in Severe Heart Failure: In a double-blind study (COPERNICUS), 2,289 patients with heart
failure at rest or with minimal exertion and left ventricular ejection fraction <25% (mean 20%), despite
digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol.
Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or
up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg.
The study was conducted in Eastern and Western Europe, the United States, Israel, and Canada.
Similar numbers of subjects per group (about 100) withdrew during the titration period.
The primary end point of the trial was all-cause mortality, but cause-specific mortality and the
risk of death or hospitalization (total, cardiovascular [CV], or congestive heart failure [CHF]) were
also examined. The developing trial data were followed by a data monitoring committee, and mortality
analyses were adjusted for these multiple looks. The trial was stopped after a median follow-up of
10 months because of an observed 35% reduction in mortality (from 19.7% per patient year on placebo
to 12.8% on carvedilol, hazard ratio 0.65, 95% CI 0.52 – 0.81, p = 0.0014, adjusted) (see Figure 1).
The results of COPERNICUS are shown in Table 1.
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Table 1. Results of COPERNICUS
End point
Placebo
N = 1,133
Carvedilol
N = 1,156
Hazard ratio
(95% CI)
%
Reduction
Nominal p
value
Mortality
190
130
0.65
(0.52 – 0.81)
35
0.00013
Mortality + all
hospitalization
507
425
0.76
(0.67 – 0.87)
24
0.00004
Mortality + CV
hospitalization
395
314
0.73
(0.63 – 0.84)
27
0.00002
Mortality + CHF
hospitalization
357
271
0.69
(0.59 – 0.81)
31
0.000004
Figure 1. Survival Analysis for COPERNICUS (intent-to-treat)
p = 0.0014
% Survival
Carvedilol
Placebo
0
3
6
9
12
15
18
21
Months
100
90
80
60
70
0
The effect on mortality was principally the result of a reduction in the rate of sudden death
among patients without worsening heart failure.
Patients' global assessments, in which carvedilol-treated patients were compared to placebo,
were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-
treatment showed improvement, worsening or no change compared to baseline. Patients treated with
carvedilol showed significant improvements in global assessments compared with those treated with
placebo in COPERNICUS.
The protocol also specified that hospitalizations would be assessed. Fewer patients on COREG
than on placebo were hospitalized for any reason (372 vs. 432, p = 0.0029), for cardiovascular reasons
(246 vs. 314, p = 0.0003), or for worsening heart failure (198 vs. 268, p = 0.0001).
COREG had a consistent and beneficial effect on all-cause mortality as well as the combined
end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall study
population and in all subgroups examined, including men and women, elderly and non-elderly, blacks
and non-blacks, and diabetics and non-diabetics (see Figure 2).
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Figure 2. Effects on Mortality for Subgroups in COPERNICUS
Left Ventricular Dysfunction Following Myocardial Infarction: CAPRICORN was a
double-blind study comparing carvedilol and placebo in 1,959 patients with a recent myocardial
infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without
symptoms of heart failure. Patients given carvedilol received 6.25 mg twice daily, titrated as tolerated
to 25 mg twice daily. Patients had to have a systolic blood pressure >90 mm Hg, a sitting heart rate
>60 beats/minute, and no contraindication to β-blocker use. Treatment of the index infarction included
aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and
acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor
blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline
population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood
pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage
achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a
23% risk reduction in patients treated with carvedilol (95% CI 2-40%, p = 0.03), as shown in Figure 3.
The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were
cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or
related to pump failure (both types of death were reduced by carvedilol). Another study endpoint, total
mortality and all-cause hospitalization, did not show a significant improvement.
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed
in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar reduction in the risk of
myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in
heart failure.
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Figure 3. Survival Analysis for CAPRICORN (intent-to-treat)
Figure 4. Effects on Mortality for Subgroups in CAPRICORN
Hypertension: COREG was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at
total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed 12.5 mg.
At 50 mg/day, COREG reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at
25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed
a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about
7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers, responses were smaller in
black than non-black patients. There were no age- or gender-related differences in response.
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related blood
pressure response was accompanied by a dose-related increase in adverse effects (see ADVERSE
REACTIONS).
Hypertensive Patients with Type 2 Diabetes Mellitus (GEMINI): In a double-blind study,
COREG, added to an ACE inhibitor or angiotensin receptor blocker, was evaluated in a population
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with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at
baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5
months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean
change from baseline of 0.02%, 95% CI -0.06 to 0.10, p = NS) (see PRECAUTIONS, Effects on
Glycemic Control in Type 2 Diabetic Patients).
INDICATIONS AND USAGE
Congestive Heart Failure: COREG is indicated for the treatment of mild-to-severe heart failure of
ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitor, and digitalis, to
increase survival and, also, to reduce the risk of hospitalization (see CLINICAL TRIALS).
Left Ventricular Dysfunction Following Myocardial Infarction: COREG is indicated to
reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a
myocardial infarction and have a left ventricular ejection fraction of ≤40% (with or without
symptomatic heart failure) (see CLINICAL TRIALS).
Hypertension: COREG is also indicated for the management of essential hypertension. It can be
used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics (see
PRECAUTIONS, Drug Interactions).
CONTRAINDICATIONS
COREG is contraindicated in patients with bronchial asthma (2 cases of death from status
asthmaticus have been reported in patients receiving single doses of COREG) or related
bronchospastic conditions, second- or third-degree AV block, sick sinus syndrome or severe
bradycardia (unless a permanent pacemaker is in place), or in patients with cardiogenic shock or who
have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients
should first be weaned from intravenous therapy before initiating COREG.
Use of COREG in patients with clinically manifest hepatic impairment is not recommended.
COREG is contraindicated in patients with hypersensitivity to any component of the product.
WARNINGS
Cessation of Therapy with COREG: Patients with coronary artery disease, who are being
treated with COREG, should be advised against abrupt discontinuation of therapy. Severe
exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias
have been reported in angina patients following the abrupt discontinuation of therapy with
β-blockers. The last 2 complications may occur with or without preceding exacerbation of the
angina pectoris. As with other β-blockers, when discontinuation of COREG is planned, the
patients should be carefully observed and advised to limit physical activity to a minimum.
COREG should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or
acute coronary insufficiency develops, it is recommended that COREG be promptly reinstituted,
at least temporarily. Because coronary artery disease is common and may be unrecognized, it
may be prudent not to discontinue COREG therapy abruptly even in patients treated only for
hypertension or heart failure (See DOSAGE AND ADMINISTRATION.)
Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial
insufficiency in patients with peripheral vascular disease. Caution should be exercised in such
individuals.
Anesthesia and Major Surgery: If treatment with COREG is to be continued perioperatively,
particular care should be taken when anesthetic agents which depress myocardial function, such as
ether, cyclopropane, and trichloroethylene, are used. See OVERDOSAGE for information on treatment
of bradycardia and hypertension.
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Diabetes and Hypoglycemia: In general, β-blockers may mask some of the manifestations of
hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced
hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous
hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned
about these possibilities. In congestive heart failure patients, there is a risk of worsening
hyperglycemia (see PRECAUTIONS, Effects on Glycemic Control in Type 2 Diabetic Patients).
Thyrotoxicosis: β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as
tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of
hyperthyroidism or may precipitate thyroid storm.
PRECAUTIONS
General: In clinical trials, COREG caused bradycardia in about 2% of hypertensive patients, 9% of
congestive heart failure patients, and 6.5% of myocardial infarction patients with left ventricular
dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural
hypotension occurred in 9.7% and syncope in 3.4% of patients receiving COREG compared to 3.6%
and 2.5% of placebo patients, respectively. The risk for these events was highest during the first
30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of
therapy in 0.7% of COREG patients, compared to 0.4% of placebo patients. In a long-term,
placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension
occurred in 15.1% and syncope in 2.9% of heart failure patients receiving COREG compared to 8.7%
and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in
1.1% of COREG patients, compared to 0.8% of placebo patients.
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily
following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy
in 1% of patients.
In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or
postural hypotension occurred in 20.2% of patients receiving COREG compared to 12.6% of placebo
patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause
for discontinuation of therapy in 2.5% of patients receiving COREG, compared to 0.2% of placebo
patients.
To decrease the likelihood of syncope or excessive hypotension, treatment should be initiated
with 3.125 mg twice daily for congestive heart failure patients, and at 6.25 mg twice daily for
hypertensive patients and survivors of an acute myocardial infarction with left ventricular dysfunction.
Dosage should then be increased slowly, according to recommendations in the DOSAGE AND
ADMINISTRATION section, and the drug should be taken with food. During initiation of therapy, the
patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could
result should syncope occur.
Rarely, use of carvedilol in patients with congestive heart failure has resulted in deterioration of
renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure
<100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal
insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with
these risk factors it is recommended that renal function be monitored during up-titration of carvedilol
and the drug discontinued or dosage reduced if worsening of renal function occurs.
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such
symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until
clinical stability resumes (see DOSAGE AND ADMINISTRATION). Occasionally it is necessary to
lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent
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successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of patients
with severe heart failure, worsening heart failure during the first 3 months was reported to a similar
degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening
heart failure was reported less frequently in patients treated with carvedilol than with placebo.
Worsening heart failure observed during long-term therapy is more likely to be related to the patients’
underlying disease than to treatment with carvedilol.
In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of
any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there
has been no experience with its use in this condition. Therefore, caution should be taken in the
administration of carvedilol to patients suspected of having pheochromocytoma.
Agents with non-selective β-blocking activity may provoke chest pain in patients with
Prinzmetal’s variant angina. There has been no clinical experience with carvedilol in these patients
although the α-blocking activity may prevent such symptoms. However, caution should be taken in the
administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.
Effects on Glycemic Control in Type 2 Diabetic Patients: In congestive heart failure patients
with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to
intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when
carvedilol dosing is initiated, adjusted, or discontinued. Studies designed to examine the effects of
carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a study designed to examine the effects of carvedilol on glycemic control in a population with
mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse
effect on glycemic control, based on HbA1c measurements (see CLINICAL TRIALS, Hypertensive
Patients with Type 2 Diabetes Mellitus (GEMINI)).
Risk of Anaphylactic Reaction: While taking β-blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
Nonallergic Bronchospasm (e.g., chronic bronchitis and emphysema): Patients with
bronchospastic disease should, in general, not receive β-blockers. COREG may be used with caution,
however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is
prudent, if COREG is used, to use the smallest effective dose, so that inhibition of endogenous or
exogenous β-agonists is minimized.
In clinical trials of patients with congestive heart failure, patients with bronchospastic disease
were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In
such patients, it is recommended that carvedilol be used with caution. The dosing recommendations
should be followed closely and the dose should be lowered if any evidence of bronchospasm is
observed during up-titration.
Information for Patients: Patients taking COREG should be advised of the following:
• they should not interrupt or discontinue using COREG without a physician’s advice.
• congestive heart failure patients should consult their physician if they experience signs or symptoms
of worsening heart failure such as weight gain or increasing shortness of breath.
• they may experience a drop in blood pressure when standing, resulting in dizziness and, rarely,
fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur.
• if patients experience dizziness or fatigue, they should avoid driving or hazardous tasks.
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• they should consult a physician if they experience dizziness or faintness, in case the dosage should
be adjusted.
• they should take COREG with food.
• diabetic patients should report any changes in blood sugar levels to their physician.
• contact lens wearers may experience decreased lacrimation.
Drug Interactions: (Also see CLINICAL PHARMACOLOGY, Pharmacokinetic Drug-Drug
Interactions.)
Inhibitors of CYP2D6; poor metabolizers of debrisoquin: Interactions of carvedilol with
strong inhibitors of CYP2D6 (such as quinidine, fluoxetine, paroxetine, and propafenone) have not
been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of
carvedilol (see CLINICAL PHARMACOLOGY). Retrospective analysis of side effects in clinical
trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably
resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.
Catecholamine-depleting agents: Patients taking both agents with β-blocking properties
and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should
be observed closely for signs of hypotension and/or severe bradycardia.
Clonidine: Concomitant administration of clonidine with agents with β-blocking properties
may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with
agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should be
discontinued first. Clonidine therapy can then be discontinued several days later by gradually
decreasing the dosage.
Cyclosporine: Modest increases in mean trough cyclosporine concentrations were observed
following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic
vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to
maintain cyclosporine concentrations within the therapeutic range, while in the remainder no
adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20%
in these patients. Due to wide interindividual variability in the dose adjustment required, it is
recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol
therapy and that the dose of cyclosporine be adjusted as appropriate.
Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are
administered concomitantly. Both digoxin and COREG slow AV conduction. Therefore, increased
monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG.
Inducers and inhibitors of hepatic metabolism: Rifampin reduced plasma
concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no
change in Cmax.
Calcium channel blockers: Isolated cases of conduction disturbance (rarely with
hemodynamic compromise) have been observed when COREG is co-administered with diltiazem. As
with other agents with β-blocking properties, if COREG is to be administered orally with calcium
channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure
be monitored.
Insulin or oral hypoglycemics: Agents with β-blocking properties may enhance the
blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or
oral hypoglycemics, regular monitoring of blood glucose is recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In 2-year studies conducted in rats
given carvedilol at doses up to 75 mg/kg/day (12 times the maximum recommended human dose
[MRHD] when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the
MRHD on a mg/m2 basis), carvedilol had no carcinogenic effect.
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Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames
and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo
human lymphocyte cell tests for clastogenicity.
At doses ≥200 mg/kg/day (≥32 times the MRHD as mg/m2) carvedilol was toxic to adult rats
(sedation, reduced weight gain) and was associated with a reduced number of successful matings,
prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete
resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of
fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
Pregnancy: Teratogenic Effects: Pregnancy Category C. Studies performed in pregnant rats
and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of
300 mg/kg/day (50 times the MRHD as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the
MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic
dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the
frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the
no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as
mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and
well-controlled studies in pregnant women. COREG should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Studies in rats have
shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and
are excreted in breast milk. There was increased mortality at one week post-partum in neonates from
rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester
through day 22 of lactation. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, 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. The effects of other α- and β-blocking agents have included
perinatal and neonatal distress.
Pediatric Use: Safety and efficacy in patients younger than 18 years of age have not been
established.
Geriatric Use: Of the 765 patients with congestive heart failure randomized to COREG in US
clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older.
Of the 1,156 patients randomized to COREG in a long-term, placebo-controlled trial in severe heart
failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of
3,025 patients receiving COREG in congestive heart failure trials worldwide, 42% were 65 years of
age or older.
Of the 975 myocardial infarction patients randomized to COREG in the CAPRICORN trial,
48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.
Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were treated
with COREG, 21% (436) were 65 years of age or older. Of 3,722 patients receiving COREG in
hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.
With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly vs. 6%
in younger patients), no overall differences in the safety or effectiveness (See Figures 2 and 4.) were
observed between the older subjects and younger subjects in each of these populations. Similarly, other
reported clinical experience has not identified differences in responses between the elderly and
younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
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ADVERSE REACTIONS
COREG has been evaluated for safety in patients with congestive heart failure (mild,
moderate, and severe heart failure), in patients with left ventricular dysfunction following
myocardial infarction and in hypertensive patients. The observed adverse event profile was
consistent with the pharmacology of the drug and the health status of the patients in the
clinical trials. Adverse events reported for each of these patient populations are provided
below. Excluded are adverse events considered too general to be informative, and those not reasonably
associated with the use of the drug because they were associated with the condition being treated or are
very common in the treated population. Rates of adverse events were generally similar across
demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks).
Congestive Heart Failure: COREG has been evaluated for safety in congestive heart failure in
more than 4,500 patients worldwide of whom more than 2,100 participated in placebo-controlled
clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials
received COREG for at least 6 months and 30% received COREG for at least 12 months. In the
COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with COREG for up to
5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared
COREG in daily doses up to 100 mg (n = 765) to placebo (n = 437), and in a multinational clinical trial
in severe heart failure (COPERNICUS) that compared COREG in daily doses up to 50 mg (n = 1,156)
with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and
placebo patients. In placebo-controlled clinical trials, the only cause of discontinuation >1%, and
occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the
COPERNICUS trial).
Table 2 shows adverse events reported in patients with mild-to-moderate heart failure enrolled
in US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS
trial. Shown are adverse events that occurred more frequently in drug-treated patients than
placebo-treated patients with an incidence of >3% in patients treated with carvedilol regardless of
causality. Median study medication exposure was 6.3 months for both carvedilol and placebo patients
in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure
patients. The adverse event profile of COREG observed in the long-term COMET study was generally
similar to that observed in the US Heart Failure Trials.
Table 2. Adverse Events (% Occurrence ) Occurring More Frequently with COREG Than With
Placebo in Patients With Mild-to-Moderate Heart Failure Enrolled in US Heart Failure Trials or
in Patients With Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Patients
Treated with Carvedilol, Regardless of Causality)
Mild-to-Moderate HF
Severe Heart Failure
COREG
Placebo
COREG
Placebo
(n = 765)
(n = 437)
(n = 1,156)
(n = 1,133)
Body as a Whole
Asthenia
7
7
11
9
Fatigue
24
22
-
-
Digoxin level increased
5
4
2
1
Edema generalized
5
3
6
5
Edema dependent
4
2
-
-
Cardiovascular
Bradycardia
9
1
10
3
Hypotension
9
3
14
8
Syncope
3
3
8
5
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Mild-to-Moderate HF
Severe Heart Failure
COREG
Placebo
COREG
Placebo
(n = 765)
(n = 437)
(n = 1,156)
(n = 1,133)
Angina Pectoris
2
3
6
4
Central Nervous System
Dizziness
32
19
24
17
Headache
8
7
5
3
Gastrointestinal
Diarrhea
12
6
5
3
Nausea
9
5
4
3
Vomiting
6
4
1
2
Metabolic
Hyperglycemia
12
8
5
3
Weight increase
10
7
12
11
BUN increased
6
5
-
-
NPN increased
6
5
-
-
Hypercholesterolemia
4
3
1
1
Edema peripheral
2
1
7
6
Musculoskeletal
Arthralgia
6
5
1
1
Respiratory
Cough Increased
8
9
5
4
Rales
4
4
4
2
Vision
Vision abnormal
5
2
-
-
Cardiac failure and dyspnea were also reported in these studies, but the rates were equal or
greater in patients who received placebo.
The following adverse events were reported with a frequency of >1% but ≤3% and more
frequently with COREG in either the US placebo-controlled trials in patients with mild-to-moderate
heart failure, or in patients with severe heart failure in the COPERNICUS trial.
Incidence >1% to ≤3%
Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block,
palpitation, hypertension.
Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.
Gastrointestinal: Melena, periodontitis.
Liver and Biliary System: SGPT increased, SGOT increased.
Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline
phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia,
creatinine increased.
Musculoskeletal: Muscle cramps.
Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocytopenia.
Psychiatric: Somnolence.
Reproductive, male: Impotence.
Special Senses: Blurred vision.
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Urinary System: Renal insufficiency, albuminuria, hematuria.
Left Ventricular Dysfunction Following Myocardial Infarction: COREG has been evaluated
for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the
CAPRICORN trial which involved 969 patients who received COREG and 980 who received placebo.
Approximately 75% of the patients received COREG for at least 6 months and 53% received COREG
for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with
COREG and placebo, respectively.
The most common adverse events reported with COREG in the CAPRICORN trial were
consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The
only additional adverse events reported in CAPRICORN in >3% of the patients and more commonly
on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with
a frequency of >1% but ≤3% and more frequently with COREG: flu syndrome, cerebrovascular
accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis and gout.
The overall rates of discontinuations due to adverse events were similar in both groups of patients. In
this database, the only cause of discontinuation >1%, and occurring more often on carvedilol was
hypotension (1.5% on carvedilol, 0.2% on placebo).
Hypertension: COREG has been evaluated for safety in hypertension in more than 2,193 patients in
US clinical trials and in 2,976 patients in international clinical trials. Approximately 36% of the total
treated population received COREG for at least 6 months. In general, COREG was well tolerated at
doses up to 50 mg daily. Most adverse events reported during COREG therapy were of mild to
moderate severity. In US controlled clinical trials directly comparing COREG monotherapy in doses
up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of COREG patients discontinued for adverse
events vs. 5.2% of placebo patients. Although there was no overall difference in discontinuation rates,
discontinuations were more common in the carvedilol group for postural hypotension (1% vs. 0). The
overall incidence of adverse events in US placebo-controlled trials was found to increase with
increasing dose of COREG. For individual adverse events this could only be distinguished for
dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to
50 mg.
Table 3 shows adverse events in US placebo-controlled clinical trials for hypertension that
occurred with an incidence of >1% regardless of causality, and that were more frequent in drug-treated
patients than placebo-treated patients.
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Table 3. Adverse Events in US Placebo-Controlled Hypertension Trials Incidence ≥1%,
Regardless of Causality*
Adverse Reactions
COREG
Placebo
(n = 1,142)
(n = 462)
% occurrence
% occurrence
Cardiovascular
Bradycardia
2
—
Postural hypotension
2
—
Peripheral Edema
1
—
Central Nervous System
Dizziness
6
5
Insomnia
2
1
Gastrointestinal
Diarrhea
2
1
Hematologic
Thrombocytopenia
1
—
Metabolic
Hypertriglyceridemia
1
—
*Shown are events with rate >1% rounded to nearest integer.
Dyspnea and fatigue were also reported in these studies, but the rates were equal or greater in
patients who received placebo.
The following adverse events not described above were reported as possibly or probably related to
COREG in worldwide open or controlled trials with COREG in patients with hypertension or
congestive heart failure.
Incidence >0.1% to ≤1%
Cardiovascular: Peripheral ischemia, tachycardia.
Central and Peripheral Nervous System: Hypokinesia.
Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients
and 0.4% of congestive heart failure patients were discontinued from therapy because of increases in
hepatic enzymes; see Laboratory Abnormalities.
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration,
abnormal thinking, paroniria, emotional lability.
Respiratory System: Asthma (see CONTRAINDICATIONS).
Reproductive: Male: decreased libido.
Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform,
photosensitivity reaction.
Special Senses: Tinnitus.
Urinary System: Micturition frequency increased.
Autonomic Nervous System: Dry mouth, sweating increased.
Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.
Hematologic: Anemia, leukopenia.
The following events were reported in ≤0.1% of patients and are potentially important:
complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions,
migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI
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hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased
BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
Laboratory Abnormalities: Reversible elevations in serum transaminases (ALT or AST) have been
observed during treatment with COREG. Rates of transaminase elevations (2- to 3-times the upper
limit of normal) observed during controlled clinical trials have generally been similar between patients
treated with COREG and those treated with placebo. However, transaminase elevations, confirmed by
rechallenge, have been observed with COREG. In a long-term, placebo-controlled trial in severe heart
failure, patients treated with COREG had lower values for hepatic transaminases than patients treated
with placebo, possibly because COREG-induced improvements in cardiac function led to less hepatic
congestion and/or improved hepatic blood flow.
COREG therapy has not been associated with clinically significant changes in serum
potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or
creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients;
fasting serum glucose was not evaluated in the congestive heart failure clinical trials.
Postmarketing Experience: Reports of aplastic anemia and severe skin reactions (Stevens-
Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been rare and received
only when carvedilol was administered concomitantly with other medications associated with such
reactions. Urinary incontinence in women (which resolved upon discontinuation of the medication)
and interstitial pneumonitis have been reported rarely.
OVERDOSAGE
The acute oral LD50 doses in male and female mice and male and female rats are over
8000 mg/kg. Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency,
cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of
consciousness, and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept under observation
and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may
be used shortly after ingestion. The following agents may be administered:
for excessive bradycardia: atropine, 2 mg IV.
to support cardiovascular function: glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed
by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at
doses according to body weight and effect.
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or
noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia,
pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics (as aerosol or IV) or
aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or
clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with
antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour
half-life of carvedilol.
Cases of overdosage with COREG alone or in combination with other drugs have been
reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced
included low blood pressure and heart rate. Standard supportive treatment was provided and
individuals recovered.
DOSAGE AND ADMINISTRATION
Congestive Heart Failure: DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY
MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG, it is
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recommended that fluid retention be minimized. The recommended starting dose of COREG is
3.125 mg, twice daily for 2 weeks. Patients who tolerate a dose of 3.125 mg twice daily may have their
dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks.
Patients should be maintained on lower doses if higher doses are not tolerated. A maximum dose of
50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over
85 kg (187 lbs).
Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases
may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within
the first hour after dosing. Thus during these periods they should avoid situations such as driving or
hazardous tasks, where symptoms could result in injury. In addition, COREG should be taken with
food to slow the rate of absorption. Vasodilatory symptoms often do not require treatment, but it may
be useful to separate the time of dosing of COREG from that of the ACE inhibitor or to reduce
temporarily the dose of the ACE inhibitor. The dose of COREG should not be increased until
symptoms of worsening heart failure or vasodilation have been stabilized.
Fluid retention (with or without transient worsening heart failure symptoms) should be treated
by an increase in the dose of diuretics.
The dose of COREG should be reduced if patients experience bradycardia (heart rate
<55 beats/minute).
Episodes of dizziness or fluid retention during initiation of COREG can generally be managed
without discontinuation of treatment and do not preclude subsequent successful titration of, or a
favorable response to, carvedilol.
Left Ventricular Dysfunction Following Myocardial Infarction: DOSAGE MUST BE
INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with COREG may
be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable
and fluid retention has been minimized. It is recommended that COREG be started at 6.25 mg twice
daily and increased after 3 to 10 days, based on tolerability to 12.5 mg twice daily, then again to the
target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or, the
rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate,
or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The
recommended dosing regimen need not be altered in patients who received treatment with an IV or oral
β-blocker during the acute phase of the myocardial infarction.
Hypertension: DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of
COREG is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured
about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased
to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic
pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to
14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full
antihypertensive effect of COREG is seen within 7 to 14 days. Total daily dose should not exceed
50 mg. COREG should be taken with food to slow the rate of absorption and reduce the incidence of
orthostatic effects.
Addition of a diuretic to COREG, or COREG to a diuretic can be expected to produce additive
effects and exaggerate the orthostatic component of COREG action.
Use in Patients with Hepatic Impairment: COREG should not be given to patients with severe
hepatic impairment (see CONTRAINDICATIONS).
HOW SUPPLIED
Tablets: White, oval, film-coated tablets: 3.125 mg–engraved with 39 and SB, in bottles of 100;
6.25 mg–engraved with 4140 and SB, in bottles of 100; 12.5 mg–engraved with 4141 and SB, in
This label may not be the latest approved by FDA.
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NDA 20-297/S-018
Page 22
bottles of 100; 25 mg–engraved with 4142 and SB, in bottles of 100. The 6.25 mg, 12.5 mg, and 25 mg
tablets are TILTAB tablets.
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.
3.125 mg 100’s: NDC 0007-4139-20
6.25 mg 100’s: NDC 0007-4140-20
12.5 mg 100’s: NDC 0007-4141-20
25 mg 100’s: NDC 0007-4142-20
COREG and TILTAB are registered trademarks of GlaxoSmithKline.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2005 GlaxoSmithKline. All rights reserved.
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custom-source
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2025-02-12T13:47:23.841135
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020297s018lbl.pdf', 'application_number': 20297, 'submission_type': 'SUPPL ', 'submission_number': 18}
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ATTENTION PHARMACIST: Detach “Patient’s Instructions for Use” from package
insert and dispense with the product.
Combivent® abcd
(ipratropium bromide and albuterol sulfate)
Inhalation Aerosol
Bronchodilator Aerosol
For Oral Inhalation Only
Rx only
Prescribing Information
DESCRIPTION
COMBIVENT Inhalation Aerosol is a combination of ipratropium bromide (as the
monohydrate) and albuterol sulfate.
Ipratropium bromide is an anticholinergic bronchodilator chemically described as
8-azoniabicyclo[3.2.1] octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl
8-(1-methylethyl)-, bromide monohydrate, (3-endo, 8-syn)-: a synthetic quaternary
ammonium compound chemically related to atropine. Ipratropium bromide is a white to
off-white crystalline substance, freely soluble in water and methanol, sparingly soluble in
ethanol, and insoluble in lipophilic solvents such as ether, chloroform and fluorocarbons.
The structural formula is:
Che
mi
ca
l
Str
uct
ur e
C20H30BrNO3•H2O
ipratropium bromide
Mol. Wt. 430.4
Albuterol sulfate, chemically known as (1,3-benzenedimethanol, α'-[[(1,1dimethylethyl)
amino] methyl]-4-hydroxy, sulfate (2:1)(salt), (±)- is a relatively selective beta2-adrenergic
bronchodilator. Albuterol is the official generic name in the United States. The World
Health Organization recommended name for the drug is salbutamol. Albuterol sulfate is a
white to off-white crystalline powder, freely soluble in water and slightly soluble in alcohol,
chloroform, and ether. The structural formula is:
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Che
mic
al
Str
uc
tu
re
(C13H21NO3)2•H2SO4
albuterol sulfate
Mol. Wt. 576.7
Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol contains a
microcrystalline suspension of ipratropium bromide and albuterol sulfate in a pressurized
metered-dose aerosol unit for oral inhalation administration. The 200 inhalation unit has a
net weight of 14.7 grams. Each actuation meters 21 mcg of ipratropium bromide and 120
mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium bromide and 103
mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the mouthpiece. The
excipients are dichlorodifluoromethane, dichlorotetrafluoroethane, and
trichloromonofluoromethane as propellants and soya lecithin.
CLINICAL PHARMACOLOGY
COMBIVENT Inhalation Aerosol is a combination of the anticholinergic bronchodilator,
ipratropium bromide, and the beta2-adrenergic bronchodilator, albuterol sulfate.
Mechanism of Action
Ipratropium bromide
Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal
studies, appears to inhibit vagally-mediated reflexes by antagonizing the action of
acetylcholine, the transmitter agent released at the neuromuscular junctions in the lung.
Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine
monophosphate (cyclic GMP) which are caused by interaction of acetylcholine with the
muscarinic receptors on bronchial smooth muscle.
Albuterol sulfate
In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a
preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is
recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth
muscle, recent data indicate that there is a population of beta2-receptors in the human heart
which comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise
function of these receptors, however, is not yet established (see WARNINGS).
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Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of
adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine
monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein
kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic
calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all
airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional
antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against
all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated
with the inhibition of release of mediators from mast cells in the airway.
Albuterol has been shown in most clinical trials to have more bronchial smooth muscle
relaxation effect than isoproterenol at comparable doses while producing fewer
cardiovascular effects. However, all beta-adrenergic drugs, including albuterol sulfate, can
produce a significant cardiovascular effect in some patients (see PRECAUTIONS).
COMBIVENT Inhalation Aerosol
Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is expected to
maximize the response to treatment in patients with chronic obstructive pulmonary disease
(COPD) by reducing bronchospasm through two distinctly different mechanisms,
anticholinergic (parasympatholytic) and sympathomimetic. Simultaneous administration of
both an anticholinergic (ipratropium bromide) and a beta2-sympathomimetic (albuterol
sulfate) is designed to benefit the patient by producing a greater bronchodilator effect than
when either drug is utilized alone at its recommended dosage.
Pharmacokinetics
Ipratropium bromide
Much of an administered dose is swallowed as shown by fecal excretion studies. Ipratropium
bromide is a quaternary amine. It is not readily absorbed into the systemic circulation either
from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and
renal excretion studies. Plasma levels of ipratropium bromide were below the assay
sensitivity limit of 100 pg/mL.
The half-life of elimination is about 2 hours after inhalation or intravenous administration.
Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and α1-acid
glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following
intravenous administration, approximately one-half of the dose is excreted unchanged in the
urine. Autoradiographic studies in rats have shown that ipratropium bromide does not
penetrate the blood-brain barrier.
Albuterol sulfate
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Albuterol is longer acting than isoproterenol in most patients because it is not a substrate for
the cellular uptake processes for catecholamines nor for metabolism by catechol-O-methyl
transferase. Instead, the drug is conjugatively metabolized to albuterol 4'-O-sulfate.
In a pharmacokinetic study in 12 healthy male volunteers of two inhalations of albuterol
sulfate, 103 mcg dose/inhalation through the mouthpiece, peak plasma albuterol
concentrations ranging from 419 to 802 pg/mL (mean 599 ± 122 pg/mL) were obtained
within three hours post-administration. Following this single-dose administration, 30.8 ±
10.2% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine. Since
albuterol sulfate is rapidly and completely absorbed, this study could not distinguish between
pulmonary and gastrointestinal absorption.
Intravenous pharmacokinetics of albuterol were studied in a comparable group of 16 healthy
male volunteers; the mean terminal half-life following a 30-minute infusion of 1.5 mg was
3.9 hours with a mean clearance of 439 mL/min/1.73 m2.
Intravenous albuterol studies in rats demonstrated that albuterol crossed the blood-brain
barrier and reached brain concentrations amounting to about 5% of the plasma
concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), the
drug achieved concentrations more than 100 times those in whole brain.
Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the
circulating maternal drug was transferred to the fetus. Disposition in fetal lungs was
comparable to maternal lungs, but fetal liver disposition was 1% of maternal liver levels.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence
of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis)
when beta-agonists and methylxanthines were administered concurrently. The significance
of these findings when applied to humans is unknown.
COMBIVENT Inhalation Aerosol
In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of
absorption and excretion of two inhalations of Combivent® (ipratropium bromide and
albuterol sulfate) Inhalation Aerosol to the two active components individually, the co
administration of ipratropium bromide and albuterol sulfate from a single canister did not
significantly alter the systemic absorption of either component.
Ipratropium bromide levels remained below detectable limits (<100 pg/mL). Peak albuterol
level obtained within 3 hours post-administration was 492 ± 132 pg/mL. Following this
single administration, 27.1 ± 5.7% of the estimated mouthpiece dose was excreted unchanged
in the 24-hour urine. From a pharmacokinetic perspective, the synergistic efficacy of
COMBIVENT Inhalation Aerosol is likely to be due to a local effect on the muscarinic and
beta2-adrenergic receptors in the lung.
Special Populations
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The pharmacokinetics of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation
Aerosol or ipratropium bromide have not been studied in patients with hepatic or renal
insufficiency or in the elderly (see PRECAUTIONS).
Drug-Drug Interactions
No specific pharmacokinetic studies were conducted to evaluate potential drug-drug
interactions.
Pharmacodynamics
Ipratropium bromide
The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-
specific effect, not a systemic one.
Controlled clinical studies have demonstrated that ipratropium bromide does not alter either
mucociliary clearance or the volume or viscosity of respiratory secretions. In studies without
a positive control, ipratropium bromide did not alter pupil size, accommodation or visual
acuity (see ADVERSE REACTIONS).
Ventilation/perfusion studies have shown no clinically significant effects on pulmonary gas
exchange or arterial oxygen tension. At recommended doses, ipratropium bromide does not
produce clinically significant changes in pulse rate or blood pressure.
Clinical Trials
In two 12-week randomized, double-blind, active-controlled clinical trials, 1067 patients with
chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator
efficacy of COMBIVENT Inhalation Aerosol (358 patients) in comparison to its components,
ipratropium bromide (362 patients) and albuterol sulfate (347 patients).
Serial FEV1 measurements (shown below as a percent change from test-day baseline)
demonstrated that COMBIVENT Inhalation Aerosol produced significantly greater
improvement in pulmonary function than either ipratropium bromide or albuterol sulfate
when given separately. The median time to onset of a 15% increase in FEV1 was 15 minutes
and the median time to peak FEV1 was one hour for COMBIVENT Inhalation Aerosol and
its components. The median duration of effect as measured by FEV1 was 4-5 hours for
COMBIVENT Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours
for albuterol sulfate.
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Percent Change in Adjusted Meana FEV1 from Test-Day Baseline - Endpoint Analysis
of the Evaluable Data Set Graph
a Adjusted for test-day baseline FEV1, center and treatment-by-center interaction
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These studies demonstrated that each component of Combivent® (ipratropium bromide and
albuterol sulfate) Inhalation Aerosol contributed to the improvement in pulmonary function
produced by the combination, especially during the first 4-5 hours after dosing, and that
COMBIVENT Inhalation Aerosol was significantly more effective than ipratropium bromide
or albuterol sulfate administered alone.
In the two controlled twelve-week studies, COMBIVENT Inhalation Aerosol did not produce
any change in the secondary efficacy parameters including symptom scores, physician global
assessments and morning PEFR, all of which were monitored throughout the study period.
INDICATIONS AND USAGE
COMBIVENT Inhalation Aerosol is indicated for use in patients with chronic obstructive
pulmonary disease (COPD) on a regular aerosol bronchodilator who continue to have
evidence of bronchospasm and who require a second bronchodilator.
CONTRAINDICATIONS
COMBIVENT Inhalation Aerosol is contraindicated in patients with a history of
hypersensitivity to soya lecithin or related food products such as soybean and peanut.
COMBIVENT Inhalation Aerosol is also contraindicated in patients hypersensitive to any
other components of the drug product or to atropine or its derivatives.
WARNINGS
1. Paradoxical Bronchospasm: COMBIVENT Inhalation Aerosol can produce paradoxical
bronchospasm that can be life-threatening. If it occurs, the preparation should be
discontinued immediately and alternative therapy instituted. It should be recognized that
paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs
with the first use of a new canister.
2. Cardiovascular Effect: The albuterol sulfate contained in COMBIVENT Inhalation
Aerosol, like other beta-adrenergic agonists, can produce a clinically significant
cardiovascular effect in some patients, as measured by pulse rate, blood pressure and/or
symptoms. Although such effects are uncommon after administration of COMBIVENT
Inhalation Aerosol at recommended doses, if they occur, discontinuation of the drug may be
indicated. In addition, beta-adrenergic agents have been reported to produce ECG changes,
such as flattening of the T wave, prolongation of the QTc interval, and ST segment
depression. Therefore, COMBIVENT Inhalation Aerosol should be used with caution in
patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias
and hypertension.
3. Do Not Exceed Recommended Dose: Fatalities have been reported in association with
excessive use of inhaled sympathomimetic drugs, in patients with asthma. The exact cause of
death is unknown, but cardiac arrest following an unexpected development of a severe acute
asthmatic crisis and subsequent hypoxia is suspected.
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4. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur
after administration of ipratropium bromide or albuterol sulfate, as demonstrated by rare
cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
5. Storage Conditions: The contents of Combivent® (ipratropium bromide and albuterol
sulfate) Inhalation Aerosol are under pressure. Do not puncture. Do not use or store near
heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw
the container into a fire or incinerator. Keep out of reach of children.
PRECAUTIONS
General
1. Effects Seen with Anticholinergic Drugs: COMBIVENT Inhalation Aerosol contains
ipratropium bromide and, therefore, should be used with caution in patients with
narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.
2. Effects Seen with Sympathomimetic Drugs: Preparations containing sympathomimetic
amines such as albuterol sulfate should be used with caution in patients with convulsive
disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive
to sympathomimetic amines. Beta-adrenergic agents may also produce significant
hypokalemia in some patients (possibly through intracellular shunting) which has the
potential to produce adverse cardiovascular effects. The decrease in serum potassium is
usually transient, not requiring supplementation.
3. Use in Hepatic or Renal Disease: COMBIVENT Inhalation Aerosol has not been studied
in patients with hepatic or renal insufficiency. It should be used with caution in those patient
populations.
Information for Patients
Patients should be cautioned to avoid spraying the aerosol into their eyes and be advised that
this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased
intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos
or colored images in association with red eyes from conjunctival and corneal congestion.
Patients should also be advised that should any combination of these symptoms develop, they
should consult their physician immediately.
The action of COMBIVENT Inhalation Aerosol should last 4-5 hours or longer.
COMBIVENT Inhalation Aerosol should not be used more frequently than recommended.
Do not increase the dose or frequency of COMBIVENT Inhalation Aerosol without
consulting your physician. If you find that treatment with COMBIVENT Inhalation Aerosol
becomes less effective for symptomatic relief, your symptoms become worse, and/or you
need to use the product more frequently than usual, medical attention should be sought
immediately. While you are taking COMBIVENT Inhalation Aerosol, other inhaled drugs
should be taken only as directed by your physician. If you are pregnant or nursing, contact
your physician about use of COMBIVENT Inhalation Aerosol. Appropriate use of
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Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol includes an
understanding of the way it should be administered (see Patient’s Instructions for Use).
Drug Interactions
COMBIVENT Inhalation Aerosol has been used concomitantly with other drugs, including
sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids,
commonly used in the treatment of chronic obstructive pulmonary disease. With the
exception of albuterol, there are no formal studies fully evaluating the interaction effects of
COMBIVENT Inhalation Aerosol and these drugs with respect to effectiveness.
Anticholinergic agents: Although ipratropium bromide is minimally absorbed into the
systemic circulation, there is some potential for an additive interaction with concomitantly
used anticholinergic medications. Caution is therefore advised in the co-administration of
COMBIVENT Inhalation Aerosol with other anticholinergic-containing drugs.
Beta-adrenergic agents: Caution is advised in the co-administration of COMBIVENT
Inhalation Aerosol and other sympathomimetic agents due to the increased risk of adverse
cardiovascular effects.
Beta-receptor blocking agents and albuterol inhibit the effect of each other. Beta-receptor
blocking agents should be used with caution in patients with hyperreactive airways.
Diuretics: The ECG changes and/or hypokalemia which may result from the administration
of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely
worsened by beta-agonists, especially when the recommended dose of the beta-agonist is
exceeded. Although the clinical significance of these effects is not known, caution is advised
in the co-administration of beta-agonist-containing drugs, such as COMBIVENT Inhalation
Aerosol, with non-potassium sparing diuretics.
Monoamine oxidase inhibitors or tricyclic antidepressants: COMBIVENT Inhalation Aerosol
should be administered with extreme caution to patients being treated with monoamine
oxidase inhibitors or tricyclic antidepressants or within two weeks of discontinuation of such
agents because the action of albuterol on the cardiovascular system may be potentiated.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ipratropium bromide
Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity
at doses up to 6 mg/kg. This dose corresponds in rats and mice to approximately 230 and
110 times the maximum recommended daily inhalation dose of ipratropium bromide in
adults, respectively, on a mg/m2 basis. Results of various mutagenicity studies (Ames test,
mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone
marrow in Chinese hamsters) were negative.
Fertility of male or female rats at oral doses up to 50 mg/kg (approximately 1,900 times the
maximum recommended daily inhalation dose in adults on a mg/m2 basis) was unaffected by
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ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately
19,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis),
ipratropium bromide produced a decrease in the conception rate.
Albuterol
Like other agents in its class, albuterol caused a significant dose-related increase in the
incidence of benign leiomyomas of the mesovarium in a two-year study in the rat at dietary
doses of 2, 10 and 50 mg/kg (approximately 15, 65 and 330 times the maximum
recommended daily inhalation dose in adults on a mg/m2 basis). In another study this effect
was blocked by the co-administration of propranolol. The relevance of these findings to
humans is not known. An 18-month study in mice at dietary doses up to 500 mg/kg
(approximately 1,600 times the maximum recommended daily inhalation dose in adults on a
mg/m2 basis) and a 99-week study in hamsters at oral doses up to 50 mg/kg (approximately
220 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis)
revealed no evidence of tumorigenicity. Studies with albuterol revealed no evidence of
mutagenesis.
Reproduction studies in rats with albuterol sulfate revealed no evidence of impaired fertility.
Pregnancy
COMBIVENT Inhalation Aerosol
Teratogenic Effects: Pregnancy Category C.
There are no adequate and well-controlled studies of Combivent® (ipratropium bromide and
albuterol sulfate) Inhalation Aerosol, ipratropium bromide or albuterol sulfate, in pregnant
women. Animal reproduction studies have not been conducted with COMBIVENT
Inhalation Aerosol. However, albuterol sulfate has been shown to be teratogenic in mice.
COMBIVENT Inhalation Aerosol should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Ipratropium bromide
Teratogenic Effects
Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1,000 mg/kg in rats
and 125 mg/kg in rabbits. These doses correspond in each species, respectively, to
approximately 190, 38,000, and 9,400 times the maximum recommended daily inhalation
dose in adults on a mg/m2 basis. Inhalation reproduction studies were conducted in rats and
rabbits at doses of 1.5 and 1.8 mg/kg (approximately 55 and 140 times the maximum
recommended daily inhalation dose in adults on a mg/m2 basis). These studies demonstrated
no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg
and above in rats (approximately 3,400 times the maximum recommended daily inhalation
dose in adults on a mg/m2 basis) embryotoxicity was observed as increased resorption. This
effect is not considered relevant to human use due to the large doses at which it was observed
and the difference in route of administration.
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Albuterol
Teratogenic Effects
Albuterol has been shown to be teratogenic in mice. A reproduction study in CD-1 mice
given albuterol subcutaneously (0.025, 0.25 and 2.5 mg/kg) showed cleft palate formation in
5 of 111 (4.5%) fetuses at 0.25 mg/kg (equivalent to the maximum recommended daily
inhalation dose in adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg
(approximately 8 times the maximum recommended daily inhalation dose in adults on a
mg/m2 basis). None was observed at 0.025 mg/kg (less than the maximum recommended
daily inhalation dose in adults). Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated
with 2.5 mg/kg isoproterenol (positive control). A reproduction study with oral albuterol in
Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg
(approximately 660 times the maximum recommended daily inhalation dose in adults on a
mg/m2 basis).
Labor and Delivery
Because of the potential for beta-agonist interference with uterine contractility, use of
Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol for the treatment
of COPD during labor should be restricted to those patients in whom the benefits clearly
outweigh the risk.
Nursing Mothers
It is not known whether the components of COMBIVENT Inhalation Aerosol are excreted in
human milk.
Ipratropium bromide
Although lipid-insoluble quaternary cations pass into breast milk, it is unlikely that the active
component, ipratropium bromide, would reach the infant to an important extent, especially
when taken by aerosol. However, because many drugs are excreted in human milk, caution
should be exercised when COMBIVENT Inhalation Aerosol is administered to a nursing
mother.
Albuterol
Because of the potential for tumorigenicity shown for albuterol in animal studies, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
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ADVERSE REACTIONS
Adverse reaction information concerning Combivent® (ipratropium bromide and albuterol
sulfate) Inhalation Aerosol is derived from two 12-week controlled clinical trials (N=358 for
COMBIVENT Inhalation Aerosol) as seen in Table 1.
Table 1
All Adverse Events (in percentages), from Two Large Double-blind,
Parallel, 12-Week Studies of Patients with COPD*
COMBIVENT
Ipratropium
Albuterol Sulfate
Ipratropium Bromide
Bromide
206 mcg QID
36 mcg/Albuterol
36 mcg QID
Sulfate
206 mcg QID
N = 358
N = 362
N = 347
Body as a Whole-General Disorders
Headache
5.6
3.9
6.6
Pain
2.5
1.9
1.2
Influenza
1.4
2.2
2.9
Chest Pain
0.3
1.4
2.9
Gastrointestinal System Disorders
Nausea
2.0
2.5
2.6
Respiratory System Disorders (Lower)
Bronchitis
12.3
12.4
17.9
Dyspnea
4.5
3.9
4.0
Coughing
4.2
2.8
2.6
Respiratory
2.5
1.7
2.3
Disorders
Pneumonia
1.4
2.5
0.6
Bronchospasm
0.3
3.9
1.7
Respiratory System Disorders (Upper)
Upper Respiratory
10.9
12.7
13.0
Tract Infection
Pharyngitis
2.2
3.3
2.3
Sinusitis
2.3
1.9
0.9
Rhinitis
1.1
2.5
2.3
*All adverse events, regardless of drug relationship, reported by two percent or more patients in one or more treatment group
in the 12-week controlled clinical trials.
Additional adverse reactions, reported in less than two percent of the patients in the
COMBIVENT Inhalation Aerosol treatment group include edema, fatigue, hypertension,
dizziness, nervousness, paresthesia, tremor, dysphonia, insomnia, diarrhea, dry mouth,
dyspepsia, vomiting, arrhythmia, palpitation, tachycardia, arthralgia, angina, increased
sputum, taste perversion, and urinary tract infection/dysuria.
Allergic-type reactions such as skin rash, angioedema of tongue, lips and face, urticaria
(including giant urticaria), laryngospasm and anaphylactic reaction have been reported with
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Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol, with positive
rechallenge in some cases. Many of these patients had a history of allergies to other drugs
and/or foods including soybean (see CONTRAINDICATIONS).
Post-Marketing Experience
In a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or
atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving
Atrovent® (ipratropium bromide) Inhalation Aerosol CFC.
Additional side effects identified from the published literature and/or post-marketing
surveillance on the use of ipratropium bromide-containing products (singly or in combination
with albuterol), include: urinary retention, mydriasis, bronchospasm (including paradoxical
bronchospasm), cases of precipitation or worsening of narrow-angle glaucoma, acute eye
pain, blurred vision, ocular irritation, nasal congestion, drying of secretions, mucosal ulcers,
irritation from aerosol, wheezing, exacerbation of COPD symptoms, hoarseness, palpitations,
heartburn, drowsiness, CNS stimulation, coordination difficulty, flushing, alopecia, itching,
hypotension, edema, gastrointestinal distress (diarrhea, nausea, vomiting), constipation,
hypokalemia, mental disorder, hyperhidrosis, muscle spasms, muscular weakness, myalgia,
and asthenia.
OVERDOSAGE
The effects of overdosage are expected to be related primarily to albuterol sulfate. Acute
overdosage with ipratropium bromide by inhalation is unlikely since ipratropium bromide is
not well absorbed systemically after aerosol or oral administration. Oral median lethal doses
of ipratropium bromide were greater than 1001 mg/kg in mice (approximately 19,000 times
the maximum recommended daily inhalation dose in adults on a mg/m2 basis); 1663 mg/kg in
rats (approximately 62,000 times the maximum recommended daily inhalation dose in adults
on a mg/m
2 basis); and 400 mg/kg in dogs (approximately 50,000 times the maximum
recommended daily inhalation dose in adults, on a mg/m2 basis). Whereas the oral median
lethal dose of albuterol sulfate in mice and rats was greater than 2,000 mg/kg (approximately
6,600 and 13,000 times the maximum recommended daily inhalation dose, respectively, in
adults on a mg/m
2 basis), the inhalational median lethal dose could not be determined.
Manifestations of overdosage with albuterol may include anginal pain, hypertension,
hypokalemia, tachycardia with rates up to 200 beats per minute and exaggeration of the
pharmacologic effects listed in ADVERSE REACTIONS. As with all sympathomimetic
aerosol medications, cardiac arrest and even death may be associated with abuse. Dialysis is
not appropriate treatment for overdosage of albuterol as an inhalation aerosol; the judicious
use of a cardiovascular beta-receptor blocker, such as metoprolol tartrate may be indicated.
DOSAGE AND ADMINISTRATION
The dose of COMBIVENT® Inhalation Aerosol is two inhalations four times a day. Patients
may take additional inhalations as required; however, the total number of inhalations should
not exceed 12 in 24 hours. Safety and efficacy of additional doses of COMBIVENT
Inhalation Aerosol beyond 12 puffs/24 hours have not been studied. Also, safety and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
efficacy of extra doses of ipratropium or albuterol in addition to the recommended doses of
Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol have not been
studied. It is recommended to “test-spray” three times before using for the first time and in
cases where the aerosol has not been used for more than 24 hours. Avoid spraying into eyes.
HOW SUPPLIED
COMBIVENT Inhalation Aerosol is supplied as a metered-dose inhaler with a white
mouthpiece that has a clear, colorless sleeve and an orange protective cap. The
COMBIVENT Inhalation Aerosol canister is to be used only with the COMBIVENT
Inhalation Aerosol mouthpiece and not with other mouthpieces. This mouthpiece should not
be used with other aerosol medications. Each actuation meters 21 mcg of ipratropium
bromide and 120 mcg of albuterol sulfate from the valve and delivers 18 mcg of ipratropium
bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base) from the
mouthpiece.
Each 14.7 gram canister provides sufficient medication for 200 actuations (NDC 0597-0013
14).
Warning: The canister should be discarded after the labeled number of actuations has been
used. The correct amount of medication in each actuation cannot be assured after this point,
even though the canister is not completely empty.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled
Room Temperature]. For best results, store the canister at room temperature before use.
Avoid excessive humidity. Shake the canister vigorously for at least 10 seconds before
use.
Address medical inquiries to: http://us.boehringer-ingelheim.com, (800) 542-6257 or
(800) 459-9906 TTY.
Note: The indented statement below is required by the Federal government’s Clean Air Act
for all products containing or manufactured with chlorofluorocarbons (CFCs):
Warning: Contains trichloromonofluoromethane (CFC-11), dichlorodifluoromethane
(CFC-12) and dichlorotetrafluoroethane (CFC-114), substances which harm public health and
the environment by destroying ozone in the upper atmosphere.
A notice similar to the above Warning has been placed in the information for the patient of
this product under the Environmental Protection Agency’s (EPA’s) regulations. The
patient’s warning states that the patient should consult his or her physician if there are any
questions about alternatives.
Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame.
Exposure to temperatures above 120°F may cause bursting. Never throw the inhaler into a
fire or incinerator.
Distributed by:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Ipratropium bromide licensed from:
Boehringer Ingelheim International GmbH
©Copyright 2008 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED
U.S. Patent No. 5,603,918
Rev: November 2008
IT9011EK0408
10004145/04
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient’s Instructions for Use
Combivent®
(ipratropium bromide and albuterol sulfate)
Inhalation Aerosol
Read complete instructions carefully before using
Use COMBIVENT Inhalation Aerosol exactly as prescribed by your doctor. Do not
change your dose or how often you use COMBIVENT Inhalation Aerosol without talking
with your doctor. Talk to your doctor if you have questions about your medical condition or
your treatment.
Tell your doctor about all of the medicines you take. COMBIVENT Inhalation Aerosol
and some other medicines may interact with each other. Do not use other inhaled medicines
with COMBIVENT Inhalation Aerosol unless prescribed by your doctor.
1. Insert metal canister into clear end of mouthpiece (see Figure 1). Make sure the
canister is fully and firmly inserted into the mouthpiece. The COMBIVENT Inhalation
Aerosol canister is to be used only with the COMBIVENT Inhalation Aerosol
mouthpiece. This mouthpiece should not be used with other inhaled medicines. Usage illustration
Figure 1
2. Remove orange protective dust cap. If the cap is not on the mouthpiece, make sure
there is nothing in the mouthpiece before use. For best results, the canister should be at
room temperature before use.
3. Shake and Test Spray. Perform this step before using for the first time, and whenever
the aerosol has not been used for more than 24 hours; otherwise, proceed directly to Step
4.
After vigorously shaking the canister for at least 10 seconds (see step 4 for instructions on
shaking), “test-spray” into the air 3 times. Avoid spraying in eyes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Shake the canister vigorously for at least 10 seconds. Hold canister as illustrated in
Figure 2.
IMPORTANT: Vigorous shaking for at least 10 seconds before each spray is very important
for proper product performance.
For best results, perform Steps 5-6 within 30 seconds of shaking the canister. Usage illustration
Figure 2
5. Breathe out (exhale) deeply through your mouth. Holding the canister upright as
shown in Figure 3, between your thumb and finger(s), put the mouthpiece in your mouth
and close your lips. Keep your eyes closed so that no medicine will be sprayed into your
eyes. Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol can
cause blurry vision, narrow-angle glaucoma or worsening of this condition or eye pain if
the medicine is sprayed into your eyes. Usage illustration
Figure 3
6. Breathe in (inhale) slowly through your mouth and at the same time spray the
product into your mouth.
To spray the product, firmly press once on the canister against the mouthpiece as shown
in Figure 4. Keep breathing in deeply. Usage illustration
Figure 4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7. Hold your breath for 10 seconds, remove the mouthpiece from your mouth and
breathe out slowly, as in Figure 5. Usage illustration
Figure 5
8. Wait approximately 2 minutes, shake the inhaler vigorously for at least 10 seconds
again (as described in Step 4), and repeat Steps 5-7.
9. Replace the orange protective dust cap after use.
10. Keep the mouthpiece clean. Wash with hot water. If soap is used, rinse thoroughly
with plain water. Dry thoroughly before use. When dry, replace cap on the mouthpiece
when not using the drug product.
11. Keep track of the number of sprays used and discard after 200 sprays. Even though
the canister is not empty, you cannot be sure of the amount of medicine in each spray
after 200 sprays.
12. If your prescribed dose does not provide relief or your breathing symptoms become
worse, get medical help right away.
Note: The indented statement below is required by the Federal government’s Clean Air Act
for all products containing or manufactured with chlorofluorocarbons (CFCs):
This product contains trichloromonofluoromethane (CFC-11),
dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114),
substances which harm the environment by destroying ozone in the upper atmosphere.
The contents of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol
are under pressure. Do not puncture the canister. Do not use or store near heat or open flame.
Exposure to temperatures above 120°F may cause bursting. Never throw the container into a
fire or incinerator.
Keep COMBIVENT Inhalation Aerosol out of reach of children.
Avoid spraying in eyes.
Address medical inquiries to: http://us.boehringer-ingelheim.com, (800) 542-6257 or
(800) 459-9906 TTY.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled
Room Temperature]. For best results, store the canister at room temperature before use.
Avoid excessive humidity.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Ipratropium bromide licensed from:
Boehringer Ingelheim International GmbH
©Copyright 2008 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED
U.S. Patent No. 5,603,918
Rev: November2008
IT9011EK0408
10004145/04
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:23.862596
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020291s026lbl.pdf', 'application_number': 20291, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
12,420
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
FRAGMIN® safely and effectively. See full prescribing information for
cancer
Months 2 – 6 150 IU/kg subcutaneous once
daily (2.1)
FRAGMIN.
Do not use as intramuscular injection. FRAGMIN should not be mixed with
other injections or infusions. (2)
FRAGMIN (dalteparin sodium injection) for Subcutaneous Use Only
Initial U.S. Approval: 1994
WARNING: SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning.
Epidural or spinal hematomas may occur in patients who are
anticoagulated with low molecular weight heparins (LMWH) or
heparinoids and are receiving neuraxial anesthesia or undergoing spinal
puncture. These hematomas may result in long-term or permanent
paralysis. Consider these risks when scheduling patients for spinal
procedures. Factors that can increase the risk of developing epidural or
spinal hematomas in these patients include:
• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as non-
steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other
anticoagulants.
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery
• Optimal timing between the administration of FRAGMIN and
neuraxial procedures is not known.
Monitor patients frequently for signs and symptoms of neurological
impairment. If neurological compromise is noted, urgent treatment is
necessary.
Consider the benefits and risks before neuraxial intervention in patients
anticoagulated or to be anticoagulated for thromboprophylaxis [see
Warnings and Precautions (5.1) and Drug Interactions (7)].
----------------------------RECENT MAJOR CHANGES-------------------------
Boxed Warning
1/2015
isk of Hemorrhage including Spinal/Epidural Hematoma (5.1)
1/2015
----------------------------INDICATIONS AND USAGE--------------------------
FRAGMIN is a low molecular weight heparin [LMWH] indicated for
•
Prophylaxis of ischemic complications of unstable angina and
non-Q-wave myocardial infarction (1.1)
•
Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip
replacement surgery or medical patients with severely restricted mobility
during acute illness (1.2)
•
Extended treatment of symptomatic venous thromboembolism (VTE) to
reduce the recurrence in patients with cancer. In these patients, the
FRAGMIN therapy begins with the initial VTE treatment and continues
for six months (1.3)
Limitations of Use
FRAGMIN is not indicated for the acute treatment of VTE.
----------------------DOSAGE AND ADMINISTRATION----------------------
Indication
Dosing Regimen
Unstable angina and
non-Q-wave MI
120 IU/kg subcutaneous every 12 hours (with
aspirin) (2.1)
DVT prophylaxis in
abdominal surgery
2500 IU subcutaneous once daily or 5000 IU
subcutaneous once daily or 2500 IU
subcutaneous followed by 2500 IU subcutaneous
12 hours later and then 5000 IU subcutaneous
once daily (2.1)
DVT prophylaxis in
hip replacement
surgery
Postoperative start – 2500 IU subcutaneous 4
to 8 hours after surgery, then 5000 IU
subcutaneous once daily or Preoperative start
– day of surgery 2500 IU subcutaneous 2 hours
before surgery followed by 2500 IU
subcutaneous 4 to 8 hours after surgery, then
5000 IU subcutaneous once daily (2.1)
Preoperative start – Evening Before Surgery
5000 IU subcutaneous followed by 5000 IU
subcutaneous 4 to 8 hours after surgery (2.1)
DVT prophylaxis in
medical patients
5000 IU subcutaneous once daily (2.1)
Extended treatment of
VTE in patients with
Month 1 – 200 IU/kg subcutaneous once daily
(2.1)
Reference ID: 3692005
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_______________________________________________________________________________________________________________________________________
----------------------DOSAGE FORMS AND STRENGTHS------------
•
Single-dose prefilled syringe: 2,500 IU/ 0.2 mL, 5,000 IU/ 0.2 mL. 7500
IU/ 0.3. mL, 10,000 IU/ 0.4 mL, 12,500 IU/ 0.5 mL, 15,000 IU/ 0.6 mL,
18,000 IU/ 0.72 mL (3)
•
Single-dose graduated syringe: 10,000 IU/ 1 mL(3)
•
Multiple dose vial: 95,000 IU /9.5 mL, 95,000 /3.8 mL (3)
-------------------------------CONTRAINDICATIONS-----------------------------
•
Active major bleeding (4)
•
History of heparin induced thrombocytopenia or heparin induced
thrombocytopenia with thrombosis. (4)
•
Hypersensitivity to dalteparin sodium (4,6.1)
•
In patients undergoing Epidural/Neuraxial anesthesia, do not administer
FRAGMIN [see Boxed Warning (4)];
o
As a treatment for unstable angina and non-Q-wave MI
o
For prolonged VTE prophylaxis.(4)
•
Hypersensitivity to heparin or pork products (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
•
Use caution in conditions with increased risk of hemorrhage (5.1)
•
Monitor thrombocytopenia of any degree closely (5.2)
•
Multiple-dose formulations contain benzyl alcohol (5.3)
•
Periodic blood counts recommended (5.4)
------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reaction is hematoma at the injection site. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eisai at (1
888-274-2378) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
•
Use FRAGMIN with care in patients receiving oral anticoagulants,
platelet inhibitors, and thrombolytic agents (7)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
•
Safety and effectiveness in pediatric patients have not been established.
(8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: [1/2015]
Reference ID: 3692005
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: CONTENTS*
WARNING: SPINAL EPIDURAL HEMATOMAS
1
INDICATIONS AND USAGE
1.1
Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
1.2
Prophylaxis of Deep Vein Thrombosis
1.3
Extended Treatment of Symptomatic Venous Thromboembolism
in Patients with Cancer
2
DOSAGE AND ADMINISTRATION
2.1
Adult Dosage
2.2
Dose Reductions for Thrombocytopenia in Patients with Cancer
and Acute Symptomatic VTE2.3 Dose
Reductions
for
Renal
Insufficiency in Extended Treatment of and Acute Symptomatic
Venous Thromboembolism
in Patients with Cancer
2.4
Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Risk of Hemorrhage including Spinal / Epidural Hematoma
5.2
Thrombocytopenia
5.3
Benzyl Alcohol
5.4
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Post-Marketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
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 Prophylaxis of Ischemic Complications in Unstable Angina and
Non-Q-Wave Myocardial Infarction
14.2 Prophylaxis of Deep Vein Thrombosis in Patients Following Hip
Replacement Surgery
14.3 Prophylaxis of Deep Vein Thrombosis Following Abdominal
Surgery in Patients at Risk for Thromboembolic Complications
14.4 Prophylaxis of Deep Vein Thrombosis in Medical Patients at
Risk for Thromboembolic Complications Due to Severely
Restricted Mobility During Acute Illness
14.5 Patients
with
Cancer
and
Acute
Symptomatic
Venous
Thromboembolism
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3692005
3
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: SPINAL/EPIDURAL HEMATOMAS
Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are
receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks
when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients
include:
•
Use of indwelling epidural catheters
•
Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other
anticoagulants.
•
A history of traumatic or repeated epidural or spinal punctures
•
A history of spinal deformity or spinal surgery
•
Optimal timing between the administration of FRAGMIN and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings
and Precautions (5.1) and Drug Interactions (7)].
1
INDICATIONS AND USAGE
1.1 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
FRAGMIN® Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently
administered with aspirin therapy [see Clinical Studies (14.1)].
1.2 Prophylaxis of Deep Vein Thrombosis
FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):
•
In patients undergoing hip replacement surgery [see Clinical Studies (14.2)];
•
In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.3)];
•
In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies (14.4)].
1.3 Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer
FRAGMIN is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE
in patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies (14.5)].
Limitations of Use
FRAGMIN is not indicated for the acute treatment of VTE.
2
DOSAGE AND ADMINISTRATION
FRAGMIN is administered by subcutaneous injection. It must not be administered by intramuscular injection.
FRAGMIN Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.
Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN activity
and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN [see Warnings and Precautions (5)].
2.1 Adult Dosage
Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial
infarction, the recommended dose of FRAGMIN Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously every 12 hours with concurrent
oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8
days. Concurrent aspirin therapy is recommended except when contraindicated.
Table 1 lists the volume of FRAGMIN, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.
Table 1
Volume of FRAGMIN to be Administered by Patient Weight, Based on
9.5 mL Vial (10,000 IU/mL)
Patient
weight (lb)
< 110
110 to 131
132 to 153
154
to
175
176 to 197
≥198
Patient
weight (kg)
< 50
50
to
59
60
to
69
70
to
79
80
to
89
≥90
Volume of
FRAGMIN (mL)
0.55
0.65
0.75
0.90
1.0
1.0
Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery: Table 2 presents the dosing options for patients undergoing hip replacement surgery.
The usual duration of administration is 5 to 10 days after surgery; up to 14 days of treatment with FRAGMIN have been well tolerated in clinical trials.
Reference ID: 3692005
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2
Dosing Options for Patients Undergoing Hip Replacement Surgery
Dose of FRAGMIN to be Given Subcutaneously
Timing of First
Dose
of FRAGMIN
Postoperative
Start
10 to 14
Hours
Before
Surgery
--
Within
2 Hours
Before
Surgery
--
4 to 8
Hours
After
Surgery1
2500 IU3
Postoperative
Period2
5000 IU once
daily
Preoperative
Start - Day of
Surgery
--
2500 IU
2500 IU3
5000 IU once
daily
Preoperative
Start - Evening
BeforeSurgery4
5000 IU
--
5000 IU
5000 IU once
daily
1 Or later, if hemostasis has not been achieved.
2 Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively.
3 Allow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly.
4 Allow approximately 24 hours between doses.
Abdominal Surgery: In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN is 2500 IU
administered by subcutaneous injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is
5 to 10 days.
In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of
FRAGMIN is 5000 IU subcutaneously the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively,
in patients with malignancy, 2500 IU of FRAGMIN can be administered subcutaneously 1 to 2 hours before surgery followed by 2500 IU subcutaneously 12 hours
later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.
Medical Patients During Acute Illness: In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5000 IU
administered by subcutaneous injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.
Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer: In patients with cancer and symptomatic venous thromboembolism, the
recommended dosing of FRAGMIN is as follows: for the first 30 days of treatment administer FRAGMIN 200 IU/kg total body weight subcutaneously once daily. The
total daily dose should not exceed 18,000 IU. Table 3 lists the dose of FRAGMIN to be administered once daily during the first month for a range of patient weights
Month 1
Table 3
Dose of FRAGMIN to be Administered Subcutaneously by Patient
Weight during the First Month
Body Weight (lbs)
Body Weight
(kg)
FRAGMIN Dose (IU)
(prefilled syringe) once
daily
≤ 124
≤ 56
10,000
125 to 150
57 to 68
12,500
151 to 181
69 to 82
15,000
182 to 216
83 to 98
18,000
≥ 217
≥ 99
18,000
Months 2 to 6
Administer FRAGMIN at a dose of approximately 150 IU/kg, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed 18,000 IU.
Table 4 lists the dose of FRAGMIN to be administered once daily for a range of patient weights during months 2-6.
Reference ID: 3692005
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4
Dose of FRAGMIN to be Administered Subcutaneously by Patient
Weight during Months 2-6
Body Weight (lbs)
Body Weight
(kg)
FRAGMIN Dose (IU)
(prefilled syringe)
once daily
≤ 124
≤ 56
7,500
125 to 150
57 to 68
10,000
151 to 181
69 to 82
12,500
182 to 216
83 to 98
15,000
≥ 217
≥ 99
18,000
Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE [see Warnings and Precaution (5) and Adverse
Reactions (6.1)].
2.2 Dose Reductions for Thrombocytopenia in Patients with Cancer and Acute Symptomatic VTE
In patients receiving FRAGMIN who experience platelet counts between 50,000 and 100,000/mm3, reduce the daily dose of FRAGMIN by 2,500 IU until the platelet
count recovers to ≥100,000/mm3. In patients receiving FRAGMIN who experience platelet counts < 50,000/mm3, discontinue FRAGMIN until the platelet count
recovers above 50,000/mm3 .
2.3 Dose Reductions for Renal Insufficiency in Extended Treatment of Acute Symptomatic Venous Thromboembolism in Patients with Cancer
In patients with severely impaired renal function (CrCl < 30 mL/min), monitor anti-Xa levels to determine the appropriate FRAGMIN dose. Target anti-Xa range is
0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6 hrs after FRAGMIN dosing and only after the patient has received 3-4 doses.
2.4 Administration
Subcutaneous injection technique: Patients should be sitting or lying down and FRAGMIN administered by deep subcutaneous injection. FRAGMIN may be injected in
a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area
around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be
inserted at a 45 to 90 degree angle.
Inspect FRAGMIN prefilled syringes and vials visually for particulate matter and discoloration prior to administration
After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.
Instructions for using the prefilled single-dose syringes preassembled with needle guard devices usage illustration
Fixed dose syringes: To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open
sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger
flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of
the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.
Graduated syringes: Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by
expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle
into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been
given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move
up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.
DOSAGE FORMS AND STRENGTHS
2,500 IU / 0.2 mL single-dose prefilled syringe
5,000 IU / 0.2 mL single-dose prefilled syringe
7,500 IU / 0.3 mL single-dose prefilled syringe
10,000 IU / 0.4 mL single-dose prefilled syringe
10,000 IU / 1 mL single-dose graduated syringe
12,500 IU / 0.5 mL single-dose prefilled syringe
15,000 IU / 0.6 mL single-dose prefilled syringe
18,000 IU / 0.72 mL single-dose prefilled syringe
95,000 IU / 3.8 mL multiple-dose vial
95,000 IU / 9.5 mL multiple-dose vial
Reference ID: 3692005
6
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
•
Active major bleeding.
•
History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.
•
Hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions) [see Adverse Reactions (6.2)].
•
In patients undergoing Epidural/Neuraxial anesthesia, do not administer FRAGMIN [see Boxed Warning, Warnings and Precautions (5.1)]];
o
As a treatment for unstable angina and non-Q-wave MI.
o
For prolonged VTE prophylaxis.
•
Hypersensitivity to heparin or pork products
5
WARNINGS AND PRECAUTIONS
5.1 Risk of Hemorrhage including Spinal / Epidural Hematoma
Spinal or epidural hemorrhage and subsequent hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial
(spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use
of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal
deformity [see Boxed Warning and Adverse Reactions (6.2) and Drug Interactions (7)].
To reduce the potential risk of bleeding associated with the concurrent use of dalteparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider
the pharmacokinetic profile of dalteparin [see Clinical Pharmacology (12.3)].
Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dalteparin is low; however, the exact timing to
reach a sufficiently low anticoagulant effect in each patient is not known. No additional hemostasis-altering medications should be administered due to the additive
effects.
Patients on preoperative FRAGMIN thromboprophylaxis can be assumed to have altered coagulation. The first postoperative FRAGMIN thrombophylaxis dose (2500
IU) should be administered 6 to 8 hrs postoperatively. The second postoperative dose (2500 or 5000 IU) should occur no sooner than 24 hrs after the first dose.
Placement or removal of a catheter should be delayed for at least 12 hours after administration of 2500 IU once daily of FRAGMIN, at least 15 hours after the
administration of 5000 IU once daily of FRAGMIN, and at least 24 hours after the administration of higher doses (200 IU/kg once daily, 120 IU/kg twice daily) of
FRAGMIN. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided.
Although a specific recommendation for timing of a subsequent FRAGMIN dose after catheter removal cannot be made, consider delaying this next dose for at least
four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.
For patients with creatinine clearance <30mL/minute, additional considerations are necessary because elimination of FRAGMIN may be more prolonged; consider
doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of FRAGMIN (2500 IU or 5000 IU once daily) and at least 48 hours for the
higher dose (200 IU/kg once daily, 120 IU/kg twice daily) [see Clinical Pharmacology (12.3)].
Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be
exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs),
bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal
hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or
reverse neurological sequelae.
Use FRAGMIN with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis,
congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or
ophthalmological surgery. FRAGMIN may enhance the risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or kidney insufficiency,
hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. Bleeding can occur at any site during therapy with FRAGMIN.
5.2 Thrombocytopenia
Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present. In clinical practice,
cases of thrombocytopenia with thrombosis, amputation and death have been observed. [see Contraindications (4)] Closely monitor thrombocytopenia of any degree.
In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of < 50,000/mm3 occurred in < 1% of patients.
In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the FRAGMIN treatment arm, platelet counts
of < 100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3 . In the same clinical trial, thrombocytopenia was
reported as an adverse event in 10.9% of patients in the FRAGMIN arm and 8.1% of patients in the OAC arm. FRAGMIN dose was decreased or interrupted in patients
whose platelet counts fell below 100,000/mm3 .
5.3 Benzyl Alcohol Preservative Risk to Premature Infants
Each multiple-dose vial of FRAGMIN contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in
premature infants. Because benzyl alcohol may cross the placenta, use caution when administering FRAGMIN preserved with benzyl alcohol to pregnant women. If
anticoagulation with FRAGMIN is needed during pregnancy, use preservative-free formulations, where possible. [see Use in Specific Populations (8.1)].
5.4 Laboratory Tests
Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with
FRAGMIN. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin
Time (APTT) are relatively insensitive measures of FRAGMIN activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN. Anti-Factor Xa
may be used to monitor the anticoagulant effect of FRAGMIN, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding
occurs during FRAGMIN therapy.
7
Reference ID: 3692005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
ADVERSE REACTIONS
The following serious adverse reactions are described in more detail in other sections of the prescribing information.
•
Risk of Hemorrhage including Spinal/Epidural Hematoma [see Warnings and Precautions (5.1)]
•
Thrombocytopenia [see Warnings and Precautions (5.2)]
•
Benzyl Alcohol preservative Risk to Premature Infants [see Warnings and Precautions (5.3)]
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 accurately reflect the rates observed in practice.
Hemorrhage
The incidence of hemorrhagic complications during treatment with FRAGMIN Injection has been low. The most commonly reported side effect is hematoma at the
injection site. The risk for bleeding varies with the indication and may increase with higher doses.
Unstable Angina and Non-Q-Wave Myocardial Infarction
Table 5 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial
infarction.
Table 5
Major Bleeding Reactions in Unstable Angina and
Non-Q-Wave Myocardial Infarction
Indication
Dosing Regimen
Unstable Angina and
Non-Q-Wave MI
FRAGMIN
120 IU/kg/12 hr subcutaneous1
n (%)
Heparin2
intravenous and subcutaneous2
n (%)
Placebo
every 12 hr subcutaneous
n (%)
Major Bleeding Reactions3,4
15/1497 (1.0)
7/731 (1.0)
4/760 (0.5)
1 Treatment was administered for 5 to 8 days.
2 Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control,
then 12,500 U subcutaneously every 12 hours for 5 to 8 days.
3 Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently.
4 Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) a transfusion was
required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding.
Hip Replacement Surgery
Table 6 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with FRAGMIN (preoperative dosing
regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.
Table 6
Bleeding Reactions Following Hip Replacement Surgery
Indication
FRAGMIN vs
Warfarin Sodium
FRAGMIN vs
Heparin
Dosing Regimen
Dosing Regimen
Hip
Replacement
Surgery
FRAGMIN2
5000 IU once daily subcutaneous
n (%)
Warfarin
Sodium1 oral
n (%)
FRAGMIN4
5000 IU once daily
subcutaneous
n (%)
Heparin
5000 U three times a day
subcutaneous
n (%)
Major Bleeding Reactions3
7/274 (2.6)
1/279 (0.4)
0
3/69 (4.3)
Other Bleeding Reactions5
Hematuria
8/274 (2.9)
5/279 (1.8)
0
0
Wound Hematoma
6/274 (2.2)
0
0
0
Injection Site Hematoma
3/274 (1.1)
NA
2/69 (2.9)
7/69 (10.1)
1 Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of
approximately 2.5.
2 Includes three treated patients who did not undergo a surgical procedure.
3 A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥2 g/dL or
transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage.
4 Includes two treated patients who did not undergo a surgical procedure.
5 Occurred at a rate of at least 2% in the group treated with FRAGMIN 5000 IU once daily.
8
Reference ID: 3692005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Six of the patients treated with FRAGMIN experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three
were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced
retroperitoneal or intracranial hemorrhage or died of bleeding complications.
In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who
started FRAGMIN before surgery; 2.5% (12/487) for patients who started FRAGMIN after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.
Abdominal Surgery
Table 7 summarizes bleeding reactions that occurred in clinical trials which studied FRAGMIN 2500 and 5000 IU administered once daily to abdominal surgery
patients.
Table 7
Bleeding Reactions Following Abdominal Surgery
Indication
FRAGMIN vs Placebo
FRAGMIN vs FRAGMIN
Dosing Regimen
Dosing Regimen
Abdominal
Surgery
FRAGMIN
2500 IU
once
daily subcutaneous
n (%)
Placebo
once daily
subcutaneous
n (%)
FRAGMIN
2500 IU
once
daily subcutaneous
n (%)
FRAGMIN
5000 IU
once
daily subcutaneous
n (%)
Postoperative
Transfusions
14/182
(7.7)
13/182
(7.1)
89/1025
(8.7)
125/1033
(12.1)
Wound
Hematoma
2/79
(2.5)
2/77
(2.6)
1/1030
(0.1)
4/1039
(0.4)
Reoperation
Due to Bleeding
1/79
(1.3)
1/78
(1.3)
2/1030
(0.2)
13/1038
(1.3)
Injection Site
Hematoma
8/172
(4.7)
2/174
(1.1)
36/1026
(3.5)
57/1035
(5.5)
Table 7 Cont.
Bleeding Reactions Following Abdominal Surgery
Indication
FRAGMIN vs Heparin
Dosing Regimen
Abdominal
Surgery
FRAGMIN
2500 IU
once
daily subcutaneous
n (%)
Heparin
5000 U
twice daily
subcutaneous
n (%)
FRAGMIN
5000 IU
once
daily subcutaneous
n (%)
Heparin
5000 U
twice daily subcutaneous
n (%)
Postoperative
Transfusions
26/459
(5.7)
36/454
(7.9)
81/508
(15.9)
63/498
(12.7)
Wound
Hematoma
16/467
(3.4)
18/467
(3.9)
12/508
(2.4)
6/498
(1.2)
Reoperation
Due to Bleeding
2/392
(0.5)
3/392
(0.8)
4/508
(0.8)
2/498
(0.4)
Injection Site
Hematoma
1/466
(0.2)
5/464
(1.1)
36/506
(7.1)
47/493
(9.5)
In a trial comparing FRAGMIN 5000 IU once daily to FRAGMIN 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding
reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing FRAGMIN 5000 IU once daily to heparin 5000 U twice daily, in the malignancy subgroup the
incidence of bleeding reactions was 3.2% and 2.7%, respectively for FRAGMIN and Heparin (n.s.).
Medical Patients with Severely Restricted Mobility During Acute Illness
Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.
Reference ID: 3692005
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8
Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness
Indication
Dosing Regimen
Medical Patients with Severely
Restricted Mobility
FRAGMIN
5000 IU once daily subcutaneous
n (%)
Placebo
once daily subcutaneous
n (%)
Major Bleeding Reactions1 at Day 14
8/1848 (0.4)
0/1833 (0)
Major Bleeding Reactions1 at Day 21
9/1848 (0.5)
3/1833 (0.2)
1 A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) intraocular,
spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥ 2 units of blood products; 4) required significant medical or surgical
intervention; or 5) led to death.
Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with FRAGMIN and
one in the group receiving placebo).
Patients with Cancer and Acute Symptomatic Venous Thromboembolism
Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous
thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2)
occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4)
led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.
At the end of the six-month study, a total of 46 (13.6%) patients in the FRAGMIN arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One
bleeding event (hemoptysis in a patient in the FRAGMIN arm at Day 71) was fatal.
Table 9
Bleeding Reactions (Major and Any) (As treated population)1
Study
period
FRAGMIN
200 IU/kg (max. 18,000 IU)
subcutaneous once daily x 1
month, then 150 IU/kg (max.
18,000 IU) subcutaneous once
daily x 5 months
OAC
FRAGMIN 200 IU/kg (max
18,000 IU) subcutaneous once
daily x 5-7 days and OAC for 6
months (target INR 2-3)
Number
at risk
Patients
with
Major
Bleeding
n (%)
Patients
with Any
Bleeding
n (%)
Number
at risk
Patients
with
Major
Bleeding
n (%)
Patients
with Any
Bleeding
n (%)
Total
during
study
338
19 (5.6)
46 (13.6)
335
12 (3.6)
62 (18.5)
Week
1
338
4 (1.2)
15 (4.4)
335
4 (1.2)
12 (3.6)
Weeks
2-4
332
9 (2.7)
17 (5.1)
321
1 (0.3)
12 (3.7)
Weeks
5-28
297
9 (3.0)
26 (8.8)
267
8 (3.0)
40 (15.0)
1 Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that
occurred at different time intervals were counted once in each interval in which the event occurred.
Thrombocytopenia
[see Warnings and Precautions (5.2)]
Elevations of Serum Transaminases
In FRAGMIN clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels
(SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients
during treatment with FRAGMIN.
In the FRAGMIN clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with FRAGMIN for up to 6 months, asymptomatic
increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of
patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI
CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.
Other
Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been
reported.
Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with FRAGMIN and reported at a
rate of at least 2% in the group treated with FRAGMIN, was reported in 4.5% of patients treated with FRAGMIN 5000 IU once daily vs 11.8% of patients treated with
heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with FRAGMIN
5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.
10
Reference ID: 3692005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2 Post-Marketing Experience
The following adverse reactions have been identified during postapproval use of FRAGMIN. 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.
Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin
sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received
additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete) [see Boxed Warning].
Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.
7
DRUG INTERACTIONS
Use FRAGMIN with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding [see Warning and
Precautions (5)].
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies of FRAGMIN use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits
received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m2) (rats) and 4800 IU/kg (40,800 IU/m2) (rabbits). These exposures were 2 to 4 times
(rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in
these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99–404 mg/kg/day). The 9.5 mL and
the 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions (5.3)].
8.3 Nursing Mothers
Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate
postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/ml) in breast milk that were equivalent to a milk/plasma ratio of <0.025-0.224. Oral
absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be
exercised when FRAGMIN is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of patients in clinical studies of FRAGMIN, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in
effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance
and literature reports have not revealed additional differences in the safety of FRAGMIN between elderly and younger patients. Give careful attention to dosing
intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight (< 45 kg) and those
predisposed to decreased renal function [see Warnings and Precautions (5) and Clinical Pharmacology (12)].
10 OVERDOSAGE
An excessive dosage of FRAGMIN Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine
sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of FRAGMIN given. If the APTT measured 2 to 4 hours after the first infusion remains
prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of FRAGMIN may be administered. Even with these additional doses of protamine, the
APTT may remain more prolonged than would usually be found following administration of unfractionated heparin. In all cases, the anti-Factor Xa activity is never
completely neutralized (maximum about 60 to 75%).
Take particular care to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions.
Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, give protamine sulfate only when resuscitation techniques and
treatment for anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products.
11 DESCRIPTION
FRAGMIN Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a
needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe
contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin
sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively),
for a total of 95,000 anti-Factor Xa IU per vial.
Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are
preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to
7.5. [See Dosage and Administration (2) and How Supplied (16)
Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic
purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with
an average molecular weight of 5000 and about 90% of the material within the range 2000–9000. The molecular weight distribution is:
< 3000 daltons
3.0–15%
3000 to 8000 daltons
65.0–78.0%
> 8000 daltons
14.0–26.0%
Reference ID: 3692005
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
STRUCTURAL FORMULA structural formula
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dalteparin is a low molecular weight heparin with antithrombotic properties. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In humans,
dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).
12.2 Pharmacodynamics
Doses of FRAGMIN Injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects
did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT.
Subcutaneous administration of doses of 5000 IU twice daily of FRAGMIN for seven consecutive days to patients undergoing abdominal surgery did not markedly
affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
12.3 Pharmacokinetics
Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous doses of 2500, 5000 and 10,000 IU were 0.19 ± 0.04, 0.41 ± 0.07 and 0.82 ± 0.10
IU/mL, respectively, and were attained in about 4 hours in most subjects. Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa activity, was 87
± 6%. Increasing the dose from 2500 to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was greater than proportional by about one-third.
Peak anti-Factor Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Factor Xa
activity with twice-daily dosing of 100 IU/kg subcutaneously for up to 7 days.
The volume of distribution for dalteparin anti-Factor Xa activity was 40 to 60 mL/kg. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal
volunteers following single intravenous bolus doses of 30 and 120 anti-Factor Xa IU/kg were 24.6 ± 5.4 and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean
disposition half-lives were 1.47 ± 0.3 and 2.5 ± 0.3 hours.
Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5
hours) are observed following subcutaneous dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean
terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU FRAGMIN was 5.7 ± 2.0 hours, i.e. considerably longer than values
observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Dalteparin sodium has not been tested for its carcinogenic potential in long-term animal studies. It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell
forward mutation test and human lymphocyte chromosomal aberration test and in the in vivo mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to
1200 IU/kg (7080 IU/m2) did not affect the fertility or reproductive performance of male and female rats.
14 CLINICAL STUDIES
14.1 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
In a double-blind, randomized, placebo-controlled clinical trial, patients who recently experienced unstable angina with EKG changes or non-Q-wave myocardial
infarction (MI) were randomized to FRAGMIN Injection 120 IU/kg or placebo every 12 hours subcutaneously. In this trial, unstable angina was defined to include only
angina with EKG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was
initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 to 8 days. A total of 1506 patients were enrolled
and treated; 746 received FRAGMIN and 760 received placebo. The mean age of the study population was 68 years (range 40 to 90 years) and the majority of patients
were white (99.7%) and male (63.9%). The combined incidence of the endpoint of death or myocardial infarction was lower for FRAGMIN compared with placebo at 6
days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for
intravenous heparin or intravenous. nitroglycerin, and revascularization was also lower for FRAGMIN than for placebo (see Table 10).
Table 10
Efficacy of FRAGMIN in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication
Dosing Regimen
FRAGMIN
120 IU/kg/every 12 hr subcutaneous
n (%)
Placebo
every
12 hr subcutaneous
n (%)
All Treated Unstable Angina and Non-Q-Wave MI
Patients
746
760
Primary Endpoints - 6 day timepoint
Death, MI
13/741 (1.8)1
36/757 (4.8)
Secondary Endpoints - 6 day timepoint
Death, MI, intravenous heparin, i.v. nitroglycerin,
Revascularization
59/739 (8.0)1
106/756 (14.0)
1 p-value = 0.001
12
Reference ID: 3692005
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, controlled trial designed to evaluate long-term treatment with FRAGMIN (days 6 to 45), data were also collected comparing 1-week (5 to 8
days) treatment of FRAGMIN 120 IU/kg every 12 hours subcutaneously with heparin at an APTT-adjusted dosage. All patients, except when contraindicated, were
treated concurrently with aspirin (100 to 165 mg per day). Of the 1499 patients enrolled, 1482 patients were treated; 751 received FRAGMIN and 731 received heparin.
The mean age of the study population was 64 years (range 25 to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the
combined endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for FRAGMIN and 7.6% for heparin
(p=0.323).
14.2 Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery
In an open-label randomized study, FRAGMIN 5000 IU administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients
undergoing hip replacement surgery. Treatment with FRAGMIN was initiated with a 2500 IU dose subcutaneously within 2 hours before surgery, followed by a 2500
IU dose subcutaneously the evening of the day of surgery. Then, a dosing regimen of FRAGMIN 5000 IU subcutaneously once daily was initiated on the first
postoperative day. The first dose of warfarin sodium was given the evening before surgery, then continued daily at a dose adjusted for INR 2 to 3. Treatment in both
groups was then continued for 5 to 9 days postoperatively. Of the 580 patients enrolled, 553 were treated and 550 underwent surgery. Of those who underwent surgery,
271 received FRAGMIN and 279 received warfarin sodium. The mean age of the study population was 63 years (range 20 to 92 years) and the majority of patients were
white (91.1%) and female (52.9%). The incidence of deep vein thrombosis (DVT), as determined by evaluable venography, was significantly lower for the group
treated with FRAGMIN compared with patients treated with warfarin sodium (see Table 11).
Reference ID: 3692005
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 11
Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis
Following Hip Replacement Surgery
Indication
Dosing Regimen
FRAGMIN
5000 IU once daily1 subcutaneous
n (%)
Warfarin Sodium
once daily2 oral
n (%)
All Treated Hip Replacement Surgery Patients
271
279
Treatment Failures in Evaluable Patients
DVT, Total
28/192 (14.6)3
49/190 (25.8)
Proximal DVT
10/192 (5.2)4
16/190 (8.4)
PE
2/271 (0.7)
2/279 (0.7)
1 The daily dose on the day of surgery was divided: 2500 IU was given two hours before surgery and again in the evening of the day of surgery.
2 Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of
approximately 2.5
3 p-value = 0.006
4 p-value = 0.185
In a second single-center, double-blind study of patients undergoing hip replacement surgery, FRAGMIN 5000 IU once daily subcutaneously starting the evening
before surgery, was compared with heparin 5000 U subcutaneously three times a day, starting the morning of surgery. Treatment in both groups was continued for up to
9 days postoperatively. Of the 140 patients enrolled, 139 were treated and 136 underwent surgery. Of those who underwent surgery, 67 received FRAGMIN and 69
received heparin. The mean age of the study population was 69 years (range 42 to 87 years) and the majority of patients were female (58.8%). In the intent-to-treat
analysis, the incidence of proximal DVT was significantly lower for patients treated with FRAGMIN compared with patients treated with heparin (6/67 vs 18/69;
p=0.012). The incidence of pulmonary embolism detected by lung scan was also significantly lower in the group treated with FRAGMIN (9/67 vs 19/69; p=0.032).
A third multi-center, double-blind, randomized study evaluated a postoperative dosing regimen of FRAGMIN for thromboprophylaxis following total hip replacement
surgery. Patients received either FRAGMIN or warfarin sodium, randomized into one of three treatment groups. One group of patients received the first dose of
FRAGMIN 2500 IU subcutaneous within 2 hours before surgery, followed by another dose of FRAGMIN 2500 IU subcutaneous at least 4 hours (6.6 ± 2.3 hr) after
surgery. Another group received the first dose of FRAGMIN 2500 IU subcutaneous at least 4 hours (6.6 ± 2.4 hr) after surgery. Then, both of these groups began a
dosing regimen of FRAGMIN 5000 IU once daily subcutaneous on postoperative day 1. The third group of patients received warfarin sodium the evening of the day of
surgery, then continued daily at a dose adjusted to maintain INR 2 to 3. Treatment for all groups was continued for 4 to 8 days postoperatively, after which time all
patients underwent bilateral venography.
In the total enrolled study population of 1501 patients, 1472 patients were treated; 496 received FRAGMIN (first dose before surgery), 487 received FRAGMIN (first
dose after surgery) and 489 received warfarin sodium. The mean age of the study population was 63 years (range 18 to 91 years) and the majority of patients were white
(94.4%) and female (51.8%).
Administration of the first dose of FRAGMIN after surgery was as effective in reducing the incidence of thromboembolic reactions as administration of the first dose of
FRAGMIN before surgery (44/336 vs 37/338; p=0.448). Both dosing regimens of FRAGMIN were more effective than warfarin sodium in reducing the incidence of
thromboembolic reactions following hip replacement surgery.
14.3 Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications
Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or
who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary embolism.
FRAGMIN administered once daily subcutaneously beginning prior to surgery and continued for 5 to 10 days after surgery, reduced the risk of DVT in patients at risk
for thromboembolic complications in two double-blind, randomized, controlled clinical trials performed in patients undergoing major abdominal surgery. In the first
study, a total of 204 patients were enrolled and treated; 102 received FRAGMIN and 102 received placebo. The mean age of the study population was 64 years (range
40 to 98 years) and the majority of patients were female (54.9%). In the second study, a total of 391 patients were enrolled and treated; 195 received FRAGMIN and
196 received heparin. The mean age of the study population was 59 years (range 30 to 88 years) and the majority of patients were female (51.9%). FRAGMIN 2500 IU
was superior to placebo and similar to heparin in reducing the risk of DVT (see Tables 12 and 13).
Table 12
Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery
Indication
Dosing Regimen
FRAGMIN
2500 IU once daily subcutaneous
n (%)
Placebo
once daily subcutaneous
n (%)
All Treated Abdominal Surgery Patients
102
102
Treatment Failures in Evaluable Patients
Total Thromboembolic Reactions
4/91 (4.4)1
16/91 (17.6)
Proximal DVT
0
5/91 (5.5)
Distal DVT
4/91 (4.4)
11/91 (12.1)
PE
0
2/91 (2.2)2
1 p-value = 0.008
2 Both patients also had DVT, 1 proximal and 1 distal
14
Reference ID: 3692005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 13
Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis
Following Abdominal Surgery
Indication
Dosing Regimen
FRAGMIN
2500 IU once daily
subcutaneous
n (%)
Heparin
5000 U twice daily subcutaneous
n (%)
All Treated Abdominal Surgery Patients
195
196
Treatment Failures in Evaluable Patients
Total Thromboembolic Reactions
7/178 (3.9)1
7/174 (4.0)
Proximal DVT
3/178 (1.7)
4/174 (2.3)
Distal DVT
3/178 (1.7)
3/174 (1.7)
PE
1/178 (0.6)
0
1 p-value = 0.74
In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, FRAGMIN 5000 IU subcutaneous once daily
was compared with FRAGMIN 2500 IU subcutaneous once daily. Treatment was continued for 6 to 8 days. A total of 1375 patients were enrolled and treated; 679
received FRAGMIN 5000 IU and 696 received 2500 IU. The mean age of the combined groups was 71 years (range 40 to 95 years). The majority of patients were
female (51.0%). FRAGMIN 5000 IU once daily was more effective than FRAGMIN 2500 IU once daily in reducing the risk of DVT in patients undergoing abdominal
surgery with malignancy (see Table 14).
Table 14
Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis
Following Abdominal Surgery
Indication
Dosing Regimen
FRAGMIN
2500 IU once daily subcutaneous
n (%)
FRAGMIN
5000 IU once daily subcutaneous
n (%)
All Treated Abdominal Surgery Patients1
696
679
Treatment Failures in Evaluable Patients
Total Thromboembolic Reactions
99/656 (15.1)2
60/645 (9.3)
Proximal DVT
18/657 (2.7)
14/646 (2.2)
Distal DVT
80/657 (12.2)
41/646 (6.3)
PE
Fatal
1/674 (0.1)
1/669 (0.1)
Non-fatal
2
4
1 Major abdominal surgery with malignancy
2 p-value = 0.001
14.4 Prophylaxis of Deep Vein Thrombosis in Medical Patients at Risk for Thromboembolic Complications Due to Severely Restricted Mobility During
Acute Illness
In a double-blind, multi-center, randomized, placebo-controlled clinical trial, general medical patients with severely restricted mobility who were at risk of venous
thromboembolism were randomized to receive either FRAGMIN 5000 IU or placebo subcutaneously once daily during Days 1 to 14 of the study. These patients had an
acute medical condition requiring a projected hospital stay of at least 4 days, and were confined to bed during waking hours. The study included patients with
congestive heart failure (NYHA Class III or IV), acute respiratory failure not requiring ventilatory support, and the following acute conditions with at least one risk
factor occurring in > 1% of treated patients: acute infection (excluding septic shock), acute rheumatic disorder, acute lumbar or sciatic pain, vertebral compression, or
acute arthritis of the lower extremities. Risk factors include > 75 years of age, cancer, previous DVT/PE, obesity and chronic venous insufficiency. A total of 3681
patients were enrolled and treated: 1848 received FRAGMIN and 1833 received placebo. The mean age of the study population was 69 years (range 26 to 99 years),
92.1% were white and 51.9% were female. The primary efficacy endpoint was evaluated at Day 21 and was defined as at least one of the following within Days 1 to 21
of the study: asymptomatic DVT (diagnosed by compression ultrasound), a confirmed symptomatic DVT, a confirmed pulmonary embolism or sudden death. The
follow-up extended through Day 90.
When given at a dose of 5000 IU once a day subcutaneously, FRAGMIN significantly reduced the incidence of thromboembolic reactions including verified DVT by
Day 21 (see Table 15). The prophylactic effect was sustained through Day 90.
Reference ID: 3692005
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 15
Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness
Indication
Dosing Regimen
FRAGMIN
5000 IU once daily subcutaneous
n (%)
Placebo
once daily subcutaneous
n (%)
All Treated Medical Patients
During Acute Illness
1848
1833
Treatment failure in evaluable patients (Day 21)1
DVT, PE, or sudden death
42/1518 (2.8)2
73/1473 (5.0)
Total Thromboembolic Reactions
(Day 21)
37/1513 (2.5)
70/1470 (4.8)
Total DVT
32/1508 (2.1)
64/1464 (4.4)
Proximal DVT
29/1518 (1.9)
60/1474 (4.1)
Symptomatic VTE
10/1759 (0.6)
17/1740 (1.0)
PE
5/1759 (0.3)
6/1740 (0.3)
Sudden Death
5/1829 (0.3)
3/1807 (0.2)
1 Defined as DVT (diagnosed by compression ultrasound at Day 21 + 3),
confirmed symptomatic DVT, confirmed PE or sudden death.
2
2 p-value = 0.0015
14.5 Patients with Cancer and Acute Symptomatic Venous Thromboembolism
In a prospective, multi-center, open-label, clinical trial, 676 patients with cancer and newly diagnosed, objectively confirmed acute deep vein thrombosis (DVT) and/or
pulmonary embolism (PE) were studied. Patients were randomized to either FRAGMIN 200 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for one month)
then 150 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for five months (FRAGMIN arm) or FRAGMIN 200 IU/kg subcutaneous (max 18,000 IU
subcutaneous daily for five to seven days and oral anticoagulant for six months (OAC arm). In the OAC arm, oral anticoagulation was adjusted to maintain an INR of 2
to 3. Patients were evaluated for recurrence of symptomatic venous thromboembolism (VTE) every two weeks for six months.
The median age of patients was 64 years (range: 22 to 89 years); 51.5% of patients were females; 95.3% of patients were Caucasians. Types of tumors were:
gastrointestinal tract (23.7%), genito-urinary (21.5%), breast (16%), lung (13.3%), hematological tumors (10.4%) and other tumors (15.1%).
A total of 27 (8.0%) and 53 (15.7%) patients in the FRAGMIN and OAC arms, respectively, experienced at least one episode of an objectively confirmed, symptomatic
DVT and/or PE during the 6-month study period. Most of the difference occurred during the first month of treatment (see Table 16). The benefit was maintained over
the 6-month study period.
Table 16
Recurrent VTE in Patients with Cancer (Intention to treat population)1
Study Period
FRAGMIN arm
OAC arm
FRAGMIN 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1
month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5
months
FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once
daily x 5-7 days and OAC for 6 months (target INR 2-3)
Number at Risk
Patients with VTE
%
Number at Risk
Patients with VTE
%
Total
338
27
8.0
338
53
15.7
Week 1
338
5
1.5
338
8
2.4
Weeks 2-4
331
6
1.8
327
25
7.6
Weeks 5-28
307
16
5.2
284
20
7.0
1 Three patients in the FRAGMIN arm and 5 patients in the OAC arm experienced more than 1 VTE over the 6-month study period.
In the intent-to-treat population that included all randomized patients, the primary comparison of the cumulative probability of the first VTE recurrence over the 6
month study period was statistically significant (p < 0.01) in favor of the FRAGMIN arm, with most of the treatment difference evident in the first month.
16 HOW SUPPLIED/STORAGE AND HANDLING
After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks.
Reference ID: 3692005
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage Form
Strength
Package Size
NDC Number
2,500 IU / 0.2 mL
10 Syringes
62856-250-10
Single-dose prefilled syringe1
5,000 IU / 0.2 mL
10 Syringes
62856-500-10
7,500 IU / 0.3 mL
10 Syringes
62856-750-10
10,000 IU / 0.4mL
10 Syringes
62856-100-10
Single-dose graduated syringe2
10,000 IU / 1 mL
10 Syringes
62856-101-10
12,500 IU / 0.5mL
10 Syringes
62856-125-10
Single-dose prefilled syringe1
15,000 IU / 0.6 mL
10 Syringes
62856-150-10
18,000 IU / 0.72mL
10 Syringes
62856-180-10
Multiple dose vial
95,000 IU / 3.8 mL
3.8 mL vial
62856-251-01
Multiple dose vial
95,000 IU / 9.5 mL
9.5 mL Vial
62856-102-01
1 Single-dose prefilled syringe, affixed with a 27-gauge x 1/2 inch needle and preassembled with UltraSafe Passive™ Needle Guard devices.
2 Single-dose graduated syringe, affixed with a 27-gauge x 1/2 inch needle and preassembled with UltraSafe Passive™ Needle Guard devices. UltraSafe Passive™
Needle Guard is a trademark of Safety Syringes, Inc.
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
17 PATIENT COUNSELING INFORMATION
If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, inform
the patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any
of these symptoms occur the patient should contact his or her physician immediately.
Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Discontinue their use prior to dalteparin therapy whenever possible; if co
administration is essential, the patient’s clinical and laboratory status should be closely monitored [see Drug Interactions (7)].
Inform patients:
•
of the instructions for injecting FRAGMIN if their therapy is to continue after discharge from the hospitals.
•
it may take them longer than usual to stop bleeding.
•
they may bruise and/or bleed more easily when they are treated with FRAGMIN.
•
they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see
Warnings and Precautions (5.1, 5.2)].
•
to tell their physicians and dentists they are taking FRAGMIN and/or any other product known to affect bleeding before any surgery is scheduled and before
any new drug is taken [see Warnings and Precautions (5.1)].
•
to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see
Drug Interactions (7)].
FRAGMIN is a registered trademark of Pfizer Health AB and is licensed to Eisai Inc. company logo
Manufactured for
Eisai Inc.
Woodcliff Lake, NJ 07677
Manufactured by
Pfizer Inc
New York, NY 10017
Made in Belgium
(multiple-dose vials)
Jointly manufactured by
Pfizer Inc, New York, NY 10017
and Vetter Pharma-Fertigung, GmbH & Co. KG
Ravensburg, Germany
(prefilled syringes)
Reference ID: 3692005
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:23.997732
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020287s062lbl.pdf', 'application_number': 20287, 'submission_type': 'SUPPL ', 'submission_number': 62}
|
12,426
|
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
|
2025-02-12T13:47:24.675152
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/020298Orig1s001.pdf', 'application_number': 20298, 'submission_type': 'SUPPL ', 'submission_number': 1}
|
12,425
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use COREG
safely and effectively. See full prescribing information for COREG.
COREG® (carvedilol) tablets
Initial U.S. Approval: 1995
---------------------------RECENT MAJOR CHANGES -------------------
Warnings and Precautions, Intraoperative Floppy Iris
Month Year
Syndrome (5.14)
----------------------------INDICATIONS AND USAGE--------------------
COREG is an alpha/beta-adrenergic blocking agent indicated for the treatment
of:
•
Mild to severe chronic heart failure (1.1)
•
Left ventricular dysfunction following myocardial infarction in clinically
stable patients (1.2)
•
Hypertension (1.3)
----------------------- DOSAGE AND ADMINISTRATION ---------------
Take with food. Individualize dosage and monitor during up-titration. (2)
•
Heart failure: Start at 3.125 mg twice daily and increase to 6.25, 12.5,
and then 25 mg twice daily over intervals of at least 2 weeks. Maintain
lower doses if higher doses are not tolerated. (2.1)
•
Left ventricular dysfunction following myocardial infarction: Start at
6.25 mg twice daily and increase to 12.5 mg then 25 mg twice daily after
intervals of 3 to 10 days. A lower starting dose or slower titration may
be used. (2.2)
•
Hypertension: Start at 6.25 mg twice daily and increase if needed for
blood pressure control to 12.5 mg then 25 mg twice daily over intervals
of 1 to 2 weeks. (2.3)
---------------------DOSAGE FORMS AND STRENGTHS -------------
Tablets: 3.125, 6.25, 12.5, 25 mg (3)
-------------------------------CONTRAINDICATIONS-----------------------
•
Bronchial asthma or related bronchospastic conditions (4)
•
Second- or third-degree AV block (4)
•
Sick sinus syndrome (4)
•
Severe bradycardia (unless permanent pacemaker in place) (4)
•
Patients in cardiogenic shock or decompensated heart failure requiring the
use of IV inotropic therapy. (4)
•
Severe hepatic impairment (2.4, 4)
•
History of serious hypersensitivity reaction (e.g., Stevens-Johnson
syndrome, anaphylactic reaction, angioedema) to any component of this
medication or other medications containing carvedilol. (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
•
Acute exacerbation of coronary artery disease upon cessation of therapy:
Do not abruptly discontinue. (5.1)
•
Bradycardia, hypotension, worsening heart failure/fluid retention may
occur. Reduce the dose as needed. (5.2, 5.3, 5.4)
•
Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema):
Avoid β-blockers. (4) However, if deemed necessary, use with caution
and at lowest effective dose. (5.5)
•
Diabetes: Monitor glucose as β-blockers may mask symptoms of
hypoglycemia or worsen hyperglycemia. (5.6)
------------------------------ ADVERSE REACTIONS ----------------------
Most common adverse events (6.1):
•
Heart failure and left ventricular dysfunction following myocardial
infarction (≥10%): Dizziness, fatigue, hypotension, diarrhea,
hyperglycemia, asthenia, bradycardia, weight increase
•
Hypertension (≥5%): Dizziness
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-----------------------
•
CYP P450 2D6 enzyme inhibitors may increase and rifampin may
decrease carvedilol levels. (7.1, 7.5)
•
Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may
increase the risk of hypotension and/or severe bradycardia. (7.2)
•
Cyclosporine or digoxin levels may increase. (7.3, 7.4)
•
Both digitalis glycosides and β-blockers slow atrioventricular
conduction and decrease heart rate. Concomitant use can increase the
risk of bradycardia. (7.4)
•
Amiodarone may increase carvedilol levels resulting in further slowing
of the heart rate or cardiac conduction. (7.6)
•
Verapamil- or diltiazem-type calcium channel blockers may affect ECG
and/or blood pressure. (7.7)
•
Insulin and oral hypoglycemics action may be enhanced. (7.8)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: Month Year
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Heart Failure
1.2
Left Ventricular Dysfunction Following
My cardial Infarction
o
1.3
Hypertension
2
DOSAGE AND ADMINISTRATION
2.1
Heart Failure
2.2
Left Ventricular Dysfunction Following
My cardial Infarction
o
2.3
Hypertension
2.4
Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WA RNINGS AND PRECAUT IO NS
5.1
Cessation of Therapy
5.2
Bradycardia
5.3
Hypotension
5.4
Heart Failure/Fluid Retention
5.5
Non-allergic Bronchospasm
5.6
Glycemic Control in Type 2 Diabetes
5.7
Peripheral Vascular Disease
5.8
Deterioration of Renal Function
5.9
Anesthesia and Major Surgery
5.10
Thyrotoxicosis
5.11
Pheochromocytoma
5.12
Prinzmetal’s Variant Angina
5.13
Risk of Anaphylactic Reaction
5.14
Intraoperative Floppy Iris Syndrome
6
AD ERSE REACTIONS
V
6.1
Clinical Studies Experience
6.2
Laboratory Abnormalities
6.3
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
CYP2D6 Inhibitors and Poor Metabolizers
7.2
Hypotensive Agents
7.3
Cyclosporine
7.4
Digitalis Glycosides
7.5
Inducers/Inhibitors of Hepatic Metabolism
7.6
Amiodarone
7.7
Calcium Channel Blockers
7.8
Insulin or Oral Hypoglycemics
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.4
Specific Populations
12.5
Drug-Drug Interactions
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
14.1
Heart Failure
14.2
Left Ventricular Dysfunction Following
Myocardial Infarction
14.3
Hypertension
14.4
Hypertension With Type 2 Diabetes Mellitus
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1
Patient Advice
17.2
FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
1
Reference ID: 2896475
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
1
INDICATIONS AND USAGE
3
1.1
Heart Failure
4
COREG is indicated for the treatment of mild-to-severe chronic heart failure of ischemic
5
or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to
6
increase survival and, also, to reduce the risk of hospitalization [see Drug Interactions (7.4) and
7
Clinical Studies (14.1)].
8
1.2
Left Ventricular Dysfunction Following Myocardial Infarction
9
COREG is indicated to reduce cardiovascular mortality in clinically stable patients who
10
have survived the acute phase of a myocardial infarction and have a left ventricular ejection
11
fraction of ≤40% (with or without symptomatic heart failure) [see Clinical Studies (14.2)].
12
1.3
Hypertension
13
COREG is indicated for the management of essential hypertension [see Clinical Studies
14
(14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents,
15
especially thiazide-type diuretics [see Drug Interactions (7.2)].
16
2
DOSAGE AND ADMINISTRATION
17
COREG should be taken with food to slow the rate of absorption and reduce the
18
incidence of orthostatic effects.
19
2.1
Heart Failure
20
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A
21
PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG, it is recommended that
22
fluid retention be minimized. The recommended starting dose of COREG is 3.125 mg twice
23
daily for 2 weeks. If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg
24
twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower
25
doses if higher doses are not tolerated. A maximum dose of 50 mg twice daily has been
26
administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs).
27
Patients should be advised that initiation of treatment and (to a lesser extent) dosage
28
increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely
29
syncope) within the first hour after dosing. During these periods, patients should avoid situations
30
such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory
31
symptoms often do not require treatment, but it may be useful to separate the time of dosing of
32
COREG from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor.
33
The dose of COREG should not be increased until symptoms of worsening heart failure or
34
vasodilation have been stabilized.
35
Fluid retention (with or without transient worsening heart failure symptoms) should be
36
treated by an increase in the dose of diuretics.
Reference ID: 2896475
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
The dose of COREG should be reduced if patients experience bradycardia (heart rate
38
<55 beats/minute).
39
Episodes of dizziness or fluid retention during initiation of COREG can generally be
40
managed without discontinuation of treatment and do not preclude subsequent successful
41
titration of, or a favorable response to, carvedilol.
42
2.2
Left Ventricular Dysfunction Following Myocardial Infarction
43
DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING
44
UP-TITRATION. Treatment with COREG may be started as an inpatient or outpatient and
45
should be started after the patient is hemodynamically stable and fluid retention has been
46
minimized. It is recommended that COREG be started at 6.25 mg twice daily and increased after
47
3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg
48
twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of
49
up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or
50
fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated.
51
The recommended dosing regimen need not be altered in patients who received treatment with an
52
IV or oral β-blocker during the acute phase of the myocardial infarction.
53
2.3
Hypertension
54
DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of COREG
55
is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about
56
1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased
57
to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic
58
pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7
59
to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full
60
antihypertensive effect of COREG is seen within 7 to 14 days. Total daily dose should not
61
exceed 50 mg.
62
Concomitant administration with a diuretic can be expected to produce additive effects
63
and exaggerate the orthostatic component of carvedilol action.
64
2.4
Hepatic Impairment
65
COREG should not be given to patients with severe hepatic impairment [see
66
Contraindications (4)].
67
3
DOSAGE FORMS AND STRENGTHS
68
The white, oval, film-coated tablets are available in the following strengths: 3.125 mg–
69
engraved with 39 and SB, 6.25 mg–engraved with 4140 and SB, 12.5 mg–engraved with 4141
70
and SB, and 25 mg–engraved with 4142 and SB.
71
4
CONTRAINDICATIONS
72
COREG is contraindicated in the following conditions:
73
• Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have
74
been reported following single doses of COREG.
75
• Second- or third-degree AV block
Reference ID: 2896475
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
76
• Sick sinus syndrome
77
• Severe bradycardia (unless a permanent pacemaker is in place)
78
• Patients with cardiogenic shock or who have decompensated heart failure requiring the use of
79
intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy
80
before initiating COREG.
81
• Patients with severe hepatic impairment
82
• Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson
83
syndrome, anaphylactic reaction, angioedema) to any component of this medication or other
84
medications containing carvedilol.
85
5
WARNINGS AND PRECAUTIONS
86
5.1
Cessation of Therapy
87
Patients with coronary artery disease, who are being treated with COREG, should
88
be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and
89
the occurrence of myocardial infarction and ventricular arrhythmias have been reported in
90
angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2
91
complications may occur with or without preceding exacerbation of the angina pectoris. As
92
with other β-blockers, when discontinuation of COREG is planned, the patients should be
93
carefully observed and advised to limit physical activity to a minimum. COREG should be
94
discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary
95
insufficiency develops, it is recommended that COREG be promptly reinstituted, at least
96
temporarily. Because coronary artery disease is common and may be unrecognized, it may
97
be prudent not to discontinue therapy with COREG abruptly even in patients treated only
98
for hypertension or heart failure.
99
5.2
Bradycardia
100
In clinical trials, COREG caused bradycardia in about 2% of hypertensive patients, 9% of
101
heart failure patients, and 6.5% of myocardial infarction patients with left ventricular
102
dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
103
5.3
Hypotension
104
In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural
105
hypotension occurred in 9.7% and syncope in 3.4% of patients receiving COREG compared to
106
3.6% and 2.5% of placebo patients, respectively. The risk for these events was highest during the
107
first 30 days of dosing, corresponding to the up-titration period and was a cause for
108
discontinuation of therapy in 0.7% of patients receiving COREG, compared to 0.4% of placebo
109
patients. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS),
110
hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure
111
patients receiving COREG compared to 8.7% and 2.3% of placebo patients, respectively. These
112
events were a cause for discontinuation of therapy in 1.1% of patients receiving COREG,
113
compared to 0.8% of placebo patients.
Reference ID: 2896475
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
114
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients,
115
primarily following the initial dose or at the time of dose increase and was a cause for
116
discontinuation of therapy in 1% of patients.
117
In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or
118
postural hypotension occurred in 20.2% of patients receiving COREG compared to 12.6% of
119
placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events
120
were a cause for discontinuation of therapy in 2.5% of patients receiving COREG, compared to
121
0.2% of placebo patients.
122
Starting with a low dose, administration with food, and gradual up-titration should
123
decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration
124
(2.1, 2.2, 2.3)]. During initiation of therapy, the patient should be cautioned to avoid situations
125
such as driving or hazardous tasks, where injury could result should syncope occur.
126
5.4
Heart Failure/Fluid Retention
127
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If
128
such symptoms occur, diuretics should be increased and the carvedilol dose should not be
129
advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is
130
necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not
131
preclude subsequent successful titration of, or a favorable response to, carvedilol. In a
132
placebo-controlled trial of patients with severe heart failure, worsening heart failure during the
133
first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment
134
was maintained beyond 3 months, worsening heart failure was reported less frequently in
135
patients treated with carvedilol than with placebo. Worsening heart failure observed during
136
long-term therapy is more likely to be related to the patients’ underlying disease than to
137
treatment with carvedilol.
138
5.5
Non-allergic Bronchospasm
139
Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in
140
general, not receive β-blockers. COREG may be used with caution, however, in patients who do
141
not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG is used,
142
to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is
143
minimized.
144
In clinical trials of patients with heart failure, patients with bronchospastic disease were
145
enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In
146
such patients, it is recommended that carvedilol be used with caution. The dosing
147
recommendations should be followed closely and the dose should be lowered if any evidence of
148
bronchospasm is observed during up-titration.
149
5.6
Glycemic Control in Type 2 Diabetes
150
In general, β-blockers may mask some of the manifestations of hypoglycemia,
151
particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia
152
and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or
Reference ID: 2896475
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
153
diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these
154
possibilities.
155
In heart failure patients with diabetes, carvedilol therapy may lead to worsening
156
hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended
157
that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued.
158
Studies designed to examine the effects of carvedilol on glycemic control in patients with
159
diabetes and heart failure have not been conducted.
160
In a study designed to examine the effects of carvedilol on glycemic control in a
161
population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus,
162
carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see
163
Clinical Studies (14.4)].
164
5.7
Peripheral Vascular Disease
165
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients
166
with peripheral vascular disease. Caution should be exercised in such individuals.
167
5.8
Deterioration of Renal Function
168
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of
169
renal function. Patients at risk appear to be those with low blood pressure (systolic blood
170
pressure <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying
171
renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In
172
patients with these risk factors it is recommended that renal function be monitored during
173
up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal
174
function occurs.
175
5.9
Anesthesia and Major Surgery
176
If treatment with COREG is to be continued perioperatively, particular care should be
177
taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane,
178
and trichloroethylene, are used [see Overdosage (10) for information on treatment of
179
bradycardia and hypertension].
180
5.10 Thyrotoxicosis
181
β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia.
182
Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of
183
hyperthyroidism or may precipitate thyroid storm.
184
5.11 Pheochromocytoma
185
In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the
186
use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic
187
activities, there has been no experience with its use in this condition. Therefore, caution should
188
be taken in the administration of carvedilol to patients suspected of having pheochromocytoma.
189
5.12 Prinzmetal’s Variant Angina
190
Agents with non-selective β-blocking activity may provoke chest pain in patients with
191
Prinzmetal’s variant angina. There has been no clinical experience with carvedilol in these
192
patients although the α-blocking activity may prevent such symptoms. However, caution should
Reference ID: 2896475
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
193
194
195
196
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
229
230
be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant
angina.
5.13 Risk of Anaphylactic Reaction
While taking β-blockers, patients with a history of severe anaphylactic reaction to a
variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or
therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat
allergic reaction.
5.14 Intraoperative Floppy Iris Syndrome
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in
some patients treated with alpha-1 blockers (COREG is an alpha/beta blocker). 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 ophthalmologist should be prepared for possible
modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or
viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker
therapy prior to cataract surgery.
6
ADVERSE REACTIONS
6.1
Clinical Studies Experience
COREG has been evaluated for safety in patients with heart failure (mild, moderate, and
severe), in patients with left ventricular dysfunction following myocardial infarction and in
hypertensive patients. The observed adverse event profile was consistent with the pharmacology
of the drug and the health status of the patients in the clinical trials. Adverse events reported for
each of these patient populations are provided below. Excluded are adverse events considered
too general to be informative, and those not reasonably associated with the use of the drug
because they were associated with the condition being treated or are very common in the treated
population. Rates of adverse events were generally similar across demographic subsets (men and
women, elderly and non-elderly, blacks and non-blacks).
Heart Failure: COREG has been evaluated for safety in heart failure in more than
4,500 patients worldwide of whom more than 2,100 participated in placebo-controlled clinical
trials. Approximately 60% of the total treated population in placebo-controlled clinical trials
received COREG for at least 6 months and 30% received COREG for at least 12 months. In the
COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with COREG for
up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that
compared COREG in daily doses up to 100 mg (n = 765) to placebo (n = 437), and in a
multinational clinical trial in severe heart failure (COPERNICUS) that compared COREG in
daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse
experiences were similar in carvedilol and placebo patients. In placebo-controlled clinical trials,
Reference ID: 2896475
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
231
the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness
232
(1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).
233
Table 1 shows adverse events reported in patients with mild-to-moderate heart failure
234
enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the
235
COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated
236
patients than placebo-treated patients with an incidence of >3% in patients treated with
237
carvedilol regardless of causality. Median study medication exposure was 6.3 months for both
238
carvedilol and placebo patients in the trials of mild-to-moderate heart failure, and 10.4 months in
239
the trial of severe heart failure patients. The adverse event profile of COREG observed in the
240
long-term COMET study was generally similar to that observed in the US Heart Failure Trials.
241
Reference ID: 2896475
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
242
Table 1. Adverse Events (%) Occurring More Frequently With COREG Than With
243
Placebo in Patients With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart
244
Failure Trials or in Patients With Severe Heart Failure in the COPERNICUS Trial
245
(Incidence >3% in Patients Treated With Carvedilol, Regardless of Causality)
Mild-to-Moderate HF
Severe HF
COREG
Placebo
COREG
Placebo
(n = 765)
(n = 437)
(n = 1,156)
(n = 1,133)
Body as a Whole
Asthenia
Fatigue
Digoxin level increased
Edema generalized
Edema dependent
7
24
5
5
4
7
22
4
3
2
11
—
2
6
—
9
—
1
5
—
Cardiovascular
Bradycardia
Hypotension
Syncope
Angina pectoris
9
9
3
2
1
3
3
3
10
14
8
6
3
8
5
4
Central Nervous System
Dizziness
Headache
32
8
19
7
24
5
17
3
Gastrointestinal
Diarrhea
Nausea
Vomiting
12
9
6
6
5
4
5
4
1
3
3
2
Metabolic
Hyperglycemia
Weight increase
BUN increased
NPN increased
Hypercholesterolemia
Edema peripheral
12
10
6
6
4
2
8
7
5
5
3
1
5
12
—
—
1
7
3
11
—
—
1
6
Musculoskeletal
Arthralgia
6
5
1
1
Respiratory
Cough increased
Rales
8
4
9
4
5
4
4
2
Vision
Vision abnormal
5
2
—
—
Reference ID: 2896475
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246
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
247
Cardiac failure and dyspnea were also reported in these studies, but the rates were equal
248
or greater in patients who received placebo.
249
The following adverse events were reported with a frequency of >1% but ≤3% and more
250
frequently with COREG in either the US placebo-controlled trials in patients with
251
mild-to-moderate heart failure, or in patients with severe heart failure in the COPERNICUS trial.
252
Incidence >1% to ≤3%
253
Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
254
Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV
255
block, palpitation, hypertension.
256
Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.
257
Gastrointestinal: Melena, periodontitis.
258
Liver and Biliary System: SGPT increased, SGOT increased.
259
Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased
260
alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss,
261
hyperkalemia, creatinine increased.
262
Musculoskeletal: Muscle cramps.
263
Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocytopenia.
264
Psychiatric: Somnolence.
265
Reproductive, male: Impotence.
266
Special Senses: Blurred vision.
267
Urinary System: Renal insufficiency, albuminuria, hematuria.
268
Left Ventricular Dysfunction Following Myocardial Infarction: COREG has been
269
evaluated for safety in survivors of an acute myocardial infarction with left ventricular
270
dysfunction in the CAPRICORN trial which involved 969 patients who received COREG and
271
980 who received placebo. Approximately 75% of the patients received COREG for at least
272
6 months and 53% received COREG for at least 12 months. Patients were treated for an average
273
of 12.9 months and 12.8 months with COREG and placebo, respectively.
274
The most common adverse events reported with COREG in the CAPRICORN trial were
275
consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial.
276
The only additional adverse events reported in CAPRICORN in >3% of the patients and more
277
commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events
278
were reported with a frequency of >1% but ≤3% and more frequently with COREG: Flu
279
syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression,
280
gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse
281
events were similar in both groups of patients. In this database, the only cause of discontinuation
282
>1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on
283
placebo).
284
Hypertension: COREG has been evaluated for safety in hypertension in more than
285
2,193 patients in US clinical trials and in 2,976 patients in international clinical trials.
286
Approximately 36% of the total treated population received COREG for at least 6 months. Most
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287
adverse events reported during therapy with COREG were of mild to moderate severity. In US
288
controlled clinical trials directly comparing COREG in doses up to 50 mg (n = 1,142) to placebo
289
(n = 462), 4.9% of patients receiving COREG discontinued for adverse events versus 5.2% of
290
placebo patients. Although there was no overall difference in discontinuation rates,
291
discontinuations were more common in the carvedilol group for postural hypotension (1% versus
292
0). The overall incidence of adverse events in US placebo-controlled trials increased with
293
increasing dose of COREG. For individual adverse events this could only be distinguished for
294
dizziness, which increased in frequency from 2% to 5% as total daily dose increased from
295
6.25 mg to 50 mg.
296
Table 2 shows adverse events in US placebo-controlled clinical trials for hypertension
297
that occurred with an incidence of ≥1% regardless of causality, and that were more frequent in
298
drug-treated patients than placebo-treated patients.
299
300
Table 2. Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials
301
(Incidence ≥1%, Regardless of Causality)*
COREG
Placebo
(n = 1,142)
(n = 462)
Cardiovascular
Bradycardia
Postural hypotension
Peripheral edema
2
2
1
—
—
—
Central Nervous System
Dizziness
Insomnia
6
2
5
1
Gastrointestinal
Diarrhea
2
1
Hematologic
Thrombocytopenia
1
—
Metabolic
Hypertriglyceridemia
1
—
302
* Shown are events with rate >1% rounded to nearest integer.
303
304
Dyspnea and fatigue were also reported in these studies, but the rates were equal or
305
greater in patients who received placebo.
306
The following adverse events not described above were reported as possibly or probably
307
related to COREG in worldwide open or controlled trials with COREG in patients with
308
hypertension or heart failure.
309
Incidence >0.1% to ≤1%
310
Cardiovascular: Peripheral ischemia, tachycardia.
311
Central and Peripheral Nervous System: Hypokinesia.
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Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension
313
patients and 0.4% of heart failure patients were discontinued from therapy because of increases
314
in hepatic enzymes) [see Adverse Reactions (6.2)].
315
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration,
316
abnormal thinking, paroniria, emotional lability.
317
Respiratory System: Asthma [see Contraindications (4)].
318
Reproductive, male: Decreased libido.
319
Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform,
320
photosensitivity reaction.
321
Special Senses: Tinnitus.
322
Urinary System: Micturition frequency increased.
323
Autonomic Nervous System: Dry mouth, sweating increased.
324
Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.
325
Hematologic: Anemia, leukopenia.
326
The following events were reported in ≤0.1% of patients and are potentially important:
327
Complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder,
328
convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative
329
dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing,
330
respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
331
6.2
Laboratory Abnormalities
332
Reversible elevations in serum transaminases (ALT or AST) have been observed during
333
treatment with COREG. Rates of transaminase elevations (2- to 3-times the upper limit of
334
normal) observed during controlled clinical trials have generally been similar between patients
335
treated with COREG and those treated with placebo. However, transaminase elevations,
336
confirmed by rechallenge, have been observed with COREG. In a long-term, placebo-controlled
337
trial in severe heart failure, patients treated with COREG had lower values for hepatic
338
transaminases than patients treated with placebo, possibly because improvements in cardiac
339
function induced by COREG led to less hepatic congestion and/or improved hepatic blood flow.
340
COREG has not been associated with clinically significant changes in serum potassium,
341
total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or
342
creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive
343
patients; fasting serum glucose was not evaluated in the heart failure clinical trials.
344
6.3
Postmarketing Experience
345
The following adverse reactions have been identified during post-approval use of
346
COREG. Because these reactions are reported voluntarily from a population of uncertain size, it
347
is not always possible to reliably estimate their frequency or establish a causal relationship to
348
drug exposure.
349
Reports of aplastic anemia and severe skin reactions (Stevens-Johnson syndrome, toxic
350
epidermal necrolysis, and erythema multiforme) have been rare and received only when
351
carvedilol was administered concomitantly with other medications associated with such
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352
reactions. Rare reports of hypersensitivity reactions (e.g., anaphylactic reaction, angioedema, and
353
urticaria) have been received for COREG and COREG CR®, including cases occurring after the
354
initiation of COREG CR in patients previously treated with COREG. Urinary incontinence in
355
women (which resolved upon discontinuation of the medication) and interstitial pneumonitis
356
have been reported rarely.
357
7
DRUG INTERACTIONS
358
7.1
CYP2D6 Inhibitors and Poor Metabolizers
359
Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as
360
quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would
361
be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical
362
Pharmacology (12.3)]. Retrospective analysis of side effects in clinical trials showed that poor
363
2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from
364
vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.
365
7.2
Hypotensive Agents
366
Patients taking both agents with β-blocking properties and a drug that can deplete
367
catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely
368
for signs of hypotension and/or severe bradycardia.
369
Concomitant administration of clonidine with agents with β-blocking properties may
370
potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with
371
agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should
372
be discontinued first. Clonidine therapy can then be discontinued several days later by gradually
373
decreasing the dosage.
374
7.3
Cyclosporine
375
Modest increases in mean trough cyclosporine concentrations were observed following
376
initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular
377
rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to
378
maintain cyclosporine concentrations within the therapeutic range, while in the remainder no
379
adjustment was needed. On the average for the group, the dose of cyclosporine was reduced
380
about 20% in these patients. Due to wide interindividual variability in the dose adjustment
381
required, it is recommended that cyclosporine concentrations be monitored closely after initiation
382
of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
383
7.4
Digitalis Glycosides
384
Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease
385
heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are
386
increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore,
387
increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing
388
COREG [see Clinical Pharmacology (12.5)].
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389
7.5
Inducers/Inhibitors of Hepatic Metabolism
390
Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical
391
Pharmacology (12.5)]. Cimetidine increased AUC by about 30% but caused no change in Cmax
392
[see Clinical Pharmacology (12.5)].
393
7.6
Amiodarone
394
Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P
395
glycoprotein, increased concentrations of the S(-)-enantiomer of carvedilol by at least 2-fold [see
396
Clinical Pharmacology (12.5)]. The concomitant administration of amiodarone or other CYP2C9
397
inhibitors such as fluconazole with COREG may enhance the β-blocking properties of carvedilol
398
resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed
399
for signs of bradycardia or heart block, particularly when one agent is added to pre-existing
400
treatment with the other.
401
7.7
Calcium Channel Blockers
402
Conduction disturbance (rarely with hemodynamic compromise) has been observed when
403
COREG is co-administered with diltiazem. As with other agents with β-blocking properties, if
404
COREG is to be administered with calcium channel blockers of the verapamil or diltiazem type,
405
it is recommended that ECG and blood pressure be monitored.
406
7.8
Insulin or Oral Hypoglycemics
407
Agents with β-blocking properties may enhance the blood-sugar-reducing effect of
408
insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics,
409
regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)].
410
8
USE IN SPECIFIC POPULATIONS
411
8.1
Pregnancy
412
Pregnancy Category C. Studies performed in pregnant rats and rabbits given carvedilol
413
revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the
414
maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of
415
75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body
416
weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which
417
was accompanied by an elevation in the frequency of fetuses with delayed skeletal development
418
(missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was
419
60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the
420
MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women.
421
COREG should be used during pregnancy only if the potential benefit justifies the potential risk
422
to the fetus.
423
8.3
Nursing Mothers
424
It is not known whether this drug is excreted in human milk. Studies in rats have shown
425
that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and
426
are excreted in breast milk. There was increased mortality at one week post-partum in neonates
427
from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last
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428
trimester through day 22 of lactation. Because many drugs are excreted in human milk and
429
because of the potential for serious adverse reactions in nursing infants from β-blockers,
430
especially bradycardia, a decision should be made whether to discontinue nursing or to
431
discontinue the drug, taking into account the importance of the drug to the mother. The effects of
432
other α- and β-blocking agents have included perinatal and neonatal distress.
433
8.4
Pediatric Use
434
Effectiveness of COREG in patients younger than 18 years of age has not been
435
established.
436
In a double-blind trial, 161 children (mean age 6 years, range 2 months to 17 years; 45%
437
less than 2 years old) with chronic heart failure [NYHA class II-IV, left ventricular ejection
438
fraction <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular
439
dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who
440
were receiving standard background treatment were randomized to placebo or to 2 dose levels of
441
carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4-6 heart beats
442
per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric subjects
443
than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical
444
outcomes. Adverse reactions in this trial that occurred in greater than 10% of patients treated
445
with COREG and at twice the rate of placebo-treated patients included chest pain (17% versus
446
6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
447
8.5
Geriatric Use
448
Of the 765 patients with heart failure randomized to COREG in US clinical trials, 31%
449
(235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the
450
1,156 patients randomized to COREG in a long-term, placebo-controlled trial in severe heart
451
failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older.
452
Of 3,025 patients receiving COREG in heart failure trials worldwide, 42% were 65 years of age
453
or older.
454
Of the 975 myocardial infarction patients randomized to COREG in the CAPRICORN
455
trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.
456
Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were
457
treated with COREG, 21% (436) were 65 years of age or older. Of 3,722 patients receiving
458
COREG in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.
459
With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly
460
versus 6% in younger patients), no overall differences in the safety or effectiveness (see Figures
461
2 and 4) were observed between the older subjects and younger subjects in each of these
462
populations. Similarly, other reported clinical experience has not identified differences in
463
responses between the elderly and younger subjects, but greater sensitivity of some older
464
individuals cannot be ruled out.
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s
tructural formula
465
10
OVERDOSAGE
466
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency,
467
cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of
468
consciousness, and generalized seizures may also occur.
469
The patient should be placed in a supine position and, where necessary, kept under
470
observation and treated under intensive-care conditions. Gastric lavage or pharmacologically
471
induced emesis may be used shortly after ingestion. The following agents may be administered:
472
for excessive bradycardia: Atropine, 2 mg IV.
473
to support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds,
474
followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline,
475
adrenaline) at doses according to body weight and effect.
476
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or
477
noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant
478
bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics
479
(as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV
480
injection of diazepam or clonazepam is recommended.
481
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment
482
with antidotes must be continued for a sufficiently long period of time consistent with the 7- to
483
10-hour half-life of carvedilol.
484
Cases of overdosage with COREG alone or in combination with other drugs have been
485
reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced
486
included low blood pressure and heart rate. Standard supportive treatment was provided and
487
individuals recovered.
488
11
DESCRIPTION
489
Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is
490
(±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. Carvedilol is a
491
racemic mixture with the following structure:
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49
493
COREG is a white, oval, film-coated tablet containing 3.125 mg, 6.25 mg, 12.5 mg, or
494
25 mg of carvedilol. The 6.25 mg, 12.5 mg, and 25 mg tablets are TILTAB® tablets. Inactive
495
ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium
496
stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide.
497
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a
498
molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene
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For current labeling information, please visit https://www.fda.gov/drugsatfda
499
chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in
500
ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal
501
fluid (simulated, TS without pancreatin, pH 7.5).
502
12
CLINICAL PHARMACOLOGY
503
12.1 Mechanism of Action
504
COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is
505
present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and
506
S(-) enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.
507
12.2 Pharmacodynamics
508
Heart Failure: The basis for the beneficial effects of COREG in heart failure is not
509
established.
510
Two placebo-controlled studies compared the acute hemodynamic effects of COREG to
511
baseline measurements in 59 and 49 patients with NYHA class II-IV heart failure receiving
512
diuretics, ACE inhibitors, and digitalis. There were significant reductions in systemic blood
513
pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial
514
effects on cardiac output, stroke volume index, and systemic vascular resistance were small and
515
variable.
516
These studies measured hemodynamic effects again at 12 to 14 weeks. COREG
517
significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure,
518
systemic vascular resistance, and heart rate, while stroke volume index was increased.
519
Among 839 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in
520
4 US placebo-controlled trials, average left ventricular ejection fraction (EF) measured by
521
radionuclide ventriculography increased by 9 EF units (%) in patients receiving COREG and by
522
2 EF units in placebo patients at a target dose of 25-50 mg twice daily. The effects of carvedilol
523
on ejection fraction were related to dose. Doses of 6.25 mg twice daily, 12.5 mg twice daily, and
524
25 mg twice daily were associated with placebo-corrected increases in EF of 5 EF units, 6 EF
525
units, and 8 EF units, respectively; each of these effects were nominally statistically significant.
526
Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the
527
beneficial effects of COREG in patients with left ventricular dysfunction following an acute
528
myocardial infarction is not established.
529
Hypertension: The mechanism by which β-blockade produces an antihypertensive effect
530
has not been established.
531
β-adrenoreceptor blocking activity has been demonstrated in animal and human studies
532
showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise-
533
and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia.
534
Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
535
α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies,
536
showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes
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537
vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the
538
reduction of blood pressure and usually are seen within 30 minutes of drug administration.
539
Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in
540
the standing than in the supine position, and symptoms of postural hypotension (1.8%), including
541
rare instances of syncope, can occur. Following oral administration, when postural hypotension
542
has occurred, it has been transient and is uncommon when COREG is administered with food at
543
the recommended starting dose and titration increments are closely followed [see Dosage and
544
Administration (2)].
545
In hypertensive patients with normal renal function, therapeutic doses of COREG
546
decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma
547
flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive
548
patients with normal renal function were similar after COREG and placebo.
549
COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte
550
levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It
551
also increases levels of atrial natriuretic peptide.
552
12.3 Pharmacokinetics
553
COREG is rapidly and extensively absorbed following oral administration, with absolute
554
bioavailability of approximately 25% to 35% due to a significant degree of first-pass
555
metabolism. Following oral administration, the apparent mean terminal elimination half-life of
556
carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional
557
to the oral dose administered. When administered with food, the rate of absorption is slowed, as
558
evidenced by a delay in the time to reach peak plasma levels, with no significant difference in
559
extent of bioavailability. Taking COREG with food should minimize the risk of orthostatic
560
hypotension.
561
Carvedilol is extensively metabolized. Following oral administration of radiolabelled
562
carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity
563
in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted
564
unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and
565
glucuronidation. The oxidative metabolites are further metabolized by conjugation via
566
glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile
567
into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites
568
with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite
569
is approximately 13 times more potent than carvedilol for β-blockade.
570
Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity.
571
Plasma concentrations of the active metabolites are about one-tenth of those observed for
572
carvedilol and have pharmacokinetics similar to the parent.
573
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of
574
R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral
575
administration in healthy subjects. The mean apparent terminal elimination half-lives for
576
R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
577
The primary P450 enzymes responsible for the metabolism of both R(+) and
578
S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent
579
CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and
580
5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be
581
of primary importance in the O-methylation pathway of S(-)-carvedilol.
582
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of
583
debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma
584
concentrations of R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels
585
of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this
586
enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The
587
pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of
588
S-mephenytoin (patients deficient in cytochrome P450 2C19).
589
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The
590
plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is
591
a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L,
592
indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to
593
700 mL/min.
594
12.4 Specific Populations
595
Heart Failure: Steady-state plasma concentrations of carvedilol and its enantiomers
596
increased proportionally over the 6.25 to 50 mg dose range in patients with heart failure.
597
Compared to healthy subjects, heart failure patients had increased mean AUC and Cmax values
598
for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 patients
599
with NYHA class IV heart failure. The mean apparent terminal elimination half-life for
600
carvedilol was similar to that observed in healthy subjects.
601
Geriatric: Plasma levels of carvedilol average about 50% higher in the elderly compared
602
to young subjects.
603
Hepatic Impairment: Compared to healthy subjects, patients with severe liver
604
impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is
605
contraindicated in patients with severe liver impairment.
606
Renal Impairment: Although carvedilol is metabolized primarily by the liver, plasma
607
concentrations of carvedilol have been reported to be increased in patients with renal
608
impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations
609
of carvedilol were observed in hypertensive patients with moderate to severe renal impairment
610
compared to a control group of hypertensive patients with normal renal function. However, the
611
ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were
612
less pronounced, approximately 12% to 26% higher in patients with impaired renal function.
613
Consistent with its high degree of plasma protein-binding, carvedilol does not appear to
614
be cleared significantly by hemodialysis.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
615
12.5 Drug-Drug Interactions
616
Since carvedilol undergoes substantial oxidative metabolism, the metabolism and
617
pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450
618
enzymes.
619
Amiodarone: In a pharmacokinetic study conducted in 106 Japanese patients with heart
620
failure, coadministration of small loading and maintenance doses of amiodarone with carvedilol
621
resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-)-carvedilol
622
[see Drug Interactions (7.6)].
623
Cimetidine: In a pharmacokinetic study conducted in 10 healthy male subjects,
624
cimetidine (1,000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change
625
in Cmax [see Drug Interactions (7.5)].
626
Digoxin: Following concomitant administration of carvedilol (25 mg once daily) and
627
digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin
628
were increased by 14% and 16%, respectively, in 12 hypertensive patients [see Drug
629
Interactions (7.4)].
630
Glyburide: In 12 healthy subjects, combined administration of carvedilol (25 mg once
631
daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic
632
interaction for either compound.
633
Hydrochlorothiazide: A single oral dose of carvedilol 25 mg did not alter the
634
pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 patients with
635
hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.
636
Rifampin: In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin
637
(600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70% [see Drug
638
Interactions (7.5)].
639
Torsemide: In a study of 12 healthy subjects, combined oral administration of carvedilol
640
25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant
641
differences in their pharmacokinetics compared with administration of the drugs alone.
642
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state
643
prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin
644
following concomitant administration with warfarin in 9 healthy volunteers.
645
13
NONCLINICAL TOXICOLOGY
646
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
647
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times
648
the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times
649
the MRHD on a mg/m2 basis), carvedilol had no carcinogenic effect.
650
Carvedilol was negative when tested in a battery of genotoxicity assays, including the
651
Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and
652
in vivo human lymphocyte cell tests for clastogenicity.
Reference ID: 2896475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
653
At doses ≥200 mg/kg/day (≥32 times the MRHD as mg/m2) carvedilol was toxic to adult
654
rats (sedation, reduced weight gain) and was associated with a reduced number of successful
655
matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and
656
complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity
657
and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
658
14
CLINICAL STUDIES
659
14.1 Heart Failure
660
A total of 6,975 patients with mild to severe heart failure were evaluated in
661
placebo-controlled studies of carvedilol.
662
Mild-to-Moderate Heart Failure: Carvedilol was studied in 5 multicenter,
663
placebo-controlled studies, and in 1 active-controlled study (COMET study) involving patients
664
with mild-to-moderate heart failure.
665
Four US multicenter, double-blind, placebo-controlled studies enrolled 1,094 patients
666
(696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction ≤0.35.
667
The vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were
668
assigned to the studies based upon exercise ability. An Australia-New Zealand double-blind,
669
placebo-controlled study enrolled 415 patients (half randomized to carvedilol) with less severe
670
heart failure. All protocols excluded patients expected to undergo cardiac transplantation during
671
the 7.5 to 15 months of double-blind follow-up. All randomized patients had tolerated a 2-week
672
course on carvedilol 6.25 mg twice daily.
673
In each study, there was a primary end point, either progression of heart failure (1 US
674
study) or exercise tolerance (2 US studies meeting enrollment goals and the Australia-New
675
Zealand study). There were many secondary end points specified in these studies, including
676
NYHA classification, patient and physician global assessments, and cardiovascular
677
hospitalization. Other analyses not prospectively planned included the sum of deaths and total
678
cardiovascular hospitalizations. In situations where the primary end points of a trial do not show
679
a significant benefit of treatment, assignment of significance values to the other results is
680
complex, and such values need to be interpreted cautiously.
681
The results of the US and Australia-New Zealand trials were as follows:
682
Slowing Progression of Heart Failure: One US multicenter study (366 subjects) had as
683
its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and
684
sustained increase in heart failure medications. Heart failure progression was reduced, during an
685
average follow-up of 7 months, by 48% (p = 0.008).
686
In the Australia-New Zealand study, death and total hospitalizations were reduced by
687
about 25% over 18 to 24 months. In the 3 largest US studies, death and total hospitalizations
688
were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 studies. The
689
Australia-New Zealand results were statistically borderline.
690
Functional Measures: None of the multicenter studies had NYHA classification as a
691
primary end point, but all such studies had it as a secondary end point. There was at least a trend
Reference ID: 2896475
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
692
toward improvement in NYHA class in all studies. Exercise tolerance was the primary end point
693
in 3 studies; in none was a statistically significant effect found.
694
Subjective Measures: Health-related quality of life, as measured with a standard
695
questionnaire (a primary end point in 1 study), was unaffected by carvedilol. However, patients’
696
and investigators’ global assessments showed significant improvement in most studies.
697
Mortality: Death was not a pre-specified end point in any study, but was analyzed in all
698
studies. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2
699
studies.
700
COMET Trial: In this double-blind trial, 3,029 patients with NYHA class II-IV heart
701
failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol
702
(target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg
703
twice daily). The mean age of the patients was approximately 62 years, 80% were males, and the
704
mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the patients
705
had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE
706
inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering
707
agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was
708
42 mg per day.
709
The study had 2 primary end points: All-cause mortality and the composite of death plus
710
hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause
711
mortality carried most of the statistical weight and was the primary determinant of the study size.
712
All-cause mortality was 34% in the patients treated with carvedilol and was 40% in the
713
immediate-release metoprolol group (p = 0.0017; hazard ratio = 0.83, 95%CI 0.74-0.93). The
714
effect on mortality was primarily due to a reduction in cardiovascular death. The difference
715
between the 2 groups with respect to the composite end point was not significant (p = 0.122).
716
The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release
717
metoprolol.
718
719
Table 3. Results of COMET
End point
Carvedilol
N = 1,511
Metoprolol
N = 1,518
Hazard ratio
(95% CI)
All-cause mortality
34%
40%
0.83
0.74 – 0.93
Mortality + all hospitalization
74%
76%
0.94
0.86 – 1.02
Cardiovascular death
30%
35%
0.80
0.70 – 0.90
Sudden death
Death due to circulatory failure
Death due to stroke
14%
11%
0.9%
17%
13%
2.5%
0.81
0.83
0.33
0.68 – 0.97
0.67 – 1.02
0.18 – 0.62
720
721
It is not known whether this formulation of metoprolol at any dose or this low dose of
722
metoprolol in any formulation has any effect on survival or hospitalization in patients with heart
723
failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in
Reference ID: 2896475
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
724
heart failure, but it is not evidence that carvedilol improves outcome over the formulation of
725
metoprolol (TOPROL-XL®) with benefits in heart failure.
726
Severe Heart Failure (COPERNICUS): In a double-blind study (COPERNICUS),
727
2,289 patients with heart failure at rest or with minimal exertion and left ventricular ejection
728
fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%)
729
were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of
730
3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum
731
of 6 weeks. Most subjects achieved the target dose of 25 mg. The study was conducted in
732
Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects
733
per group (about 100) withdrew during the titration period.
734
The primary end point of the trial was all-cause mortality, but cause-specific mortality
735
and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were
736
also examined. The developing trial data were followed by a data monitoring committee, and
737
mortality analyses were adjusted for these multiple looks. The trial was stopped after a median
738
follow-up of 10 months because of an observed 35% reduction in mortality (from 19.7% per
739
patient year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI 0.52 – 0.81,
740
p = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.
741
742
Table 4. Results of COPERNICUS Trial in Patients With Severe Heart Failure
End point
Placebo
(N = 1,133)
Carvedilol
(N = 1,156)
Hazard ratio
(95% CI)
%
Reduction
Nominal
p value
Mortality
190
130
0.65
(0.52 – 0.81)
35
0.00013
Mortality + all
hospitalization
507
425
0.76
(0.67 – 0.87)
24
0.00004
Mortality + CV
hospitalization
395
314
0.73
(0.63 – 0.84)
27
0.00002
Mortality + HF
hospitalization
357
271
0.69
(0.59 – 0.81)
31
0.000004
743
Cardiovascular = CV; Heart failure = HF.
744
Reference ID: 2896475
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
745
Figure 1. Survival Analysis for COPERNICUS (intent-to-treat)
graph
747
748
The effect on mortality was principally the result of a reduction in the rate of sudden
749
death among patients without worsening heart failure.
750
Patients' global assessments, in which carvedilol-treated patients were compared to
751
placebo, were based on pre-specified, periodic patient self-assessments regarding whether
752
clinical status post-treatment showed improvement, worsening or no change compared to
753
baseline. Patients treated with carvedilol showed significant improvements in global assessments
754
compared with those treated with placebo in COPERNICUS.
755
The protocol also specified that hospitalizations would be assessed. Fewer patients on
756
COREG than on placebo were hospitalized for any reason (372 versus 432, p = 0.0029), for
757
cardiovascular reasons (246 versus 314, p = 0.0003), or for worsening heart failure (198 versus
758
268, p = 0.0001).
759
COREG had a consistent and beneficial effect on all-cause mortality as well as the
760
combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in
761
the overall study population and in all subgroups examined, including men and women, elderly
762
and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).
763
764
Figure 2. Effects on Mortality for Subgroups in COPERNICUS
Reference ID: 2896475
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
graph
765
766
767
14.2 Left Ventricular Dysfunction Following Myocardial Infarction
768
CAPRICORN was a double-blind study comparing carvedilol and placebo in
769
1,959 patients with a recent myocardial infarction (within 21 days) and left ventricular ejection
770
fraction of ≤40%, with (47%) or without symptoms of heart failure. Patients given carvedilol
771
received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Patients had to have a
772
systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no
773
contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV
774
or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute
775
angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor
776
blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%).
777
Baseline population characteristics included an average age of 63 years, 74% male, 95%
778
Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of
779
hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of
780
follow-up was 15 months.
781
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group,
782
indicating a 23% risk reduction in patients treated with carvedilol (95% CI 2-40%, p = 0.03), as
783
shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly
784
all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these
785
deaths were sudden or related to pump failure (both types of death were reduced by carvedilol).
786
Another study end point, total mortality and all-cause hospitalization, did not show a significant
787
improvement.
788
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction
789
observed in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar
790
reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo
791
controlled trials of carvedilol in heart failure.
792
Reference ID: 2896475
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
793
Figure 3. Survival Analysis for CAPRICORN (intent-to-treat)
graph
795
796
Figure 4. Effects on Mortality for Subgroups in CAPRICORN
graph
798
799
14.3 Hypertension
800
COREG was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at
801
total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed
802
12.5 mg. At 50 mg/day, COREG reduced sitting trough (12-hour) blood pressure by about
803
9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak
804
blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart
805
rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers,
806
responses were smaller in black than non-black patients. There were no age- or gender-related
807
differences in response.
Reference ID: 2896475
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
808
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related
809
blood pressure response was accompanied by a dose-related increase in adverse effects [see
810
Adverse Reactions (6)].
811
14.4 Hypertension With Type 2 Diabetes Mellitus
812
In a double-blind study (GEMINI), COREG, added to an ACE inhibitor or angiotensin
813
receptor blocker, was evaluated in a population with mild-to-moderate hypertension and well
814
controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated
815
to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse
816
effect on glycemic control, based on HbA1c measurements (mean change from baseline of
817
0.02%, 95% CI -0.06 to 0.10, p = NS) [see Warnings and Precautions (5.6)].
818
16
HOW SUPPLIED/STORAGE AND HANDLING
819
The white, oval, film-coated tablets are available in the following strengths: 3.125 mg–
820
engraved with 39 and SB, in bottles of 100; 6.25 mg–engraved with 4140 and SB, in bottles of
821
100; 12.5 mg–engraved with 4141 and SB, in bottles of 100; 25 mg–engraved with 4142 and SB,
822
in bottles of 100. The 6.25 mg, 12.5 mg, and 25 mg tablets are TILTAB tablets.
823
• 3.125 mg 100’s: NDC 0007-4139-20
824
• 6.25 mg 100’s: NDC 0007-4140-20
825
• 12.5 mg 100’s: NDC 0007-4141-20
826
• 25 mg 100’s: NDC 0007-4142-20
827
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.
828
17
PATIENT COUNSELING INFORMATION
829
See FDA-Approved Patient Labeling (17.2).
830
17.1 Patient Advice
831
Patients taking COREG should be advised of the following:
832
• Patients should take COREG with food.
833
• Patients should not interrupt or discontinue using COREG without a physician’s advice.
834
• Patients with heart failure should consult their physician if they experience signs or
835
symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
836
• Patients may experience a drop in blood pressure when standing, resulting in dizziness and,
837
rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood
838
pressure occur.
839
• If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.
840
• Patients should consult a physician if they experience dizziness or faintness, in case the
841
dosage should be adjusted.
842
• Diabetic patients should report any changes in blood sugar levels to their physician.
843
• Contact lens wearers may experience decreased lacrimation.
844
17.2 FDA-Approved Patient Labeling
845
Patient labeling is provided as a tear-off leaflet at the end of this full prescribing
846
information.
Reference ID: 2896475
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
847
848
COREG, COREG CR, and TILTAB are registered trademarks of GlaxoSmithKline.
849
TOPROL-XL is a registered trademark of the AstraZeneca group of companies.
850
company logo
852
Manufactured for
853
GlaxoSmithKline
854
Research Triangle Park, NC 27709
855
Manufactured by
856
Patheon Puerto Rico, Inc.
857
Manati, PR 00674 USA
858
859
©Year, GlaxoSmithKline. All rights reserved.
860
861
Month Year
862
CRG:XXPI
Reference ID: 2896475
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
863
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
864
-------------------------------------------------------------------------------------------------------------
865
866
867
PATIENT INFORMATION
868
COREG® (Co-REG)
869
Carvedilol Tablets
870
871
Read the Patient Information that comes with COREG before you start taking it and each time
872
you get a refill. There may be new information. This information does not take the place of
873
talking with your doctor about your medical condition or your treatment. If you have any
874
questions about COREG, ask your doctor or pharmacist.
875
876
What is COREG?
877
COREG is a prescription medicine that belongs to a group of medicines called “beta-blockers”.
878
COREG is used, often with other medicines, for the following conditions:
879
• To treat patients with high blood pressure (hypertension)
880
• To treat patients who had a heart attack that worsened how well the heart pumps
881
• To treat patients with certain types of heart failure
882
883
COREG is not approved for use in children under 18 years of age.
884
885
Who should not take COREG?
886
Do not take COREG if you:
887
• Have severe heart failure and are hospitalized in the intensive care unit or require certain
888
intravenous medications that help support circulation (inotropic medications)
889
• Are prone to asthma or other breathing problems
890
• Have a slow heartbeat or a heart that skips a beat (irregular heartbeat)
891
• Have liver problems
892
• Are allergic to any of the ingredients in COREG. The active ingredient is carvedilol. See the
893
end of this leaflet for a list of all the ingredients in COREG.
894
895
What should I tell my doctor before taking COREG?
896
Tell your doctor about all of your medical conditions, including if you:
897
• Have asthma or other lung problems (such as bronchitis or emphysema)
898
• Have problems with blood flow in your feet and legs (peripheral vascular disease) COREG
899
can make some of your symptoms worse.
900
• Have diabetes
901
• Have thyroid problems
902
• Have a condition called pheochromocytoma
Reference ID: 2896475
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
903
• Have had severe allergic reactions
904
• Are pregnant or trying to become pregnant. It is not known if COREG is safe for your unborn
905
baby. You and your doctor should talk about the best way to control your high blood pressure
906
during pregnancy.
907
• Are breastfeeding. It is not known if COREG passes into your breast milk. You should not
908
breastfeed while using COREG.
909
• Are scheduled for surgery and will be given anesthetic agents
910
• Are scheduled for cataract surgery and have taken or are currently taking COREG.
911
• Are taking prescription or non-prescription medicines, vitamins, and herbal supplements.
912
COREG and certain other medicines can affect each other and cause serious side effects.
913
COREG may affect the way other medicines work. Also, other medicines may affect how
914
well COREG works.
915
916
Keep a list of all the medicines you take. Show this list to your doctor and pharmacist before you
917
start a new medicine.
918
919
How should I take COREG?
920
It is important for you to take your medicine every day as directed by your doctor. If you
921
stop taking COREG suddenly, you could have chest pain and/or a heart attack. If your
922
doctor decides that you should stop taking COREG, your doctor may slowly lower your
923
dose over a period of time before stopping it completely.
924
• Take COREG exactly as prescribed. Your doctor will tell you how many tablets to take and
925
how often. In order to minimize possible side effects, your doctor might begin with a low
926
dose and then slowly increase the dose.
927
• Do not stop taking COREG and do not change the amount of COREG you take without
928
talking to your doctor.
929
• Tell your doctor if you gain weight or have trouble breathing while taking COREG.
930
• Take COREG with food.
931
• If you miss a dose of COREG, take your dose as soon as you remember, unless it is time to
932
take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same
933
time.
934
• If you take too much COREG, call your doctor or poison control center right away.
935
936
What should I avoid while taking COREG?
937
• COREG can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or
938
do anything that needs you to be alert if you have these symptoms.
939
940
What are possible side effects of COREG?
941
• Low blood pressure (which may cause dizziness or fainting when you stand up). If these
942
happen, sit or lie down right away and tell your doctor.
Reference ID: 2896475
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
943
• Tiredness. If you feel tired or dizzy you should not drive, use machinery, or do anything
944
that needs you to be alert.
945
• Slow heartbeat.
946
• Changes in your blood sugar. If you have diabetes, tell your doctor if you have any
947
changes in your blood sugar levels.
948
• COREG may hide some of the symptoms of low blood sugar, especially a fast heartbeat.
949
• COREG may mask the symptoms of hyperthyroidism (overactive thyroid).
950
• Worsening of severe allergic reactions.
951
• Rare but serious allergic reactions (including hives or swelling of the face, lips, tongue,
952
and/or throat that may cause difficulty in breathing or swallowing) have happened in
953
patients who were on COREG. These reactions can be life-threatening.
954
955
Other side effects of COREG include shortness of breath, weight gain, diarrhea, and fewer tears
956
or dry eyes that become bothersome if you wear contact lenses.
957
958
Call your doctor if you have any side effects that bother you or don’t go away.
959
960
How should I store COREG?
961
• Store COREG at less than 86°F (30°C). Keep the tablets dry.
962
• Safely, throw away COREG that is out of date or no longer needed.
963
• Keep COREG and all medicines out of the reach of children.
964
965
General Information about COREG
966
Medicines are sometimes prescribed for conditions other than those described in patient
967
information leaflets. Do not use COREG for a condition for which it was not prescribed. Do not
968
give COREG to other people, even if they have the same symptoms you have. It may harm them.
969
970
This leaflet summarizes the most important information about COREG. If you would like more
971
information, talk with your doctor. You can ask your doctor or pharmacist for information about
972
COREG that is written for healthcare professionals. You can also find out more about COREG
973
by visiting the website www.COREG.com or calling 1-888-825-5249. This call is free.
974
975
What are the ingredients in COREG?
976
Active Ingredient: Carvedilol.
977
978
Inactive Ingredients: Colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium
979
stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide.
980
981
Carvedilol tablets come in the following strengths: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg.
982
983
COREG is a registered trademark of GlaxoSmithKline.
Reference ID: 2896475
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
985
Manufactured for
986
GlaxoSmithKline
987
Research Triangle Park, NC 27709
988
Manufactured by
989
Patheon Puerto Rico, Inc.
990
Manati, PR 00674 USA
991
992
©Year, GlaxoSmithKline. All rights reserved.
993
994
Revised: Month Year
995
CRG:XPIL
Reference ID: 2896475
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:24.926578
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020297s033lbl.pdf', 'application_number': 20297, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
12,427
|
ORTHO-CEPT® TABLETS
(DESOGESTREL AND 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-CEPT, 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
ORTHO-CEPT® Tablets provide an oral contraceptive regimen of 21 light orange round tablets
each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en
20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne
3,17,diol). Inactive ingredients include colloidal silicone dioxide, corn starch, ferric oxide,
hypromellose, lactose, polyethylene glycol, povidone, stearic acid, talc, titanium dioxide, and
vitamin E. Each green tablet contains the following inactive ingredients: FD&C Blue No.1
Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate, polyethylene glycol,
pregelatinized starch, talc and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Combined 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 changes in the
endometrium which reduce the likelihood of implantation.
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
Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the
biologically active metabolite of desogestrel, combines high progestational activity with minimal
intrinsic androgenicity.91,92 The relevance of this latter finding in humans is unknown.
Pharmacokinetics
Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its
biologically active metabolite. Following oral administration, the relative bioavailability of
desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.
In the third cycle of use after a single dose of ORTHO-CEPT®, maximum concentrations of 3
keto-desogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are reached at 1.4 ± 0.8 hours. The area
under the curve (AUC0-∞) is 33,858 ± 11,043 pg/mL·hr after a single dose. At steady state,
attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are
reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are
1,400 ± 560 pg/mL. The AUC0-24 at steady state is 52,299 ± 17,878 pg/mL·hr. The mean AUC0-∞
for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state.
This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding
of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex
hormone-binding globulin levels which are induced by the daily administration of ethinyl
estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment
cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).
The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. In
addition
to
3-keto-desogestrel,
other
phase
I
metabolites
are
3α-OH-desogestrel,
3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to
have any pharmacologic effects, and are further converted in part by conjugation (phase II
metabolism) into polar metabolites, mainly sulfates and glucuronides.
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a
single dose of ORTHO-CEPT®, the relative bioavailability is approximately 83%.
In the third cycle of use after a single dose of ORTHO-CEPT®, maximum concentrations of
ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours. The AUC0-∞ is 1,471 ± 268
pg/mL·hr after a single dose. At steady state, attained from at least day 19 onwards, maximum
ethinyl estradiol concentrations of 141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The
minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC0-24 at
steady state is 1,117 ± 302 pg/mL·hr. The mean AUC0-∞ for ethinyl estradiol following a single
dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state.
This finding indicates linear kinetics for ethinyl estradiol.
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The elimination half-life is 26 ± 6.8 hours at steady state. Ethinyl estradiol is subject to a
significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping
gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II
metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl
estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites,
which are excreted in bile, can undergo enterohepatic circulation.
INDICATIONS AND USAGE
ORTHO-CEPT® Tablets are indicated for the prevention of pregnancy in women who elect to
use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for
users of combined 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 these methods can result in
lower failure rates.
In a clinical trial with ORTHO-CEPT®, 1,195 subjects completed 11,656 cycles and a total of 10
pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy)
pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the
drug correctly.
Table 1:
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
Year of Use
at One Year*
Method
Typical Use†
Perfect Use‡
(1)
(2)
(3)
(4)
Chance#
85
85
SpermicidesÞ
26
6
40
Periodic abstinence
25
63
Calendar
9
Ovulation Method
3
Sympto-Thermalß
2
Post-Ovulation
1
Withdrawal
19
4
Capà
Parous Women
40
26
42
Nulliparous Women
20
9
56
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Table 1:
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
Year of Use
at One Year*
Method
Typical Use†
Perfect Use‡
(1)
(2)
(3)
(4)
Sponge
Parous Women
40
20
42
Nulliparous Women
20
9
56
Diaphragmà
20
6
56
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
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
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Table 1:
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 Year*
Method
(1)
Typical Use†
(2)
Perfect Use‡
(3)
(4)
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of
pregnancy by at least 75%.§
Lactation 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, Kowel 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 FDA 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 4 yellow pills).
¶ However, to maintain effective protection against pregnancy, another method of contraception must be used as
soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or
the baby reaches 6 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.
ß 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-CEPT® has not been studied for and is not indicated for use in emergency
contraception.
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
Cerebral vascular or coronary artery disease (current or history)
Valvular heart disease with complications
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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-CEPT, 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 formulations of higher doses of estrogens and
progestogens than those in common use today. The effect of long-term use of the oral
contraceptives with formulations of lower doses of both estrogens and progestogens remains to
be determined.
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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 Disorder and Other Vascular Problems
a. 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 non-users 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
Several epidemiologic studies indicate that third generation oral contraceptives, including those
containing desogestrel, are associated with a higher risk of venous thromboembolism than
certain second generation oral contraceptives. In general, these studies indicate an approximate
2-fold increased risk, which corresponds to an additional 1-2 cases of venous thromboembolism
per 10,000 women-years of use. However, data from additional studies have not shown this 2
fold increase in risk.
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 breastfeed.
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b. 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 in women 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.)
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.
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.
Receptor binding and animal studies have shown that desogestrel or its active metabolite has
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minimal androgenic activity (see CLINICAL PHARMACOLOGY), although these findings
have not been confirmed in adequate and well-controlled clinical trials.
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 nature and
absolute amount of progestogens used in the contraceptives. The 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 old
who had used oral contraceptives for five or more years, but this increased risk was not
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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 0.050 mg 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 2). 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 risk 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.
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Table 2:
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 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
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 combined oral contraceptives (COC). 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 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.
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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 oral contraceptives are 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.
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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 In
general, progestogens increase insulin secretion and create insulin resistance, this effect varying
with different progestational agents.17,66 In the nondiabetic woman, oral contraceptives appear to
have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and
diabetic women 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 1.a. and 1.d.), changes in serum triglycerides and lipoprotein
levels have been reported in oral contraceptive users.
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 and
concentrations of progestogens.
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,69 and there is no difference in
the occurrence of hypertension among former and never users.68,70,71
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.
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11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral
contraceptives, especially during the first three months of use. Nonhormonal 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 pre-existent.
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 oral contraceptives, the medication should be
discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver
function.
Reference ID: 3383539
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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
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.
Reference ID: 3383539
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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]).
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
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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, 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 oral contraceptives but to use other forms of contraception until she
has completely weaned her child.
13. Pediatric Use
Safety and efficacy of ORTHO-CEPT® 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. 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.
Reference ID: 3383539
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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
Change in weight (increase or decrease)
Change in cervical erosion and secretion
Reference ID: 3383539
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Diminution in lactation when given immediately postpartum
Cholestatic jaundice
Migraine
Allergic reaction, including rash, urticaria, and 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
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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 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 of 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
Effects from long-term use:
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
To achieve maximum contraceptive effectiveness, ORTHO-CEPT® must be taken exactly as
directed and at intervals not exceeding 24 hours. ORTHO-CEPT® is available in a blister card
with a tablet dispenser which is preset for a Sunday Start. Day 1 Start is also provided.
Day 1 Start
The dosage of ORTHO-CEPT® for the initial cycle of therapy is one light orange "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". Tablets are taken without interruption as follows: One
light orange "active" tablet daily for 21 days, then one green "reminder" tablet daily for 7 days.
After 28 tablets have been taken, a new course is started and a light orange "active" tablet is
taken the next day.
Reference ID: 3383539
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The use of ORTHO-CEPT® 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.) If the patient starts on ORTHO-CEPT®
postpartum, and has not yet had a period, she should be instructed to use another method of
contraception until a light orange "active" tablet has been taken daily for 7 days. The possibility
of ovulation and conception prior to initiation of medication should be considered. If the patient
misses one (1) light orange "active" tablet in Weeks 1, 2, or 3, the light orange "active" tablet
should be taken as soon as she remembers. If the patient misses two (2) light orange "active"
tablets in Week 1 or Week 2, the patient should take two (2) light orange "active" tablets the day
she remembers and two (2) light orange "active" tablets the next day; and then continue taking
one (1) light orange "active" 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) light orange "active" tablets
in the third week or misses three (3) or more light orange "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.
Sunday Start
When taking ORTHO-CEPT®, the first light orange "active" tablet should be taken on the first
Sunday after menstruation begins. If the period begins on Sunday, the first light orange "active"
tablet is taken on that day. If switching directly from another oral contraceptive, the first light
orange "active" tablet should be taken on the first Sunday after the last ACTIVE tablet of the
previous product. Tablets are taken without interruption as follows: One light orange "active"
tablet daily for 21 days, then one green "reminder" tablet daily for 7 days. After 28 tablets have
been taken, a new course is started and a light orange "active" tablet is taken the next day
(Sunday). When initiating a Sunday start regimen, another method of contraception should be
used until after the first 7 consecutive days of administration.
The use of ORTHO-CEPT® for contraception may be initiated 4 weeks postpartum. 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.) If the patient starts on ORTHO-CEPT® postpartum, and
has not yet had a period, she should be instructed to use another method of contraception until a
light orange "active" tablet has been taken daily for 7 days. The possibility of ovulation and
Reference ID: 3383539
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conception prior to initiation of medication should be considered. If the patient misses one (1)
light orange active tablet in Weeks 1, 2, or 3, the light orange "active" tablet should be taken as
soon as she remembers. If the patient misses two (2) light orange "active" tablets in Week 1 or
Week 2, the patient should take two (2) light orange "active" tablets the day she remembers and
two (2) light orange "active" tablets the next day; and then continue taking one (1) light orange
"active" 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) light orange "active" tablets in the third week or
misses three (3) or more light orange "active" tablets in a row, the patient should continue taking
one light orange "active" 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.
ADDITIONAL INSTRUCTIONS FOR ALL DOSING REGIMENS
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.
HOW SUPPLIED
ORTHO-CEPT® Tablets are available in a blister card (NDC 50458-196-01) with a tablet
dispenser (unfilled). The blister card contains 28 tablets, as follows: 21 light orange, round,
convex, beveled edged, coated tablets imprinted "ORTHO" on one side and "D 150" on the other
side containing 0.15 mg desogestrel together with 0.03 mg ethinyl estradiol, and 7 green, round,
convex, beveled edged, coated tablets imprinted "ORTHO P" on both sides containing inert
Reference ID: 3383539
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ingredients. ORTHO-CEPT® Tablets are packaged in a carton (NDC 50458-196-15) containing 6
blister cards and 6 unfilled tablet dispensers.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049.
66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In
Progesterone and Progestin. Edited by Bardin CW, Milgrom E, Mauvis-Jarvis P. 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
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277-288. (Monographs of the Mario Negri Institute for Pharmacological Research,
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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.
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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-controlled study of oral contraceptive use and breast cancer.
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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.
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82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral
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83. Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the Royal
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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
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87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral
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89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br. J.
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lipid and carbohydrate metabolism. N Engl J Med 1990; 323:1375-81.
91. Kloosterboer, HJ et al. Selectivity in progesterone and androgen receptor binding of
progestogens used in oral contraception. Contraception 1988; 38:325-32.
92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim
Forsch/ Drug Res, 1983; 33(I),2:231-6.
93. Data on file, Organon Inc.
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96. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal
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cancer and 100 239 women without breast cancer from 54 epidemiological studies.
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Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882.
98. Improving access to quality care in family planning: Medical eligibility criteria for
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99. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks
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Pharmacol Ther 2006;44(3):113-118.
101.Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine
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BRIEF SUMMARY PATIENT PACKAGE INSERT
ORTHO-CEPT® (desogestrel and ethinyl estradiol) Tablets
This product (like all oral contraceptives) is intended to prevent pregnancy. It 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, and when taken correctly without missing any pills, have a failure rate of
approximately 1% per year. The typical failure rate is approximately 5% per year 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.
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 life-threatening 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.
Do not use ORTHO-CEPT® 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 such effects are nausea, vomiting,
bleeding between menstrual periods, weight gain, breast tenderness, headache, and difficulty
wearing contact lenses. These side effects, especially nausea and vomiting, may subside within
the first three months of use.
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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) or 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 patient
labeling 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.
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
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contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause
such cancers.
Taking the 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. The
detailed patient information labeling gives you further information which you should read and
discuss with your healthcare professional.
This product (like all oral contraceptives) is intended to prevent pregnancy. It does 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, do not stop taking the pill. The problem will usually go away. If it
doesn’t go away, check with your healthcare professional.
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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.
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 light orange "active" pills (with hormones) to take for 3 weeks,
followed by 1 week of green "reminder" pills (without hormones).
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills,
3) check picture of pill pack and additional instructions for using this package
below.
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.
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WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO-CEPT® is
available in a blister card with a 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.
DAY 1 START:
1. Take the first light orange "active" pill of the first pack during the first 24 hours of your
period.
2. 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.
SUNDAY START:
1. Take the first light orange "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.
2. 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).
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 green "reminder" pill. Do not wait any
days between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 light orange "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.
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2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 light orange "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 light orange "active" pills in a row in THE 3RD WEEK:
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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 light orange "active" pills in a row (during the first 3 weeks):
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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.
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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 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 LIGHT ORANGE "ACTIVE" PILL EACH DAY until you can reach
your healthcare professional.
INSTRUCTIONS FOR USE
1. Open the compact. Place the blister into the compact, with the tablets facing up, so that
the V notch in the blister card matches up with the V shaped post at the top of the
compact. Press down firmly on each edge of the blister card and make sure that the edge
of the blister card is firmly seated under each of the nibs inside the compact (see
picture).
There are 21 light orange “active” pills and 7 green “reminder” pills.
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2. If you are to start pill-taking on Sunday, take your first light orange pill on the first
Sunday after your menstrual period begins. If your period begins on Sunday, take your
first pill that day. Remove the first pill at the top of the dispenser (Sunday) by pressing
the pill through the hole in the bottom of the dispenser.
3. If you are to start pill-taking on “Day 1”, choose a light orange pill that corresponds with
the day of the week on which you are taking the first pill. Remove that light orange pill
by pressing the pill through the hole in the bottom of the dispenser.
4. Continue taking one pill daily, clockwise, until no pills remain in the outer ring.
5. The next day take the green pill from the inner ring that corresponds with the day of the
week it happens to be. Take a green pill each day until all seven pills are taken. During
this time your period should begin.
6. After you have taken all the green pills, begin a new blister card (see Step 1 above in
“Instructions for Use”) and take the first light orange “active” pill on the next day, even if
your period is not yet over.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
DETAILED PATIENT LABELING
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not
protect against HIV infection (AIDS) and other sexually transmitted diseases.
PLEASE NOTE: This labeling is revised from time to time as important new medical
information becomes available. Therefore, please review this labeling carefully.
The following oral contraceptive product contains a combination of a progestogen and estrogen,
the two kinds of female hormones:
ORTHO-CEPT® (desogestrel and ethinyl estradiol) Tablets
Each light orange tablet contains 0.15 mg desogestrel and 0.03 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
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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
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% (1
pregnancy per 100 women per year of use). Typical failure rates, including women who do not
always take the pills exactly as directed, are approximately 5% per year. 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%
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
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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
Liver tumor (benign or cancerous)
Known or suspected pregnancy
If you plan to have surgery with prolonged bed rest
Tell your healthcare professional if you have ever had any of these conditions. Your healthcare
professional can recommend another 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
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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. The risks of these side effects may be greater with desogestrel
containing oral contraceptives, such as ORTHO-CEPT®, than with certain other low-dose pills.
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 three to 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. The risk of venous thromboembolic disease associated with oral contraceptives does not
increase with length of use and disappears after pill use is stopped. 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.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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 pills 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.
Reference ID: 3383539
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 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
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 (7-26 deaths per 100,000 women, depending on
age). Among pill users who do not smoke, the risk of death is always lower than that associated
with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per
100,000 women, compared to 28 associated with pregnancy at that age. 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)
Reference ID: 3383539
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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
1. 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
Reference ID: 3383539
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 before
doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you
may be pregnant. 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 oral contraceptives if pregnancy is confirmed.
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, oral contraceptives may decrease the amount and quality of your milk. If possible, do
not use 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 starting 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
Reference ID: 3383539
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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-CEPT® less effective.
Some medicines and grapefruit juice may increase your level of the hormone ethinyl estradiol if
used together, including:
•
acetaminophen
•
ascorbic acid
•
medicines that affect how your liver breaks down other medicines (itraconazole,
ketoconazole, voriconazole, and fluconazole)
•
certain HIV medicines (atazanavir, indinavir)
•
atorvastatin
•
rosuvastatin
•
etravirine
Reference ID: 3383539
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
This product (like all oral contraceptives) is intended to prevent pregnancy. It does 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, 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.
Reference ID: 3383539
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 light orange "active" pills (with hormones) to take for 3 weeks,
followed by 1 week of green "reminder" pills (without hormones).
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.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO-CEPT® is
available in a blister card with a 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.
DAY 1 START:
Reference ID: 3383539
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1. Take the first light orange "active" pill of the first pack during the first 24 hours of your
period.
2. 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.
SUNDAY START:
1. Take the first light orange "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.
2. 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).
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 green "reminder" pill. Do not wait any
days between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 light orange "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 light orange "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.
Reference ID: 3383539
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 light orange "active" pills in a row in THE 3RD WEEK:
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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 light orange "active" pills in a row (during the first 3 weeks):
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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 green "reminder" pills in Week 4:
THROW AWAY the pills you missed.
Reference ID: 3383539
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 LIGHT ORANGE "ACTIVE" PILL EACH DAY until you can
reach your healthcare professional.
PREGNANCY DUE TO PILL FAILURE
When taken correctly without missing any pills, oral contraceptives are highly effective;
however the typical failure rate of large numbers of pill users is 5% per year when women who
miss pills are included. 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.
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.
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
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 combined 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.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
Keep out of reach of children.
Product of The Netherlands
Jointly Manufactured by
Janssen Ortho, LLC
Manati, Puerto Rico 00674 and
NV Organon
Oss, The Netherlands
Manufactured for
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560
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
© Janssen Pharmaceuticals, Inc. 1998
Revised October 2013
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
---------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------
----------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
AUDREY L GASSMAN
10/03/2013
Reference ID: 3383539
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:25.032775
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020301Orig1s025lbl.pdf', 'application_number': 20301, 'submission_type': 'SUPPL ', 'submission_number': 25}
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1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
COREG safely and effectively. See full prescribing information for
COREG.
COREG® (carvedilol) tablets
Initial U.S. Approval: 1995
------------------RECENT MAJOR CHANGES ------------------------------------
Warnings and Precautions, Glycemic August 2006
Control in Type 2 Diabetes (5.6)
--------------------INDICATIONS AND USAGE------------------------------------
COREG is an alpha/beta-adrenergic blocking agent indicated for the
treatment of:
•
Mild to severe chronic heart failure (1.1)
•
Left ventricular dysfunction following myocardial infarction in
clinically stable patients (1.2)
•
Hypertension (1.3)
-------------- DOSAGE AND ADMINISTRATION --------------------------------
Take with food. Individualize dosages and monitor during up-titration.
(2)
•
Heart failure: Start at 3.125 mg twice daily and increase to 6.25,
12.5, and then 25 mg twice daily over intervals of at least 2
weeks. Maintain lower doses if higher doses are not tolerated.
(2.1)
•
Left ventricular dysfunction following myocardial infarction:
Start at 6.25 mg twice daily and increase to 12.5 mg then 25 mg
twice daily after intervals of 3 to 10 days. A lower starting dose or
slower titration may be used. (2.2)
•
Hypertension: Start at 6.25 mg twice daily and increase if needed
for blood pressure control to 12.5 mg then 25 mg twice daily over
intervals of 1 to 2 weeks. (2.3)
----------------DOSAGE FORMS AND STRENGTHS---------------------------
Tablets: 3.125, 6.25, 12.5, 25 mg (3)
---------------------------CONTRAINDICATIONS-----------------------------------
•
Bronchial asthma or related bronchospastic conditions (4)
•
Second- or third-degree AV block (4)
•
Sick sinus syndrome (4)
•
Severe bradycardia (unless permanent pacemaker in place) (4)
•
Patients in cardiogenic shock or decompensated heart failure
requiring the use of IV inotropic therapy. (4)
•
Severe hepatic impairment (2.4, 4)
•
Hypersensitivity to carvedilol (e.g. Stevens-Johnson syndrome)
(4)
------------------WARNINGS AND PRECAUTIONS------------------------------
•
Acute exacerbation of coronary artery disease upon cessation of
therapy: Do not abruptly discontinue. (5.1)
•
Bradycardia, hypotension, worsening heart failure/fluid retention
may occur. Reduce the dose as needed. (5.2, 5.3, 5.4)
•
Non-allergic bronchospasm (e.g., chronic bronchitis and
emphysema): Avoid β-blockers. (4) However, if deemed
necessary, use with caution and at lowest effective dose. (5.5)
•
Diabetes: Monitor glucose as β-blockers may mask symptoms of
hypoglycemia or worsen hyperglycemia. (5.6)
----------------------------ADVERSE REACTIONS ---------------------------------
Most common adverse events (6.1):
•
Heart failure and left ventricular dysfunction following
myocardial infarction (≥10%): Dizziness, fatigue, hypotension,
diarrhea, hyperglycemia, asthenia, bradycardia, weight increase
•
Hypertension (≥5%): Dizziness
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 ----------------------------------
•
CYP P450 2D6 enzyme inhibitors may increase and rifampin may
decrease carvedilol levels. (7.1, 7.5)
•
Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine)
may increase the risk of hypotension and/or severe bradycardia.
(7.2)
•
Cyclosporine or digoxin levels may increase. (7.3, 7.4)
•
Verapamil- or diltiazem-type calcium channel blockers may
affect ECG and/or blood pressure. (7.6)
•
Insulin and oral hypoglycemics action may be enhanced. (7.7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 2/2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
----------------------------------------------------------------------------------------------------------------------------
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Heart Failure
1.2
Left Ventricular Dysfunction following
Myocardial Infarction
1.3
Hypertension
2
DOSAGE AND ADMINISTRATION
2.1
Heart Failure
2.2
Left Ventricular Dysfunction following
Myocardial Infarction
2.3
Hypertension
2.4
Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Cessation of Therapy
5.2
Bradycardia
5.3
Hypotension
5.4
Heart Failure/Fluid Retention
5.5
Non-allergic Bronchospasm
5.6
Glycemic Control in Type 2 Diabetes
5.7
Peripheral Vascular Disease
5.8
Deterioration of Renal Function
5.9
Anesthesia and Major Surgery
5.10
Thyrotoxicosis
5.11
Pheochromocytoma
5.12
Prinzmetal’s Variant Angina
5.13
Risk of Anaphylactic Reaction
6
ADVERSE REACTIONS
6.1
Clinical Studies Experience
6.2
Laboratory Abnormalities
6.3
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
CYP2D6 Inhibitors and Poor Metabolizers
7.2
Hypotensive Agents
7.3
Cyclosporine
7.4
Digoxin
7.5
Inducers/Inhibitors of Hepatic Metabolism
7.6
Calcium Channel Blockers
7.7
Insulin or Oral Hypoglycemics
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.4
Specific Populations
12.5
Drug-Drug Interactions
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
14.1
Heart Failure
14.2
Left Ventricular Dysfunction following
Myocardial Infarction
14.3
Hypertension
14.4
Hypertension with Type 2 Diabetes Mellitus
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1
Patient Advice
17.2
FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are
not listed
______________________________________________________________________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
FULL PRESCRIBING INFORMATION
1
1
INDICATIONS AND USAGE
2
1.1
Heart Failure
3
COREG is indicated for the treatment of mild-to-severe chronic heart failure of ischemic
4
or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to
5
increase survival and, also, to reduce the risk of hospitalization [see Clinical Studies (14.1)].
6
1.2
Left Ventricular Dysfunction Following Myocardial Infarction
7
COREG is indicated to reduce cardiovascular mortality in clinically stable patients who
8
have survived the acute phase of a myocardial infarction and have a left ventricular ejection
9
fraction of ≤40% (with or without symptomatic heart failure) [see Clinical Studies (14.2)].
10
1.3
Hypertension
11
COREG is indicated for the management of essential hypertension [see Clinical Studies
12
(14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents,
13
especially thiazide-type diuretics [see Drug Interactions (7.2)].
14
2
DOSAGE AND ADMINISTRATION
15
COREG should be taken with food to slow the rate of absorption and reduce the
16
incidence of orthostatic effects.
17
2.1
Heart Failure
18
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A
19
PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG, it is recommended that
20
fluid retention be minimized. The recommended starting dose of COREG is 3.125 mg twice
21
daily for 2 weeks. If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg
22
twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower
23
doses if higher doses are not tolerated. A maximum dose of 50 mg twice daily has been
24
administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs).
25
Patients should be advised that initiation of treatment and (to a lesser extent) dosage
26
increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely
27
syncope) within the first hour after dosing. During these periods, patients should avoid situations
28
such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory
29
symptoms often do not require treatment, but it may be useful to separate the time of dosing of
30
COREG from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor.
31
The dose of COREG should not be increased until symptoms of worsening heart failure or
32
vasodilation have been stabilized.
33
Fluid retention (with or without transient worsening heart failure symptoms) should be
34
treated by an increase in the dose of diuretics.
35
The dose of COREG should be reduced if patients experience bradycardia (heart rate
36
<55 beats/minute).
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Episodes of dizziness or fluid retention during initiation of COREG can generally be
38
managed without discontinuation of treatment and do not preclude subsequent successful
39
titration of, or a favorable response to, carvedilol.
40
2.2
Left Ventricular Dysfunction Following Myocardial Infarction
41
DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING
42
UP-TITRATION. Treatment with COREG may be started as an inpatient or outpatient and
43
should be started after the patient is hemodynamically stable and fluid retention has been
44
minimized. It is recommended that COREG be started at 6.25 mg twice daily and increased after
45
3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg
46
twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of
47
up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or
48
fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated.
49
The recommended dosing regimen need not be altered in patients who received treatment with an
50
IV or oral β-blocker during the acute phase of the myocardial infarction.
51
2.3
Hypertension
52
DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of COREG
53
is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about
54
1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased
55
to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic
56
pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7
57
to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full
58
antihypertensive effect of COREG is seen within 7 to 14 days. Total daily dose should not
59
exceed 50 mg.
60
Concomitant administration with a diuretic can be expected to produce additive effects
61
and exaggerate the orthostatic component of carvedilol action.
62
2.4
Hepatic Impairment
63
COREG should not be given to patients with severe hepatic impairment [see
64
Contraindications (4)].
65
3
DOSAGE FORMS AND STRENGTHS
66
The white, oval, film-coated tablets are available in the following strengths: 3.125 mg–
67
engraved with 39 and SB, 6.25 mg–engraved with 4140 and SB, 12.5 mg–engraved with 4141
68
and SB, and 25 mg–engraved with 4142 and SB.
69
4
CONTRAINDICATIONS
70
COREG is contraindicated in the following conditions:
71
• Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have
72
been reported following single doses of COREG.
73
• Second- or third-degree AV block
74
• Sick sinus syndrome
75
• Severe bradycardia (unless a permanent pacemaker is in place)
76
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
• Patients with cardiogenic shock or who have decompensated heart failure requiring the use of
77
intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy
78
before initiating COREG
79
• Patients with severe hepatic impairment
80
• Patients with a history of a serious hypersensitivity reaction to carvedilol (e.g. Stevens-
81
Johnson syndrome)
82
5
WARNINGS AND PRECAUTIONS
83
5.1
Cessation of Therapy
84
Patients with coronary artery disease, who are being treated with COREG, should
85
be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and
86
the occurrence of myocardial infarction and ventricular arrhythmias have been reported in
87
angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2
88
complications may occur with or without preceding exacerbation of the angina pectoris. As
89
with other β-blockers, when discontinuation of COREG is planned, the patients should be
90
carefully observed and advised to limit physical activity to a minimum. COREG should be
91
discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary
92
insufficiency develops, it is recommended that COREG be promptly reinstituted, at least
93
temporarily. Because coronary artery disease is common and may be unrecognized, it may
94
be prudent not to discontinue therapy with COREG abruptly even in patients treated only
95
for hypertension or heart failure.
96
5.2
Bradycardia
97
In clinical trials, COREG caused bradycardia in about 2% of hypertensive patients, 9% of
98
heart failure patients, and 6.5% of myocardial infarction patients with left ventricular
99
dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
100
5.3
Hypotension
101
In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural
102
hypotension occurred in 9.7% and syncope in 3.4% of patients receiving COREG compared to
103
3.6% and 2.5% of placebo patients, respectively. The risk for these events was highest during the
104
first 30 days of dosing, corresponding to the up-titration period and was a cause for
105
discontinuation of therapy in 0.7% of patients receiving COREG, compared to 0.4% of placebo
106
patients. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS),
107
hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure
108
patients receiving COREG compared to 8.7% and 2.3% of placebo patients, respectively. These
109
events were a cause for discontinuation of therapy in 1.1% of patients receiving COREG,
110
compared to 0.8% of placebo patients.
111
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients,
112
primarily following the initial dose or at the time of dose increase and was a cause for
113
discontinuation of therapy in 1% of patients.
114
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or
115
postural hypotension occurred in 20.2% of patients receiving COREG compared to 12.6% of
116
placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events
117
were a cause for discontinuation of therapy in 2.5% of patients receiving COREG, compared to
118
0.2% of placebo patients.
119
Starting with a low dose, administration with food, and gradual up-titration should
120
decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration
121
(2.1, 2.2, 2.3)]. During initiation of therapy, the patient should be cautioned to avoid situations
122
such as driving or hazardous tasks, where injury could result should syncope occur.
123
5.4
Heart Failure/Fluid Retention
124
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If
125
such symptoms occur, diuretics should be increased and the carvedilol dose should not be
126
advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is
127
necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not
128
preclude subsequent successful titration of, or a favorable response to, carvedilol. In a
129
placebo-controlled trial of patients with severe heart failure, worsening heart failure during the
130
first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment
131
was maintained beyond 3 months, worsening heart failure was reported less frequently in
132
patients treated with carvedilol than with placebo. Worsening heart failure observed during
133
long-term therapy is more likely to be related to the patients’ underlying disease than to
134
treatment with carvedilol.
135
5.5
Non-allergic Bronchospasm
136
Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in
137
general, not receive β-blockers. COREG may be used with caution, however, in patients who do
138
not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG is used,
139
to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is
140
minimized.
141
In clinical trials of patients with heart failure, patients with bronchospastic disease were
142
enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In
143
such patients, it is recommended that carvedilol be used with caution. The dosing
144
recommendations should be followed closely and the dose should be lowered if any evidence of
145
bronchospasm is observed during up-titration.
146
5.6
Glycemic Control in Type 2 Diabetes
147
In general, β-blockers may mask some of the manifestations of hypoglycemia,
148
particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia
149
and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or
150
diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these
151
possibilities.
152
In heart failure patients with diabetes, carvedilol therapy may lead to worsening
153
hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended
154
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued.
155
Studies designed to examine the effects of carvedilol on glycemic control in patients with
156
diabetes and heart failure have not been conducted.
157
In a study designed to examine the effects of carvedilol on glycemic control in a
158
population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus,
159
carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see
160
Clinical Studies (14.4)].
161
5.7
Peripheral Vascular Disease
162
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients
163
with peripheral vascular disease. Caution should be exercised in such individuals.
164
5.8
Deterioration of Renal Function
165
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of
166
renal function. Patients at risk appear to be those with low blood pressure (systolic blood
167
pressure <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying
168
renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In
169
patients with these risk factors it is recommended that renal function be monitored during
170
up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal
171
function occurs.
172
5.9
Anesthesia and Major Surgery
173
If treatment with COREG is to be continued perioperatively, particular care should be
174
taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane,
175
and trichloroethylene, are used [see Overdosage (10) for information on treatment of
176
bradycardia and hypertension].
177
5.10 Thyrotoxicosis
178
β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia.
179
Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of
180
hyperthyroidism or may precipitate thyroid storm.
181
5.11 Pheochromocytoma
182
In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the
183
use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic
184
activities, there has been no experience with its use in this condition. Therefore, caution should
185
be taken in the administration of carvedilol to patients suspected of having pheochromocytoma.
186
5.12 Prinzmetal’s Variant Angina
187
Agents with non-selective β-blocking activity may provoke chest pain in patients with
188
Prinzmetal’s variant angina. There has been no clinical experience with carvedilol in these
189
patients although the α-blocking activity may prevent such symptoms. However, caution should
190
be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant
191
angina.
192
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
5.13 Risk of Anaphylactic Reaction
193
While taking β-blockers, patients with a history of severe anaphylactic reaction to a
194
variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or
195
therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat
196
allergic reaction.
197
6
ADVERSE REACTIONS
198
6.1
Clinical Studies Experience
199
COREG has been evaluated for safety in patients with heart failure (mild, moderate, and
200
severe), in patients with left ventricular dysfunction following myocardial infarction and in
201
hypertensive patients. The observed adverse event profile was consistent with the pharmacology
202
of the drug and the health status of the patients in the clinical trials. Adverse events reported for
203
each of these patient populations are provided below. Excluded are adverse events considered
204
too general to be informative, and those not reasonably associated with the use of the drug
205
because they were associated with the condition being treated or are very common in the treated
206
population. Rates of adverse events were generally similar across demographic subsets (men and
207
women, elderly and non-elderly, blacks and non-blacks).
208
Heart Failure: COREG has been evaluated for safety in heart failure in more than
209
4,500 patients worldwide of whom more than 2,100 participated in placebo-controlled clinical
210
trials. Approximately 60% of the total treated population in placebo-controlled clinical trials
211
received COREG for at least 6 months and 30% received COREG for at least 12 months. In the
212
COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with COREG for
213
up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that
214
compared COREG in daily doses up to 100 mg (n = 765) to placebo (n = 437), and in a
215
multinational clinical trial in severe heart failure (COPERNICUS) that compared COREG in
216
daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse
217
experiences were similar in carvedilol and placebo patients. In placebo-controlled clinical trials,
218
the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness
219
(1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).
220
Table 1 shows adverse events reported in patients with mild-to-moderate heart failure
221
enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the
222
COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated
223
patients than placebo-treated patients with an incidence of >3% in patients treated with
224
carvedilol regardless of causality. Median study medication exposure was 6.3 months for both
225
carvedilol and placebo patients in the trials of mild-to-moderate heart failure, and 10.4 months in
226
the trial of severe heart failure patients. The adverse event profile of COREG observed in the
227
long-term COMET study was generally similar to that observed in the US Heart Failure Trials.
228
229
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Table 1. Adverse Events (%) Occurring More Frequently With COREG Than With
230
Placebo in Patients With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart
231
Failure Trials or in Patients With Severe Heart Failure in the COPERNICUS Trial
232
(Incidence >3% in Patients Treated With Carvedilol, Regardless of Causality)
233
Mild-to-Moderate HF
Severe HF
COREG
Placebo
COREG
Placebo
(n = 765)
(n = 437)
(n = 1,156)
(n = 1,133)
Body as a Whole
Asthenia
7
7
11
9
Fatigue
24
22
—
—
Digoxin level increased
5
4
2
1
Edema generalized
5
3
6
5
Edema dependent
4
2
—
—
Cardiovascular
Bradycardia
9
1
10
3
Hypotension
9
3
14
8
Syncope
3
3
8
5
Angina pectoris
2
3
6
4
Central Nervous System
Dizziness
32
19
24
17
Headache
8
7
5
3
Gastrointestinal
Diarrhea
12
6
5
3
Nausea
9
5
4
3
Vomiting
6
4
1
2
Metabolic
Hyperglycemia
12
8
5
3
Weight increase
10
7
12
11
BUN increased
6
5
—
—
NPN increased
6
5
—
—
Hypercholesterolemia
4
3
1
1
Edema peripheral
2
1
7
6
Musculoskeletal
Arthralgia
6
5
1
1
Respiratory
Cough increased
8
9
5
4
Rales
4
4
4
2
Vision
Vision abnormal
5
2
—
—
234
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For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Cardiac failure and dyspnea were also reported in these studies, but the rates were equal
235
or greater in patients who received placebo.
236
The following adverse events were reported with a frequency of >1% but ≤3% and more
237
frequently with COREG in either the US placebo-controlled trials in patients with
238
mild-to-moderate heart failure, or in patients with severe heart failure in the COPERNICUS trial.
239
Incidence >1% to ≤3%
240
Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
241
Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV
242
block, palpitation, hypertension.
243
Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.
244
Gastrointestinal: Melena, periodontitis.
245
Liver and Biliary System: SGPT increased, SGOT increased.
246
Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased
247
alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss,
248
hyperkalemia, creatinine increased.
249
Musculoskeletal: Muscle cramps.
250
Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocytopenia.
251
Psychiatric: Somnolence.
252
Reproductive, male: Impotence.
253
Special Senses: Blurred vision.
254
Urinary System: Renal insufficiency, albuminuria, hematuria.
255
Left Ventricular Dysfunction Following Myocardial Infarction: COREG has been
256
evaluated for safety in survivors of an acute myocardial infarction with left ventricular
257
dysfunction in the CAPRICORN trial which involved 969 patients who received COREG and
258
980 who received placebo. Approximately 75% of the patients received COREG for at least
259
6 months and 53% received COREG for at least 12 months. Patients were treated for an average
260
of 12.9 months and 12.8 months with COREG and placebo, respectively.
261
The most common adverse events reported with COREG in the CAPRICORN trial were
262
consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial.
263
The only additional adverse events reported in CAPRICORN in >3% of the patients and more
264
commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events
265
were reported with a frequency of >1% but ≤3% and more frequently with COREG: Flu
266
syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression,
267
gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse
268
events were similar in both groups of patients. In this database, the only cause of discontinuation
269
>1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on
270
placebo).
271
Hypertension: COREG has been evaluated for safety in hypertension in more than
272
2,193 patients in US clinical trials and in 2,976 patients in international clinical trials.
273
Approximately 36% of the total treated population received COREG for at least 6 months. Most
274
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For current labeling information, please visit https://www.fda.gov/drugsatfda
10
adverse events reported during therapy with COREG were of mild to moderate severity. In US
275
controlled clinical trials directly comparing COREG in doses up to 50 mg (n = 1,142) to placebo
276
(n = 462), 4.9% of patients receiving COREG discontinued for adverse events versus 5.2% of
277
placebo patients. Although there was no overall difference in discontinuation rates,
278
discontinuations were more common in the carvedilol group for postural hypotension (1% versus
279
0). The overall incidence of adverse events in US placebo-controlled trials increased with
280
increasing dose of COREG. For individual adverse events this could only be distinguished for
281
dizziness, which increased in frequency from 2% to 5% as total daily dose increased from
282
6.25 mg to 50 mg.
283
Table 2 shows adverse events in US placebo-controlled clinical trials for hypertension
284
that occurred with an incidence of >1% regardless of causality, and that were more frequent in
285
drug-treated patients than placebo-treated patients.
286
287
Table 2. Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials
288
(Incidence ≥1%, Regardless of Causality)*
289
COREG
Placebo
(n = 1,142)
(n = 462)
Cardiovascular
Bradycardia
2
—
Postural hypotension
2
—
Peripheral edema
1
—
Central Nervous System
Dizziness
6
5
Insomnia
2
1
Gastrointestinal
Diarrhea
2
1
Hematologic
Thrombocytopenia
1
—
Metabolic
Hypertriglyceridemia
1
—
* Shown are events with rate >1% rounded to nearest integer.
290
291
Dyspnea and fatigue were also reported in these studies, but the rates were equal or
292
greater in patients who received placebo.
293
The following adverse events not described above were reported as possibly or probably
294
related to COREG in worldwide open or controlled trials with COREG in patients with
295
hypertension or heart failure.
296
Incidence >0.1% to ≤1%
297
Cardiovascular: Peripheral ischemia, tachycardia.
298
Central and Peripheral Nervous System: Hypokinesia.
299
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11
Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension
300
patients and 0.4% of heart failure patients were discontinued from therapy because of increases
301
in hepatic enzymes) [see Adverse Reactions (6.2)].
302
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration,
303
abnormal thinking, paroniria, emotional lability.
304
Respiratory System: Asthma [see Contraindications (4)].
305
Reproductive, male: Decreased libido.
306
Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform,
307
photosensitivity reaction.
308
Special Senses: Tinnitus.
309
Urinary System: Micturition frequency increased.
310
Autonomic Nervous System: Dry mouth, sweating increased.
311
Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.
312
Hematologic: Anemia, leukopenia.
313
The following events were reported in ≤0.1% of patients and are potentially important:
314
Complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder,
315
convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative
316
dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing,
317
respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
318
6.2
Laboratory Abnormalities
319
Reversible elevations in serum transaminases (ALT or AST) have been observed during
320
treatment with COREG. Rates of transaminase elevations (2- to 3-times the upper limit of
321
normal) observed during controlled clinical trials have generally been similar between patients
322
treated with COREG and those treated with placebo. However, transaminase elevations,
323
confirmed by rechallenge, have been observed with COREG. In a long-term, placebo-controlled
324
trial in severe heart failure, patients treated with COREG had lower values for hepatic
325
transaminases than patients treated with placebo, possibly because improvements in cardiac
326
function induced by COREG led to less hepatic congestion and/or improved hepatic blood flow.
327
COREG has not been associated with clinically significant changes in serum potassium,
328
total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or
329
creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive
330
patients; fasting serum glucose was not evaluated in the heart failure clinical trials.
331
6.3
Postmarketing Experience
332
The following adverse reactions have been identified during post-approval use of
333
COREG. Because these reactions are reported voluntarily from a population of uncertain size, it
334
is not always possible to reliably estimate their frequency or establish a causal relationship to
335
drug exposure.
336
Reports of aplastic anemia and severe skin reactions (Stevens-Johnson syndrome, toxic
337
epidermal necrolysis, and erythema multiforme) have been rare and received only when
338
carvedilol was administered concomitantly with other medications associated with such
339
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
reactions. Urinary incontinence in women (which resolved upon discontinuation of the
340
medication) and interstitial pneumonitis have been reported rarely.
341
7
DRUG INTERACTIONS
342
7.1
CYP2D6 Inhibitors and Poor Metabolizers
343
Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as
344
quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would
345
be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical
346
Pharmacology (12.3)]. Retrospective analysis of side effects in clinical trials showed that poor
347
2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from
348
vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.
349
7.2
Hypotensive Agents
350
Patients taking both agents with β-blocking properties and a drug that can deplete
351
catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely
352
for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine
353
with agents with β-blocking properties may potentiate blood-pressure- and heart-rate-lowering
354
effects. When concomitant treatment with agents with β-blocking properties and clonidine is to
355
be terminated, the β-blocking agent should be discontinued first. Clonidine therapy can then be
356
discontinued several days later by gradually decreasing the dosage.
357
7.3
Cyclosporine
358
Modest increases in mean trough cyclosporine concentrations were observed following
359
initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular
360
rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to
361
maintain cyclosporine concentrations within the therapeutic range, while in the remainder no
362
adjustment was needed. On the average for the group, the dose of cyclosporine was reduced
363
about 20% in these patients. Due to wide interindividual variability in the dose adjustment
364
required, it is recommended that cyclosporine concentrations be monitored closely after initiation
365
of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
366
7.4
Digoxin
367
Digoxin concentrations are increased by about 15% when digoxin and carvedilol are
368
administered concomitantly. Both digoxin and COREG slow AV conduction. Therefore,
369
increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing
370
COREG [see Clinical Pharmacology (12.5)].
371
7.5
Inducers/Inhibitors of Hepatic Metabolism
372
Rifampin reduced plasma concentrations of carvedilol by about 70% [see Drug-Drug
373
Interactions (12.5)]. Cimetidine increased AUC by about 30% but caused no change in Cmax [see
374
Clinical Pharmacology (12.5)].
375
7.6
Calcium Channel Blockers
376
Conduction disturbance (rarely with hemodynamic compromise) has been observed when
377
COREG is co-administered with diltiazem. As with other agents with β-blocking properties, if
378
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
COREG is to be administered with calcium channel blockers of the verapamil or diltiazem type,
379
it is recommended that ECG and blood pressure be monitored.
380
7.7
Insulin or Oral Hypoglycemics
381
Agents with β-blocking properties may enhance the blood-sugar-reducing effect of
382
insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics,
383
regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)].
384
8
USE IN SPECIFIC POPULATIONS
385
8.1
Pregnancy
386
Pregnancy Category C. Studies performed in pregnant rats and rabbits given carvedilol
387
revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the MRHD
388
as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats,
389
there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day
390
(50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of
391
fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the
392
no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as
393
mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate
394
and well-controlled studies in pregnant women. COREG should be used during pregnancy only
395
if the potential benefit justifies the potential risk to the fetus.
396
8.3
Nursing Mothers
397
It is not known whether this drug is excreted in human milk. Studies in rats have shown
398
that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and
399
are excreted in breast milk. There was increased mortality at one week post-partum in neonates
400
from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last
401
trimester through day 22 of lactation. Because many drugs are excreted in human milk and
402
because of the potential for serious adverse reactions in nursing infants from β-blockers,
403
especially bradycardia, a decision should be made whether to discontinue nursing or to
404
discontinue the drug, taking into account the importance of the drug to the mother. The effects of
405
other α- and β-blocking agents have included perinatal and neonatal distress.
406
8.4
Pediatric Use
407
Effectiveness of COREG in patients younger than 18 years of age has not been
408
established.
409
In a double-blind trial, 161 children (mean age 6 years, range 2 months to 17 years; 45%
410
less than 2 years old) with chronic heart failure [NYHA class II-IV, left ventricular ejection
411
fraction <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular
412
dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who
413
were receiving standard background treatment were randomized to placebo or to two dose levels
414
of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4-6 heart
415
beats per minute, indicative of beta-blockade activity. Exposure appeared to be lower in pediatric
416
subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on
417
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of patients
418
treated with COREG and at twice the rate of placebo-treated patients included chest pain (17%
419
vs. 6%), dizziness (13% vs. 2%), and dyspnea (11% vs. 0%).
420
8.5
Geriatric Use
421
Of the 765 patients with heart failure randomized to COREG in US clinical trials, 31%
422
(235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the
423
1,156 patients randomized to COREG in a long-term, placebo-controlled trial in severe heart
424
failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older.
425
Of 3,025 patients receiving COREG in heart failure trials worldwide, 42% were 65 years of age
426
or older.
427
Of the 975 myocardial infarction patients randomized to COREG in the CAPRICORN
428
trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.
429
Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were
430
treated with COREG, 21% (436) were 65 years of age or older. Of 3,722 patients receiving
431
COREG in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.
432
With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly
433
versus 6% in younger patients), no overall differences in the safety or effectiveness (see Figures
434
2 and 4) were observed between the older subjects and younger subjects in each of these
435
populations. Similarly, other reported clinical experience has not identified differences in
436
responses between the elderly and younger subjects, but greater sensitivity of some older
437
individuals cannot be ruled out.
438
10
OVERDOSAGE
439
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency,
440
cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of
441
consciousness, and generalized seizures may also occur.
442
The patient should be placed in a supine position and, where necessary, kept under
443
observation and treated under intensive-care conditions. Gastric lavage or pharmacologically
444
induced emesis may be used shortly after ingestion. The following agents may be administered:
445
for excessive bradycardia: Atropine, 2 mg IV.
446
to support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds,
447
followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline,
448
adrenaline) at doses according to body weight and effect.
449
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or
450
noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant
451
bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics
452
(as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV
453
injection of diazepam or clonazepam is recommended.
454
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment
455
with antidotes must be continued for a sufficiently long period of time consistent with the 7- to
456
10-hour half-life of carvedilol.
457
Cases of overdosage with COREG alone or in combination with other drugs have been
458
reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced
459
included low blood pressure and heart rate. Standard supportive treatment was provided and
460
individuals recovered.
461
11
DESCRIPTION
462
Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is
463
(±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. Carvedilol is a
464
racemic mixture with the following structure:
465
466
COREG is a white, oval, film-coated tablet containing 3.125 mg, 6.25 mg, 12.5 mg, or
467
25 mg of carvedilol. The 6.25 mg, 12.5 mg, and 25 mg tablets are TILTAB® tablets. Inactive
468
ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium
469
stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide.
470
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a
471
molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene
472
chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in
473
ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal
474
fluid (simulated, TS without pancreatin, pH 7.5).
475
12
CLINICAL PHARMACOLOGY
476
12.1 Mechanism of Action
477
COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is
478
present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and
479
S(-) enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.
480
12.2 Pharmacodynamics
481
Heart Failure: The basis for the beneficial effects of COREG in heart failure is not
482
established.
483
Two placebo-controlled studies compared the acute hemodynamic effects of COREG to
484
baseline measurements in 59 and 49 patients with NYHA class II-IV heart failure receiving
485
diuretics, ACE inhibitors, and digitalis. There were significant reductions in systemic blood
486
pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial
487
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
effects on cardiac output, stroke volume index, and systemic vascular resistance were small and
488
variable.
489
These studies measured hemodynamic effects again at 12 to 14 weeks. COREG
490
significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure,
491
systemic vascular resistance, and heart rate, while stroke volume index was increased.
492
Among 839 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in
493
4 US placebo-controlled trials, average left ventricular ejection fraction (EF) measured by
494
radionuclide ventriculography increased by 9 EF units (%) in patients receiving COREG and by
495
2 EF units in placebo patients at a target dose of 25-50 mg twice daily. The effects of carvedilol
496
on ejection fraction were related to dose. Doses of 6.25 mg twice daily, 12.5 mg twice daily, and
497
25 mg twice daily were associated with placebo-corrected increases in EF of 5 EF units, 6 EF
498
units, and 8 EF units, respectively; each of these effects were nominally statistically significant.
499
Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the
500
beneficial effects of COREG in patients with left ventricular dysfunction following an acute
501
myocardial infarction is not established.
502
Hypertension: The mechanism by which β-blockade produces an antihypertensive effect
503
has not been established.
504
β-adrenoreceptor blocking activity has been demonstrated in animal and human studies
505
showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise-
506
and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia.
507
Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
508
α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies,
509
showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes
510
vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the
511
reduction of blood pressure and usually are seen within 30 minutes of drug administration.
512
Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in
513
the standing than in the supine position, and symptoms of postural hypotension (1.8%), including
514
rare instances of syncope, can occur. Following oral administration, when postural hypotension
515
has occurred, it has been transient and is uncommon when COREG is administered with food at
516
the recommended starting dose and titration increments are closely followed [see Dosage and
517
Administration (2)].
518
In hypertensive patients with normal renal function, therapeutic doses of COREG
519
decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma
520
flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive
521
patients with normal renal function were similar after COREG and placebo.
522
COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte
523
levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It
524
also increases levels of atrial natriuretic peptide.
525
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
12.3 Pharmacokinetics
526
COREG is rapidly and extensively absorbed following oral administration, with absolute
527
bioavailability of approximately 25% to 35% due to a significant degree of first-pass
528
metabolism. Following oral administration, the apparent mean terminal elimination half-life of
529
carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional
530
to the oral dose administered. When administered with food, the rate of absorption is slowed, as
531
evidenced by a delay in the time to reach peak plasma levels, with no significant difference in
532
extent of bioavailability. Taking COREG with food should minimize the risk of orthostatic
533
hypotension.
534
Carvedilol is extensively metabolized. Following oral administration of radiolabelled
535
carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity
536
in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted
537
unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and
538
glucuronidation. The oxidative metabolites are further metabolized by conjugation via
539
glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile
540
into the feces. Demethylation and hydroxylation at the phenol ring produce three active
541
metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl
542
metabolite is approximately 13 times more potent than carvedilol for β-blockade.
543
Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity.
544
Plasma concentrations of the active metabolites are about one-tenth of those observed for
545
carvedilol and have pharmacokinetics similar to the parent.
546
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of
547
R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral
548
administration in healthy subjects. The mean apparent terminal elimination half-lives for
549
R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
550
The primary P450 enzymes responsible for the metabolism of both R(+) and
551
S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent
552
CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and
553
5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be
554
of primary importance in the O-methylation pathway of S(-)-carvedilol.
555
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of
556
debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma
557
concentrations of R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels
558
of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this
559
enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The
560
pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of
561
S-mephenytoin (patients deficient in cytochrome P450 2C19).
562
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The
563
plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is
564
a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L,
565
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to
566
700 mL/min.
567
12.4 Specific Populations
568
Heart Failure: Steady-state plasma concentrations of carvedilol and its enantiomers
569
increased proportionally over the 6.25 to 50 mg dose range in patients with heart failure.
570
Compared to healthy subjects, heart failure patients had increased mean AUC and Cmax values
571
for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 patients
572
with NYHA class IV heart failure. The mean apparent terminal elimination half-life for
573
carvedilol was similar to that observed in healthy subjects.
574
Geriatric: Plasma levels of carvedilol average about 50% higher in the elderly compared
575
to young subjects.
576
Hepatic Impairment: Compared to healthy subjects, patients with severe liver
577
impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is
578
contraindicated in patients with severe liver impairment.
579
Renal Impairment: Although carvedilol is metabolized primarily by the liver, plasma
580
concentrations of carvedilol have been reported to be increased in patients with renal
581
impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations
582
of carvedilol were observed in hypertensive patients with moderate to severe renal impairment
583
compared to a control group of hypertensive patients with normal renal function. However, the
584
ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were
585
less pronounced, approximately 12% to 26% higher in patients with impaired renal function.
586
Consistent with its high degree of plasma protein-binding, carvedilol does not appear to
587
be cleared significantly by hemodialysis.
588
12.5 Drug-Drug Interactions
589
Since carvedilol undergoes substantial oxidative metabolism, the metabolism and
590
pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450
591
enzymes.
592
Rifampin: In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin
593
(600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70% [see Drug
594
Interactions (7.5)].
595
Cimetidine: In a pharmacokinetic study conducted in 10 healthy male subjects,
596
cimetidine (1000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change
597
in Cmax [see Drug Interactions (7.5)].
598
Glyburide: In 12 healthy subjects, combined administration of carvedilol (25 mg once
599
daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic
600
interaction for either compound.
601
Hydrochlorothiazide: A single oral dose of carvedilol 25 mg did not alter the
602
pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 patients with
603
hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.
604
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Digoxin: Following concomitant administration of carvedilol (25 mg once daily) and
605
digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin
606
were increased by 14% and 16%, respectively, in 12 hypertensive patients [see Drug
607
Interactions (7.5)].
608
Torsemide: In a study of 12 healthy subjects, combined oral administration of
609
carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any
610
significant differences in their pharmacokinetics compared with administration of the drugs
611
alone.
612
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state
613
prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin
614
following concomitant administration with warfarin in 9 healthy volunteers.
615
13
NONCLINICAL TOXICOLOGY
616
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
617
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times
618
the maximum recommended human dose [MRHD] when compared on a mg/m2 basis) or in mice
619
given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had no
620
carcinogenic effect.
621
Carvedilol was negative when tested in a battery of genotoxicity assays, including the
622
Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and
623
in vivo human lymphocyte cell tests for clastogenicity.
624
At doses ≥200 mg/kg/day (≥32 times the MRHD as mg/m2) carvedilol was toxic to adult
625
rats (sedation, reduced weight gain) and was associated with a reduced number of successful
626
matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and
627
complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity
628
and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
629
14
CLINICAL STUDIES
630
14.1 Heart Failure
631
A total of 6,975 patients with mild to severe heart failure were evaluated in
632
placebo-controlled studies of carvedilol.
633
Mild-to-Moderate Heart Failure: Carvedilol was studied in 5 multicenter,
634
placebo-controlled studies, and in 1 active-controlled study (COMET study) involving patients
635
with mild-to-moderate heart failure.
636
Four US multicenter, double-blind, placebo-controlled studies enrolled 1,094 patients
637
(696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction ≤0.35.
638
The vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were
639
assigned to the studies based upon exercise ability. An Australia-New Zealand double-blind,
640
placebo-controlled study enrolled 415 patients (half randomized to carvedilol) with less severe
641
heart failure. All protocols excluded patients expected to undergo cardiac transplantation during
642
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
the 7.5 to 15 months of double-blind follow-up. All randomized patients had tolerated a 2-week
643
course on carvedilol 6.25 mg twice daily.
644
In each study, there was a primary end point, either progression of heart failure (1 US
645
study) or exercise tolerance (2 US studies meeting enrollment goals and the Australia-New
646
Zealand study). There were many secondary end points specified in these studies, including
647
NYHA classification, patient and physician global assessments, and cardiovascular
648
hospitalization. Other analyses not prospectively planned included the sum of deaths and total
649
cardiovascular hospitalizations. In situations where the primary end points of a trial do not show
650
a significant benefit of treatment, assignment of significance values to the other results is
651
complex, and such values need to be interpreted cautiously.
652
The results of the US and Australia-New Zealand trials were as follows:
653
Slowing Progression of Heart Failure: One US multicenter study (366 subjects) had as
654
its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and
655
sustained increase in heart failure medications. Heart failure progression was reduced, during an
656
average follow-up of 7 months, by 48% (p = 0.008).
657
In the Australia-New Zealand study, death and total hospitalizations were reduced by
658
about 25% over 18 to 24 months. In the 3 largest US studies, death and total hospitalizations
659
were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 studies. The
660
Australia-New Zealand results were statistically borderline.
661
Functional Measures: None of the multicenter studies had NYHA classification as a
662
primary end point, but all such studies had it as a secondary end point. There was at least a trend
663
toward improvement in NYHA class in all studies. Exercise tolerance was the primary end point
664
in 3 studies; in none was a statistically significant effect found.
665
Subjective Measures: Health-related quality of life, as measured with a standard
666
questionnaire (a primary end point in 1 study), was unaffected by carvedilol. However, patients’
667
and investigators’ global assessments showed significant improvement in most studies.
668
Mortality: Death was not a pre-specified end point in any study, but was analyzed in all
669
studies. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2
670
studies.
671
COMET Trial: In this double-blind trial, 3,029 patients with NYHA class II-IV heart
672
failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol
673
(target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg
674
twice daily). The mean age of the patients was approximately 62 years, 80% were males, and the
675
mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the patients
676
had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE
677
inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering
678
agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was
679
42 mg per day.
680
The study had 2 primary end points: All-cause mortality and the composite of death plus
681
hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause
682
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
mortality carried most of the statistical weight and was the primary determinant of the study size.
683
All-cause mortality was 34% in the patients treated with carvedilol and was 40% in the
684
immediate-release metoprolol group (p = 0.0017; hazard ratio = 0.83, 95%CI 0.74-0.93). The
685
effect on mortality was primarily due to a reduction in cardiovascular death. The difference
686
between the 2 groups with respect to the composite end point was not significant (p = 0.122).
687
The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release
688
metoprolol.
689
690
Table 3. Results of COMET
691
End point
Carvedilol
N = 1,511
Metoprolol
N = 1,518
Hazard ratio
(95% CI)
All cause mortality
34%
40%
0.83
0.74 – 0.93
Mortality + all hospitalization
74%
76%
0.94
0.86 – 1.02
Cardiovascular death
30%
35%
0.80
0.70 – 0.90
Sudden death
14%
17%
0.81
0.68 – 0.97
Death due to circulatory failure
11%
13%
0.83
0.67 – 1.02
Death due to stroke
0.9%
2.5%
0.33
0.18 – 0.62
692
It is not known whether this formulation of metoprolol at any dose or this low dose of
693
metoprolol in any formulation has any effect on survival or hospitalization in patients with heart
694
failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in
695
heart failure, but it is not evidence that carvedilol improves outcome over the formulation of
696
metoprolol (Toprol XL) with benefits in heart failure.
697
Severe Heart Failure (COPERNICUS): In a double-blind study (COPERNICUS),
698
2,289 patients with heart failure at rest or with minimal exertion and left ventricular ejection
699
fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%)
700
were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of
701
3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum
702
of 6 weeks. Most subjects achieved the target dose of 25 mg. The study was conducted in
703
Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects
704
per group (about 100) withdrew during the titration period.
705
The primary end point of the trial was all-cause mortality, but cause-specific mortality
706
and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were
707
also examined. The developing trial data were followed by a data monitoring committee, and
708
mortality analyses were adjusted for these multiple looks. The trial was stopped after a median
709
follow-up of 10 months because of an observed 35% reduction in mortality (from 19.7% per
710
patient year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI 0.52 – 0.81,
711
p = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.
712
713
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Table 4. Results of COPERNICUS Trial in Patients With Severe Heart Failure
714
715
End point
Placebo
(N = 1,133)
Carvedilol
(N = 1,156)
Hazard ratio
(95% CI)
%
Reduction
Nominal
p value
Mortality
190
130
0.65
(0.52 – 0.81)
35
0.00013
Mortality + all
hospitalization
507
425
0.76
(0.67 – 0.87)
24
0.00004
Mortality + CV
hospitalization
395
314
0.73
(0.63 – 0.84)
27
0.00002
Mortality + HF
hospitalization
357
271
0.69
(0.59 – 0.81)
31
0.000004
Cardiovascular = CV; Heart failure = HF.
716
717
Figure 1. Survival Analysis for COPERNICUS (intent-to-treat)
718
719
720
721
722
The effect on mortality was principally the result of a reduction in the rate of sudden
723
death among patients without worsening heart failure.
724
Patients' global assessments, in which carvedilol-treated patients were compared to
725
placebo, were based on pre-specified, periodic patient self-assessments regarding whether
726
clinical status post-treatment showed improvement, worsening or no change compared to
727
baseline. Patients treated with carvedilol showed significant improvements in global assessments
728
compared with those treated with placebo in COPERNICUS.
729
The protocol also specified that hospitalizations would be assessed. Fewer patients on
730
COREG than on placebo were hospitalized for any reason (372 versus 432, p = 0.0029), for
731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
cardiovascular reasons (246 versus 314, p = 0.0003), or for worsening heart failure (198 versus
732
268, p = 0.0001).
733
COREG had a consistent and beneficial effect on all-cause mortality as well as the
734
combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in
735
the overall study population and in all subgroups examined, including men and women, elderly
736
and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).
737
738
Figure 2. Effects on Mortality for Subgroups in COPERNICUS
739
740
741
742
14.2 Left Ventricular Dysfunction Following Myocardial Infarction
743
CAPRICORN was a double-blind study comparing carvedilol and placebo in
744
1,959 patients with a recent myocardial infarction (within 21 days) and left ventricular ejection
745
fraction of ≤40%, with (47%) or without symptoms of heart failure. Patients given carvedilol
746
received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Patients had to have a
747
systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no
748
contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV
749
or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute
750
angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor
751
blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%).
752
Baseline population characteristics included an average age of 63 years, 74% male, 95%
753
Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of
754
hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of
755
follow-up was 15 months.
756
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group,
757
indicating a 23% risk reduction in patients treated with carvedilol (95% CI 2-40%, p = 0.03), as
758
shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly
759
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these
760
deaths were sudden or related to pump failure (both types of death were reduced by carvedilol).
761
Another study end point, total mortality and all-cause hospitalization, did not show a significant
762
improvement.
763
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction
764
observed in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar
765
reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-
766
controlled trials of carvedilol in heart failure.
767
768
Figure 3. Survival Analysis for CAPRICORN (intent-to-treat)
769
770
771
772
Figure 4. Effects on Mortality for Subgroups in CAPRICORN
773
774
775
776
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
14.3 Hypertension
777
COREG was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at
778
total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed
779
12.5 mg. At 50 mg/day, COREG reduced sitting trough (12-hour) blood pressure by about
780
9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak
781
blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart
782
rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers,
783
responses were smaller in black than non-black patients. There were no age- or gender-related
784
differences in response.
785
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related
786
blood pressure response was accompanied by a dose-related increase in adverse effects [see
787
Adverse Reactions (6)].
788
14.4 Hypertension With Type 2 Diabetes Mellitus
789
In a double-blind study (GEMINI), COREG, added to an ACE inhibitor or angiotensin
790
receptor blocker, was evaluated in a population with mild-to-moderate hypertension and well-
791
controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated
792
to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse
793
effect on glycemic control, based on HbA1c measurements (mean change from baseline of
794
0.02%, 95% CI -0.06 to 0.10, p = NS) [see Warnings and Precautions (5.6)].
795
16
HOW SUPPLIED/STORAGE AND HANDLING
796
The white, oval, film-coated tablets are available in the following strengths: 3.125 mg–
797
engraved with 39 and SB, in bottles of 100; 6.25 mg–engraved with 4140 and SB, in bottles of
798
100; 12.5 mg–engraved with 4141 and SB, in bottles of 100; 25 mg–engraved with 4142 and SB,
799
in bottles of 100. The 6.25 mg, 12.5 mg, and 25 mg tablets are TILTAB tablets.
800
• 3.125 mg 100’s: NDC 0007-4139-20
801
• 6.25 mg 100’s: NDC 0007-4140-20
802
• 12.5 mg 100’s: NDC 0007-4141-20
803
• 25 mg 100’s: NDC 0007-4142-20
804
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant
805
container.
806
17
PATIENT COUNSELING INFORMATION
807
See 17.2 for FDA-approved Patient Labeling
808
17.1 Patient Advice
809
Patients taking COREG should be advised of the following:
810
• Patients should take COREG with food.
811
• Patients should not interrupt or discontinue using COREG without a physician’s advice.
812
• Patients with heart failure should consult their physician if they experience signs or
813
symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
814
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
• Patients may experience a drop in blood pressure when standing, resulting in dizziness and,
815
rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood
816
pressure occur.
817
• If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.
818
• Patients should consult a physician if they experience dizziness or faintness, in case the
819
dosage should be adjusted.
820
• Diabetic patients should report any changes in blood sugar levels to their physician.
821
• Contact lens wearers may experience decreased lacrimation.
822
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
823
-------------------------------------------------------------------------------------------------------------
824
17.2 FDA-Approved Patient Labeling
825
826
PATIENT INFORMATION – Rx only
827
COREG®
(Co-REG)
828
Carvedilol Tablets
829
830
Read the Patient Information that comes with COREG before you start taking it and each time
831
you get a refill. There may be new information. This information does not take the place of
832
talking with your doctor about your medical condition or your treatment. If you have any
833
questions about COREG, ask your doctor or pharmacist.
834
WHAT IS COREG?
835
COREG is a prescription medicine that belongs to a group of medicines called “beta-blockers”.
836
COREG is used, often with other medicines, for the following conditions:
837
• To treat patients with high blood pressure (hypertension)
838
• To treat patients who had a heart attack that worsened how well the heart pumps
839
• To treat patients with certain types of heart failure
840
841
COREG is not approved for use in children under 18 years of age.
842
WHO SHOULD NOT TAKE COREG?
843
Do not take COREG if you:
844
• Have severe heart failure and are hospitalized in the intensive care unit or require certain
845
intravenous medications that help support circulation (inotropic medications)
846
• Are prone to asthma or other breathing problems
847
• Have a slow heartbeat or a heart that skips a beat (irregular heartbeat)
848
• Have liver problems
849
• Are allergic to any of the ingredients in COREG. The active ingredient is carvedilol. See
850
the end of this leaflet for a list of all the ingredients in COREG.
851
WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING COREG?
852
Tell your doctor about all of your medical conditions, including if you:
853
• Have asthma or other lung problems (such as bronchitis or emphysema)
854
• Have problems with blood flow in your feet and legs (peripheral vascular disease)
855
COREG can make some of your symptoms worse.
856
• Have diabetes
857
• Have thyroid problems
858
• Have a condition called pheochromocytoma
859
• Have had severe allergic reactions
860
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
• Are pregnant or trying to become pregnant. It is not known if COREG is safe for your
861
unborn baby. You and your doctor should talk about the best way to control your high
862
blood pressure during pregnancy.
863
• Are breastfeeding. It is not known if COREG passes into your breast milk. You should
864
not breastfeed while using COREG.
865
• Are scheduled for surgery and will be given anesthetic agents
866
• Are taking prescription or non-prescription medicines, vitamins, and herbal supplements.
867
COREG and certain other medicines can affect each other and cause serious side effects.
868
COREG may affect the way other medicines work. Also, other medicines may affect how
869
well COREG works
870
871
Keep a list of all the medicines you take. Show this list to your doctor and pharmacist before you
872
start a new medicine.
873
HOW SHOULD I TAKE COREG?
874
It is important for you to take your medicine every day as directed by your doctor. If you
875
stop taking COREG suddenly, you could have chest pain and/or a heart attack. If your
876
doctor decides that you should stop taking COREG, your doctor may slowly lower your
877
dose over a period of time before stopping it completely.
878
• Take COREG exactly as prescribed. Your doctor will tell you how many tablets to take
879
and how often. In order to minimize possible side effects, your doctor might begin with a
880
low dose and then slowly increase the dose.
881
• Do not stop taking COREG and do not change the amount of COREG you take
882
without talking to your doctor.
883
• Tell your doctor if you gain weight or have trouble breathing while taking COREG.
884
• Take COREG with food.
885
• If you miss a dose of COREG, take your dose as soon as you remember, unless it is time
886
to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the
887
same time.
888
• If you take too much COREG, call your doctor or poison control center right away.
889
WHAT SHOULD I AVOID WHILE TAKING COREG?
890
COREG can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do
891
anything that needs you to be alert if you have these symptoms.
892
WHAT ARE POSSIBLE SIDE EFFECTS OF COREG?
893
• Low blood pressure (which may cause dizziness or fainting when you stand up). If
894
these happen, sit or lie down right away and tell your doctor.
895
• Tiredness. If you feel tired or dizzy you should not drive, use machinery, or do anything
896
that needs you to be alert.
897
• Slow heart beat
898
• Changes in your blood sugar. If you have diabetes, tell your doctor if you have any
899
changes in your blood sugar levels.
900
• COREG may hide some of the symptoms of low blood sugar, especially a fast heartbeat.
901
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
• COREG may mask the symptoms of hyperthyroidism (overactive thyroid).
902
• Worsening of severe allergic reactions.
903
904
Other side effects of COREG include shortness of breath, weight gain, diarrhea, and fewer tears
905
or dry eyes that become bothersome if you wear contact lenses.
906
Call your doctor if you have any side effects that bother you or don’t go away.
907
How should I store COREG?
908
• Store COREG at less than 86°F (30°C). Keep the tablets dry.
909
• Safely, throw away COREG that is out of date or no longer needed.
910
• Keep COREG and all medicines out of the reach of children.
911
GENERAL INFORMATION ABOUT COREG
912
Medicines are sometimes prescribed for conditions other than those described in patient
913
information leaflets. Do not use COREG for a condition for which it was not prescribed. Do not
914
give COREG to other people, even if they have the same symptoms you have. It may harm them.
915
916
This leaflet summarizes the most important information about COREG. If you would like more
917
information, talk with your doctor. You can ask your doctor or pharmacist for information about
918
COREG that is written for healthcare professionals. You can also find out more about COREG
919
by visiting the website www.COREG.com or calling 1-888-825-5249. This call is free.
920
WHAT ARE THE INGREDIENTS IN COREG?
921
Active Ingredient: Carvedilol
922
923
Inactive Ingredients: Colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium
924
stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide
925
926
Carvedilol tablets come in the following strengths: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg
927
928
929
COREG and TILTAB are registered trademarks of GlaxoSmithKline.
930
931
932
GlaxoSmithKline
933
Research Triangle Park, NC 27709
934
©Year GlaxoSmithKline. All rights reserved.
935
936
937
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:25.077597
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020297s022lbl.pdf', 'application_number': 20297, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
12,428
|
Final clean 08 Aug 2008
ORTHO-CEPT® TABLETS
(desogestrel and ethinyl estradiol)
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
DESCRIPTION
ORTHO-CEPT Tablets provide an oral contraceptive regimen of 21 light orange
round
tablets
each
containing
0.15
mg
desogestrel
(13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en- 20-yn-17-ol) and 0.03 mg
ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17,diol). Inactive
ingredients include colloidal silicone dioxide, corn starch, ferric oxide, hypromellose,
lactose, polyethylene glycol, povidone, stearic acid, talc, titanium dioxide, and
vitamin E. Each green tablet contains the following inactive ingredients: FD&C Blue
No.1 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate,
polyethylene glycol, pregelatinized starch, talc and titanium dioxide. chemical structure
CLINICAL PHARMACOLOGY
Pharmacodynamics
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 changes in the endometrium which reduce the likelihood of implantation.
Receptor binding studies, as well as studies in animals, have shown that
3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high
progestational activity with minimal intrinsic androgenicity.91,92 The relevance of this
latter finding in humans is unknown.
Pharmacokinetics
Desogestrel is rapidly and almost completely absorbed and converted into
3-keto-desogestrel, its biologically active metabolite. Following oral administration,
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
the relative bioavailability of desogestrel, as measured by serum levels of
3-keto-desogestrel, is approximately 84%.
In the third cycle of use after a single dose of ORTHO-CEPT, maximum
concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are
reached at 1.4 ± 0.8 hours. The area under the curve (AUC
0-∞) is
33,858 ± 11,043 pg/mL⋅hr after a single dose. At steady state, attained from at least
day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are reached at
1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are
1,400 ± 560 pg/mL. The AUC0-24 at steady state is 52,299 ± 17,878 pg/mL⋅hr. The
mean AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the
mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are
non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding
globulin in the cycle, attributed to increased sex hormone-binding globulin levels
which are induced by the daily administration of ethinyl estradiol. Sex
hormone-binding globulin levels increased significantly in the third treatment cycle
from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).
The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at
steady state. In addition to 3-keto-desogestrel, other phase I metabolites are
3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other
metabolites are not known to have any pharmacologic effects, and are further
converted in part by conjugation (phase II metabolism) into polar metabolites, mainly
sulfates and glucuronides.
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use
after a single dose of ORTHO-CEPT, the relative bioavailability is approximately
83%.
In the third cycle of use after a single dose of ORTHO-CEPT, maximum
concentrations of ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours.
The AUC0-∞ is 1,471 ± 268 pg/mL⋅hr after a single dose. At steady state, attained
from at least day 19 onwards, maximum ethinyl estradiol concentrations of
141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The minimum serum levels of
ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC0-24, at steady state is
1,117 ± 302 pg/mL⋅hr. The mean AUC0-∞ for ethinyl estradiol following a single dose
during treatment cycle 3 does not significantly differ from the mean AUC0-24 at
steady state. This finding indicates linear kinetics for ethinyl estradiol.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
The elimination half-life is 26 ± 6.8 hours at steady state. Ethinyl estradiol is subject
to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl
estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic
conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl
estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both
ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo
enterohepatic circulation.
INDICATIONS AND USAGE
ORTHO-CEPT Tablets are indicated for the prevention of pregnancy in women who
elect to use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table I 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 these methods can result in lower failure rates.
In a clinical trial with ORTHO-CEPT, 1,195 subjects completed 11,656 cycles and a
total of 10 pregnancies were reported. This represents an overall user-efficacy (typical
user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes
patients who did not take the drug correctly.
TABLE I: 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 within the
First Year of Use
Continuing Use
at One Year3
Method
Typical Use 1
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
Withdrawal
19
4
Cap7
Parous Women
40
26
42
(Continued)
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
TABLE I:
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. (Continued)
% of Women Experiencing an
% of Women
Unintended Pregnancy within the
Continuing Use
First Year of Use
at One Year3
Method
Typical Use 1
Perfect Use2
Nulliparous Women
20
9
56
Sponge
Parous Women
40
20
42
Nulliparous Women
20
9
56
Diaphragm7
20
6
56
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
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected
intercourse reduces the risk of pregnancy by at least 75%.9
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10
Source: Trussel J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK,
Kowel 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
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.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
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The treatment schedule is one dose within 72 hours after unprotected intercourse, and a
second dose 12 hours after the first dose. The FDA 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 4 yellow pills).
10 10 However, to maintain effective protection against pregnancy, another method of contraception
must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is
reduced, bottle feeds are introduced, or the baby reaches 6 months of age.
ORTHO-CEPT has not been studied for and is not indicated for use in emergency
contraception.
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 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.
5
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Final clean 08 Aug 2008
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 formulations of higher doses
of estrogens and progestogens than those in common use today. The effect of long
term use of the oral contraceptives with formulations of lower doses 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 Disorder and Other Vascular Problems
a.
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 non-users 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
6
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Final clean 08 Aug 2008
Several epidemiologic studies indicate that third generation oral contraceptives,
including those containing desogestrel, are associated with a higher risk of venous
thromboembolism than certain second generation oral contraceptives. In general,
these studies indicate an approximate 2-fold increased risk, which corresponds to an
additional 1-2 cases of venous thromboembolism per 10,000 women-years of use.
However, data from additional studies have not shown this 2-fold increase in risk.
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.
b.
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 in women 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 Table II)
7
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Final clean 08 Aug 2008
TABLE II. CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS
BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE
(Adapted from P.M. Layde and V. Beral, ref # 12.) CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE
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.
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. Receptor binding and animal studies have shown that
desogestrel or its active metabolite has minimal androgenic activity (see CLINICAL
PHARMACOLOGY), although these findings have not been confirmed in adequate
and well-controlled clinical trials.
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
8
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Final clean 08 Aug 2008
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 nature and absolute amount of
progestogens used in the contraceptives. The 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 old 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 0.050 mg 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 III).
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
9
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Final clean 08 Aug 2008
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 risk 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 III: 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 and
15-19
20
25
30
35
40-44
outcome
24
29
34
39
No fertility control methods*
7.0
7.4
9.1
14.8
25.7
28.2
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
* 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. However, this excess risk
appears to decrease over time after discontinuation of combination oral contraceptives
10
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Final clean 08 Aug 2008
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 combination oral contraceptives before
age 20. Most studies show a similar pattern of risk with combination oral
contraceptives 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 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.
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.
11
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Final clean 08 Aug 2008
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 oral contraceptives
are 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 In general, progestogens increase insulin secretion and create insulin
resistance, this effect varying with different progestational agents.17,66 In the
nondiabetic woman, oral contraceptives appear to have no effect on fasting blood
glucose.67 Because of these demonstrated effects, prediabetic and diabetic women
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 1.a. and 1.d.), changes in serum
triglycerides and lipoprotein levels have been reported in oral contraceptive users.
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
12
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Final clean 08 Aug 2008
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 and concentrations of
progestogens.
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,69 and there is no difference in the occurrence of hypertension among
former and never users.68,70,71
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. Nonhormonal 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 pre-existent.
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.
13
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Final clean 08 Aug 2008
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 oral contraceptives, 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
coadministered 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,
14
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Final clean 08 Aug 2008
phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and
bosentan. Several cases of contraceptive failure and breakthrough bleeding have been
reported in the literature with concomitant administration of antibiotics such as
ampicillin and tetracyclines. However, clinical pharmacology studies investigating
drug interaction between combined oral contraceptives and these antibiotics have
reported inconsistent results.
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 cyclosporin, 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.
15
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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.
16
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Final clean 08 Aug 2008
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, 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 oral
contraceptives but to use other forms of contraception until she has completely
weaned her child.
13.
Pediatric Use
Safety and efficacy of ORTHO-CEPT 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. 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
• Gall bladder disease
• Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use of
oral contraceptives
Oral contraceptives:
17
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Final clean 08 Aug 2008
• 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
• Allergic reaction, including rash, urticaria, and 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
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Final clean 08 Aug 2008
• 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
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 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 of mestranol.73-78
Effects on menses:
• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
• decreased incidence of dysmenorrhea
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Effects related to inhibition of ovulation:
• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies
Effects from long-term use:
• 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
To achieve maximum contraceptive effectiveness, ORTHO-CEPT must be taken
exactly as directed and at intervals not exceeding 24 hours. ORTHO-CEPT is
available in the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day
1 Start is also provided.
Day 1 Start
The dosage of ORTHO-CEPT for the initial cycle of therapy is one light orange
“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". Tablets are
taken without interruption as follows: One light orange “active” tablet daily for
21 days, then one green “reminder” tablet daily for 7 days. After 28 tablets have been
taken, a new course is started and a light orange “active” tablet is taken the next day.
The use of ORTHO-CEPT 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".) If the patient starts on ORTHO-CEPT postpartum, and has not
yet had a period, she should be instructed to use another method of contraception
until a light orange “active” tablet has been taken daily for 7 days. The possibility of
ovulation and conception prior to initiation of medication should be considered. If the
patient misses one (1) light orange “active” tablet in Weeks 1, 2, or 3, the light orange
“active” tablet should be taken as soon as she remembers. If the patient misses two
(2) light orange “active” tablets in Week 1 or Week 2, the patient should take
two (2) light orange “active” tablets the day she remembers and two (2) light orange
20
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“active” tablets the next day; and then continue taking one (1) light orange “active”
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) light orange “active”
tablets in the third week or misses three (3) or more light orange “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.
Sunday Start
When taking ORTHO-CEPT, the first light orange “active” tablet should be taken on
the first Sunday after menstruation begins. If period begins on Sunday, the first light
orange “active” tablet is taken on that day. If switching directly from another oral
contraceptive, the first light orange “active” tablet should be taken on the first Sunday
after the last ACTIVE tablet of the previous product. Tablets are taken without
interruption as follows: One light orange “active” tablet daily for 21 days, then one
green “reminder” tablet daily for 7 days. After 28 tablets have been taken, a new
course is started and a light orange “active” tablet is taken the next day (Sunday).
When initiating a Sunday start regimen, another method of contraception should be
used until after the first 7 consecutive days of administration.
The use of ORTHO-CEPT for contraception may be initiated 4 weeks postpartum.
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".) If the patient starts on
ORTHO-CEPT postpartum, and has not yet had a period, she should be instructed to
use another method of contraception until a light orange “active” tablet has been
taken daily for 7 days. The possibility of ovulation and conception prior to initiation
of medication should be considered. If the patient misses one (1) light orange active
tablet in Weeks 1, 2, or 3, the light orange “active” tablet should be taken as soon as
she remembers. If the patient misses two (2) light orange “active” tablets in
Week 1 or Week 2, the patient should take two (2) light orange “active” tablets the
day she remembers and two (2) light orange “active” tablets the next day; and then
continue taking one (1) light orange “active” 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) light orange “active” tablets in the third week or misses three
(3) or more light orange “active” tablets in a row, the patient should continue taking
21
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Final clean 08 Aug 2008
one light orange “active” 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.
ADDITIONAL INSTRUCTIONS FOR ALL DOSING REGIMENS
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.
HOW SUPPLIED
ORTHO-CEPT Tablets are available in a DIALPAK® Tablet Dispenser
(NDC 0062-1796-15) containing 28 tablets, as follows: 21 light orange, round,
convex, beveled edged, coated tablets imprinted “ORTHO” on one side and
“D 150” on the other side containing 0.15 mg desogestrel together with
0.03 mg ethinyl estradiol,, and 7 green, round, convex, beveled edged, coated tablets
imprinted “ORTHO P” on both sides containing inert ingredients.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
22
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Final clean 08 Aug 2008
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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BRIEF SUMMARY PATIENT PACKAGE INSERT
ORTHO-CEPT (desogestrel and ethinyl estradiol) Tablets
This product (like all oral contraceptives) is intended to prevent pregnancy. It 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, and when taken correctly without missing any pills, have a failure
rate of approximately 1% per year. The typical failure rate is approximately 5% per
year 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.
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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
life-threatening 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, headache, 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) or 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.
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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
patient labeling 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 anticonvulsants and some
antibiotics and herbal preparations containing St. John’s Wort (hypericum
perforation) 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 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
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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. The detailed patient
information labeling gives you further information which you should read and discuss
with your healthcare professional.
This product (like all oral contraceptives) is intended to prevent pregnancy. It
does 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, 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 spermicides) until you check with
your healthcare professional.
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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 light orange “active” pills (with hormones) to take for
3 weeks, followed by 1 week of green “reminder” pills (without hormones).
3.
ALSO FIND:
1)
where on the pack to start taking pills,
2)
in what order to take the pills,
3)
check picture of pill pack and additional instructions for using this
package below.
4.
BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicides)
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-CEPT
is 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.
DAY 1 START:
1.
Take the first light orange “active” pill of the first pack during the first
24 hours of your period.
2.
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.
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SUNDAY START:
1.
Take the first light orange “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.
2.
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).
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 green "reminder" pill. Do not
wait any days between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 light orange "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 light orange "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
spermicides) as a back-up method for those 7 days.
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If you MISS 2 light orange "active" pills in a row in THE 3RD WEEK:
1.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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
spermicides) as a back-up method for those 7 days.
If you MISS 3 OR MORE light orange "active" pills in a row (during the first
3 weeks):
1.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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
spermicides) 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.
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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 LIGHT ORANGE "ACTIVE" PILL EACH DAY until you
can reach your healthcare professional.
INSTRUCTIONS FOR USE
DIALPAK® TABLET DISPENSER
1.
The DIALPAK comes to you set up for Sunday Start. If your healthcare
professional has instructed you to start pill-taking on the first SUNDAY after
your menstrual period has begun, or has instructed you to start pill-taking on
the first day of your menstrual period and that day is SUNDAY, go to the
directions in Number 3.
2.
If you are to start pill-taking on a day other than SUNDAY, the enclosed
calendar label has been provided and will be placed over the calendar printed
on the plastic in the center of the DIALPAK. To put label in place, identify
your correct starting day, locate that day on the label, line that day up with the
pill to which the word START and the black Day Arrow are pointing, remove
the label from the backing and press the label over the printed calendar on the
center plastic.
3.
When the compact is open with the cover at top, the pills should be arranged
as they are in the picture. If not, turn the ribbed outer ring until the pills are
positioned correctly. DIALPAK
4.
The first light orange “active” pill you will take is indicated by START and
lines up with the black Day Arrow in the center of the DIALPAK. If not, see
the directions in Number 3.
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5.
Push down on the first light orange “active” pill with your thumb or
forefinger. The pill will come out through a hole in the back of the package.
6.
The next day, turn the DIAL to the right using the ribbed outer ring to the next
light orange “active” pill and your second light orange “active” pill is ready to
be taken.
7.
After you have taken all 21 light orange “active” pills, take one green
“reminder” pill daily for 7 days. During this time your period should begin.
8.
After you have taken all the pills, start a new pack of pills even if your period
is not yet over.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
DETAILED PATIENT LABELING
This product (like all oral contraceptives) is intended to prevent pregnancy. It
does not protect against HIV infection (AIDS) and other sexually transmitted
diseases.
PLEASE NOTE: This labeling is revised from time to time as important new
medical information becomes available. Therefore, please review this labeling
carefully.
The following oral contraceptive product contains a combination of a progestogen
and estrogen, the two kinds of female hormones:
ORTHO-CEPT® (desogestrel and ethinyl estradiol) Tablets
Each light orange tablet contains 0.15 mg desogestrel and 0.03 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
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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
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% (1 pregnancy per 100 women per year of use). Typical failure
rates, including women who do not always take the pills exactly as directed, are
approximately 5% per year. 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%
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
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• 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)
• Known or suspected pregnancy
• If you plan to have surgery with prolonged bedrest
Tell your healthcare professional if you have ever had any of these conditions. Your
healthcare professional can recommend another 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. The risks of these
side effects may be greater with desogestrel-containing oral contraceptives, such as
ORTHO-CEPT, than with certain other low-dose pills. Rarely, clots occur in the
blood vessels of the eye and may cause blindness, double vision, or impaired vision.
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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 three to 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. The risk of venous thromboembolic disease associated with oral
contraceptives does not increase with length of use and disappears after pill use is
stopped. 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.
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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 pills 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
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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 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
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/
1.9
1.2
1.2
1.3
2.2
2.8
spermicide*
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
* 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 (7-26 deaths
per 100,000 women, depending on age). Among pill users who do not smoke, the risk
of death is always lower than that associated with pregnancy for any age group,
although over the age of 40, the risk increases to 32 deaths per 100,000 women,
compared to 28 associated with pregnancy at that age. 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:
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• 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
1.
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.
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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 before doing so. If you have not
taken the pills daily as instructed and missed a menstrual period, you may be
pregnant. 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 oral contraceptives if pregnancy is
confirmed.
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
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
yellowing of the skin (jaundice) and breast enlargement. In addition, oral
contraceptives may decrease the amount and quality of your milk. If possible,
do not use 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 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), 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 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
other products 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
This product (like all oral contraceptives) is intended to prevent
pregnancy. It does not protect against transmission of HIV (AIDS) and
other sexually transmitted diseases such as chlamydia, genital herpes,
genital warts, gonorrhea, hepatitis B, and syphilis.
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
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, 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 spermicides) 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.
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
2.
LOOK AT YOUR PILL PACK:
The pill pack has 21 light orange “active” pills (with hormones) to take for
3 weeks, followed by 1 week of green “reminder” pills (without hormones).
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 spermicides)
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-CEPT
is 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.
DAY 1 START:
1.
Take the first light orange “active” pill of the first pack during the first 24
hours of your period.
2.
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.
SUNDAY START:
1.
Take the first light orange “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.
2.
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).
48
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
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 green "reminder" pill. Do not
wait any days between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 light orange "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 light orange "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
spermicides) as a back-up method for those 7 days.
If you MISS 2 light orange "active" pills in a row in THE 3RD WEEK:
1.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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.
49
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
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
spermicides) as a back-up method for those 7 days.
If you MISS 3 OR MORE light orange "active" pills in a row (during the first 3
weeks):
1.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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
spermicides) 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 LIGHT ORANGE "ACTIVE" PILL EACH DAY until
you can reach your healthcare professional
PREGNANCY DUE TO PILL FAILURE
When taken correctly without missing any pills, oral contraceptives are highly
effective; however the typical failure rate of large numbers of pill users is 5% per
year when women who miss pills are included. If failure does occur, the risk to the
fetus is minimal.
50
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
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.
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.
51
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Final clean 08 Aug 2008
• 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.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
Distributed by
Ortho
Women’s
Health
&
Urology,
Division
of
Ortho-McNeil-Janssen
Pharmaceuticals, Inc.
Raritan, New Jersey 08869
Jointly Manufactured by
Janssen Ortho, LLC
Manati, Puerto Rico 00674 and
NV Organon
Oss, The Netherlands
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998
10031901
REVISED
PRINTED IN U.S.A.
52
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:25.330859
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020301s027lbl.pdf', 'application_number': 20301, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
12,431
|
TRASYLOL®
(aprotinin injection)
01298181
12/03
Anaphylactic or anaphylactoid reactions are possible when Trasylol® is administered.
Hypersensitivity reactions are rare in patients with no prior exposure to aprotinin. The risk
of anaphylaxis is increased in patients who are re-exposed to aprotinin-containing products.
The benefit of Trasylol® to patients undergoing primary CABG surgery should be weighed
against the risk of anaphylaxis should a second exposure to aprotinin be required. (See
WARNINGS and PRECAUTIONS).
DESCRIPTION
Trasylol® (aprotinin injection), C284H432N84O79S7, is a natural proteinase inhibitor obtained from
bovine lung. Aprotinin (molecular weight of 6512 daltons), consists of 58 amino acid residues that
are arranged in a single polypeptide chain, cross-linked by three disulfide bridges. It is supplied
as a clear, colorless, sterile isotonic solution for intravenous administration. Each milliliter
contains 10,000 KIU (Kallikrein Inhibitor Units) (1.4 mg/mL) and 9 mg sodium chloride in water for
injection. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH to 4.5-6.5.
CLINICAL PHARMACOLOGY
Mechanism of Action: Aprotinin is a broad spectrum protease inhibitor which modulates the
systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery.
SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral
inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein,
plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin
generation.
Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In
platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it
prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b).
The effects of aprotinin use in CPB involves a reduction in inflammatory response which
translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and
decreased mediastinal re-exploration for bleeding.
Pharmacokinetics: The studies comparing the pharmacokinetics of aprotinin in healthy
volunteers, cardiac patients undergoing surgery with cardiopulmonary bypass, and women
undergoing hysterectomy suggest linear pharmacokinetics over the dose range of 50,000 KIU to
2 million KIU. After intravenous (IV) injection, rapid distribution of aprotinin occurs into the total
extracellular space, leading to a rapid initial decrease in plasma aprotinin concentration.
Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time
points, (i.e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of
about 10 hours.
Average steady state intraoperative plasma concentrations were 137 KIU/mL (n=10) after
administration of the following dosage regimen: 1 million KIU IV loading dose, 1 million KIU into
the pump prime volume, 250,000 KIU per hour of operation as continuous intravenous infusion
(Regimen B). Average steady state intraoperative plasma concentrations were 250 KIU/mL in
patients (n=20) treated with aprotinin during cardiac surgery by administration of Regimen A
(exactly double Regimen B): 2 million KIU IV loading dose, 2 million KIU into the pump prime
volume, 500,000 KIU per hour of operation as continuous intravenous infusion.
Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is
excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is
excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary
excretion of unchanged aprotinin accounts for approximately 9% of the dose. Animal studies have
shown that aprotinin is accumulated primarily in the kidney. Aprotinin, after being filtered by the
glomeruli, is actively reabsorbed by the proximal tubules in which it is stored in phagolysosomes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Aprotinin is slowly degraded by lysosomal enzymes. The physiological renal handling of aprotinin
is similar to that of other small proteins, e.g., insulin.
CLINICAL TRIALS
Repeat Coronary Artery Bypass Graft Patients:
Four placebo-controlled, double-blind studies of Trasylol® were conducted in the United States; of
540 randomized patients undergoing repeat coronary artery bypass graft (CABG) surgery, 480
were valid for efficacy analysis. The following treatment regimens were used in the studies:
Trasylol® Regimen A (2 million KIU IV loading dose, 2 million KIU into the pump prime volume,
and 500,000 KIU per hour of surgery as a continuous intravenous infusion); Trasylol® Regimen B
(1 million KIU IV loading dose, 1 million KIU into the pump prime volume, and 250,000 KIU per
hour of surgery as a continuous intravenous infusion); a pump prime regimen (2 million KIU into
the pump prime volume only); and a placebo regimen (normal saline). All patients valid for
efficacy in the above studies were pooled by treatment regimen for analyses of efficacy.
In this pooled analysis, fewer patients receiving Trasylol®, either Regimen A or Regimen B,
required any donor blood compared to the pump prime only or placebo regimens. The number of
units of donor blood required by patients, the volume (milliliters) of donor blood transfused, the
number of units of donor blood products transfused, the thoracic drainage rate, and the total
thoracic drainage volumes were also reduced in patients receiving Trasylol® as compared to
placebo.
Efficacy Variables: Repeat CABG Patients
Mean (S.D.) or % of Patients
Trasylol®
Trasylol®
Trasylol®
PLACEBO
PUMP PRIME
REGIMEN
REGIMEN
VARIABLE
REGIMEN
REGIMEN†
B**
A**
N=156
N=68
N=113
N=143
% OF REPEAT CABG
76.3%
72.1%
48.7%
46.9%
PATIENTS WHO
REQUIRED
DONOR BLOOD
UNITS OF
3.7 (4.4)
2.5 (2.4)
2.2 (5.0)*
1.6 (2.9)*
DONOR BLOOD
TRANSFUSED
mL OF
1132 (1443)
756 (807)
723 (1779)* 515 (999)*
DONOR BLOOD
TRANSFUSED
PLATELETS
5.0 (10.0)
2.1 (4.6)*
1.3 (4.6)*
0.9 (4.3)*
TRANSFUSED (Donor Units)
CRYOPRECIPITATE
0.9 (3.5)
0.0 (0.0)*
0.5 (4.0)
0.1 (0.8)*
TRANSFUSED (Donor Units)
FRESH FROZEN
1.3 (2.5)
0.5 (1.4)*
0.3 (1.1)*
0.2 (0.9)*
PLASMA TRANSFUSED
(Donor Units)
THORACIC DRAINAGE
89 (77)
73 (69)
66 (244)
40 (36)*
RATE (mL/hr)
TOTAL THORACIC
1659 (1226)
1561 (1370)
1103 (2001)* 960 (849)*
DRAINAGE VOLUME (mL)a
REOPERATION FOR
1.9%
2.9%
0%
0%
DIFFUSE BLEEDING
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
† The pump prime regimen was evaluated in only one study in patients undergoing repeat
CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p<0.05
(Transfusion variables analyzed via ANOVA on ranks)
** Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and safety
are not statistically significant.
a Excludes patients who required reoperation
Primary Coronary Artery Bypass Graft Patients:
Four placebo-controlled, double-blind studies of Trasylol® were conducted in the United States; of
1745 randomized patients undergoing primary CABG surgery, 1599 were valid for efficacy
analysis. The dosage regimens used in these studies were identical to those used in the repeat
CABG studies described above (Regimens A, B, pump prime, and placebo). All patients valid for
efficacy were pooled by treatment regimen.
In this pooled analysis, fewer patients receiving Trasylol® Regimens A, B, and pump prime
required any donor blood in comparison to the placebo regimen. The number of units of donor
blood required by patients, the volume of donor blood transfused, the number of units of donor
blood products transfused, the thoracic drainage rate, and total thoracic drainage volumes were
also reduced in patients receiving Trasylol® as compared to placebo.
Efficacy Variables: Primary CABG Patients
Mean (S.D.) or % of Patients
Trasylol®
Trasylol®
Trasylol®
PLACEBO
PUMP PRIME
REGIMEN
REGIMEN
VARIABLE
REGIMEN
REGIMEN†
B**
A**
N=624
N=159
N=175
N=641
% OF PRIMARY CABG
53.5%
32.7%*
37.1%*
36.8%*
PATIENTS WHO
REQUIRED
DONOR BLOOD
UNITS OF
1.7 (2.4)
0.9 (1.6)*
1.0 (1.6)*
0.9 (1.4)*
DONOR BLOOD
TRANSFUSED
mL OF
584 (840)
286 (518)*
313 (505)*
295 (503)*
DONOR BLOOD
TRANSFUSED
PLATELETS
1.3 (3.7)
0.5 (2.4)*
0.3 (1.6)*
0.3 (1.5)*
TRANSFUSED (Donor Units)
CRYOPRECIPITATE
0.5 (2.2)
0.0 (0.0)*
0.1 (0.8)*
0.0 (0.0)*
TRANSFUSED (Donor Units)
FRESH FROZEN
0.6 (1.7)
0.2 (1.7)*
0.2 (0.8)*
0.2 (0.9)*
PLASMA TRANSFUSED
(Donor Units)
THORACIC DRAINAGE
87 (67)
51 (36)*
45 (31)*
39 (32)*
RATE (mL/hr)
TOTAL THORACIC
1232 (711)
852 (653)*
792 (465)*
705 (493)*
DRAINAGE VOLUME (mL)
REOPERATION FOR
1.4%
0.6%
0%
0%*
DIFFUSE BLEEDING
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
† The pump prime regimen was evaluated in only one study in patients undergoing primary
CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p<0.05
(Transfusion variables analyzed via ANOVA on ranks)
** Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and safety
are not statistically significant.
Additional subgroup analyses showed no diminution in benefit with increasing age. Male and
female patients benefited from Trasylol® with a reduction in the average number of units of donor
blood transfused. Although male patients did better than female patients in terms of the
percentage of patients who required any donor blood transfusions, the number of female patients
studied was small.
A double-blind, randomized, Canadian study compared Trasylol® Regimen A (n=28) and placebo
(n=23) in primary cardiac surgery patients (mainly CABG) requiring cardiopulmonary bypass who
were treated with aspirin within 48 hours of surgery. The mean total blood loss (1209.7 mL vs.
2532.3 mL) and the mean number of units of packed red blood cells transfused (1.6 units vs 4.3
units) were significantly less (p<0.008) in the Trasylol® group compared to the placebo group.
In a U.S. randomized study of Trasylol® Regimen A and Regimen B versus the placebo regimen
in 212 patients undergoing primary aortic and/or mitral valve replacement or repair, no benefit
was found for Trasylol® in terms of the need for transfusion or the number of units of blood
required.
INDICATIONS AND USAGE
Trasylol is indicated for prophylactic use to reduce perioperative blood loss and the need for
blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery
bypass graft surgery.
CONTRAINDICATIONS
Hypersensitivity to aprotinin.
WARNINGS
Anaphylactic or anaphylactoid reactions are possible when Trasylol® is administered.
Hypersensitivity reactions are rare in patients with no prior exposure to aprotinin. Hypersensitivity
reactions can range from skin eruptions, itching, dyspnea, nausea and tachycardia to fatal
anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or
infusion of Trasylol®, administration should be stopped immediately and emergency treatment
should be initiated. It should be noted that severe (fatal) hypersensitivity/anaphylactic reactions
can also occur in connection with application of the test dose. Even when a second exposure to
aprotinin has been tolerated without symptoms, a subsequent administration may result in severe
hypersensitivity/anaphylactic reactions.
Re-exposure to aprotinin: In a retrospective review of 387 European patient records with
documented re-exposure to Trasylol®, the incidence of hypersensitivity/anaphylactic reactions
was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently
died, 24 hours and 5 days after surgery, respectively. The relationship of these 2 deaths to
Trasylol® is unclear. This retrospective review also showed that the incidence of a hypersensitivity
or anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6
months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-
exposure greater than 6 months). Other smaller studies have shown that in case of re-exposure,
the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level.
Before initiating treatment with Trasylol® in a patient with a history of prior exposure to aprotinin or
products containing aprotinin, the recommendations below should be followed to manage a
potential hypersensitivity or anaphylactic reaction: 1) Have standard emergency treatments for
hypersensitivity or anaphylactic reactions readily available in the operating room (e.g.,
epinephrine, corticosteroids). 2) Administration of the test dose and loading dose should be done
only when the conditions for rapid cannulation (if necessary) are present. 3) Delay the addition of
Trasylol® into the pump prime solution until after the loading dose has been safely administered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Additionally, administration of H1 and H2 blockers 15 minutes before the test dose may be
considered.
PRECAUTIONS
General: Test Dose: All patients treated with Trasylol® should first receive a test dose to assess
the potential for allergic reactions. The test dose of 1 mL Trasylol® should be administered
intravenously at least 10 minutes prior to the loading dose. However, even after the uneventful
administration of the initial 1 mL test-dose, the therapeutic dose may cause an anaphylactic
reaction. If this happens the infusion of aprotinin should immediately be stopped, and standard
emergency treatment for anaphylaxis be applied. It should be noted that hypersensitivity/
anaphylactic reactions can also occur in connection with application of the test-dose. (see
WARNINGS)
Allergic Reactions: Patients with a history of allergic reactions to drugs or other agents may be at
greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to Trasylol®.
(see WARNINGS)
Loading Dose: The loading dose of Trasylol® should be given intravenously to patients in the
supine position over a 20-30 minute period. Rapid intravenous administration of Trasylol® can
cause a transient fall in blood pressure. (see DOSAGE AND ADMINISTRATION).
Use of Trasylol® in patients undergoing deep hypothermic circulatory arrest: Two U.S. case
control studies have reported contradictory results in patients receiving Trasylol® while
undergoing deep hypothermic circulatory arrest in connection with surgery of the aortic arch.
The first study showed an increase in both renal failure and mortality compared to age-matched
historical controls. Similar results were not observed, however, in a second case control study.
The strength of this association is uncertain because there are no data from randomized studies
to confirm or refute these findings.
Drug Interactions: Trasylol® is known to have antifibrinolytic activity and, therefore, may inhibit
the effects of fibrinolytic agents.
In study of nine patients with untreated hypertension, Trasylol® infused intravenously in a dose of
2 million KIU over two hours blocked the acute hypotensive effect of 100mg of captopril.
Trasylol®, in the presence of heparin, has been found to prolong the activated clotting time (ACT)
as measured by a celite surface activation method. The kaolin activated clotting time appears to
be much less affected. However, Trasylol® should not be viewed as a heparin sparing agent. (see
Laboratory Monitoring of Anticoagulation During Cardiopulmonary Bypass).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies to evaluate
the carcinogenic potential of Trasylol® or studies to determine the effect of Trasylol® on fertility
have not been performed.
Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that
Trasylol® is not a mutagen.
Pregnancy: Teratogenic Effects: Pregnancy Category B: Reproduction studies have been
performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at
intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human dose on a
mg/kg basis and 0.37 and 0.36 times the human mg/m2 dose. They have revealed no evidence of
impaired fertility or harm to the fetus due to Trasylol®. 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 Mother: Not applicable.
Pediatric Use: Safety and effectiveness in pediatric patient(s) have not been established.
Geriatric Use: Of the total of 3083 subjects in clinical studies of Trasylol®, 1100 (35.7 percent)
were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479
(43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall
differences in safety or effectiveness were observed between these subjects and younger
subjects for either dose regimen, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients.
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Laboratory Monitoring of Anticoagulation during Cardiopulmonary Bypass: Trasylol®
prolongs whole blood clotting times by a different mechanism than heparin. In the presence of
aprotinin, prolongation is dependent on the type of whole blood clotting test employed. If an
activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation,
the prolongation of the ACT by aprotinin may lead to an overestimation of the degree of
anticoagulation, thereby leading to inadequate anticoagulation. During extended extracorporeal
circulation, patients may require additional heparin, even in the presence of ACT levels that
appear adequate.
In patients undergoing CPB with Trasylol® therapy, one of the following methods may be
employed to maintain adequate anticoagulation:
1) ACT - An ACT is not a standardized coagulation test, and different formulations of the assay
are affected differently by the presence of aprotinin. The test is further influenced by variable
dilution effects and the temperature experienced during cardiopulmonary bypass. It has been
observed that Kaolin-based ACTs are not increased to the same degree by aprotinin as are
diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite ACT of 750
seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and
hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT
test regarding the interpretation of the assay in the presence of Trasylol®.
2) Fixed Heparin Dosing - A standard loading dose of heparin, administered prior to cannulation
of the heart, plus the quantity of heparin added to the prime volume of the CPB circuit, should
total at least 350 IU/kg. Additional heparin should be administered in a fixed-dose regimen based
on patient weight and duration of CPB.
3) Heparin Titration - Protamine titration, a method that is not affected by aprotinin, can be used
to measure heparin levels. A heparin dose response, assessed by protamine titration, should be
performed prior to administration of aprotinin to determine the heparin loading dose. Additional
heparin should be administered on the basis of heparin levels measured by protamine titration.
Heparin levels during bypass should not be allowed to drop below 2.7 U/mL (2.0 mg/kg) or below
the level indicated by heparin dose response testing performed prior to administration of
aprotinin.
Protamine Administration - In patients treated with Trasylol®, the amount of protamine
administered to reverse heparin activity should be based on the actual amount of heparin
administered, and not on the ACT values.
ADVERSE REACTIONS
Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Trasylol® is
generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery
and are not necessarily attributable to Trasylol® therapy. Adverse events reported, up to the time
of hospital discharge, from patients in US placebo-controlled trials are listed in the following table.
The table lists only those events that were reported in 2% or more of the Trasylol® treated
patients without regard to causal relationship.
INCIDENCE RATES OF ADVERSE EVENTS (> = 2%) BY BODY SYSTEM AND TREATMENT
FOR ALL PATIENTS FROM US PLACEBO-CONTROLLED CLINICAL TRIALS
Aprotinin
Placebo
(n = 2002)
(n = 1084)
Adverse Event
values in %
values in %
Any Event
76
77
Body as a Whole
Fever
15
14
Infection
6
7
Chest Pain
2
2
Asthenia
2
2
Cardiovascular
Atrial Fibrillation
21
23
Hypotension
8
10
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Myocardial Infarct
6
6
Atrial Flutter
6
5
Ventricular Extrasystoles
6
4
Tachycardia
6
7
Ventricular Tachycardia
5
4
Heart Failure
5
4
Pericarditis
5
5
Peripheral Edema
5
5
Hypertension
4
5
Arrhythmia
4
3
Supraventricular Tachycardia
4
3
Atrial Arrhythmia
3
3
Aprotinin
Placebo
(n = 2002)
(n = 1084)
Adverse Event
values in %
values in %
Digestive
Nausea
11
9
Constipation
4
5
Vomiting
3
4
Diarrhea
3
2
Liver Function Tests Abnormal
3
2
Hemic and Lymphatic
Anemia
2
8
Metabolic & Nutritional
Creatine Phosphokinase Increased
2
1
Musculoskeletal
Any Event
2
3
Nervous
Confusion
4
4
Insomnia
3
4
Respiratory
Lung Disorder
8
8
Pleural Effusion
7
9
Atelectasis
5
6
Dyspnea
4
4
Pneumothorax
4
4
Asthma
2
3
Hypoxia
2
1
Skin and Appendages
Rash
2
2
Urogenital
Kidney Function Abnormal
3
2
Urinary Retention
3
3
Urinary Tract Infection
2
2
In comparison to the placebo group, no increase in mortality in patients treated with Trasylol® was
observed. Additional events of particular interest from controlled US trials with an incidence of
less that 2%, are listed below:
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EVENT
Percentage of patients
Percentage of patients
treated with Trasylol
treated with Placebo
N = 2002
N = 1084
Thrombosis
1.0
0.6
Shock
0.7
0.4
Cerebrovascular Accident
0.7
2.1
Thrombophlebitis
0.2
0.5
Deep Thrombophlebitis
0.7
1.0
Lung Edema
1.3
1.5
Pulmonary Embolus
0.3
0.6
Kidney Failure
1.0
0.6
Acute Kidney Failure
0.5
0.6
Kidney Tubular Necrosis
0.8
0.4
Listed below are additional events, from controlled US trials with an incidence between 1 and 2%,
and also from uncontrolled, compassionate use trials and spontaneous post-marketing reports.
Estimates of frequency cannot be made for spontaneous post-marketing reports (italicized).
Body as a Whole: Sepsis, death, multi-system organ failure, immune system disorder,
hemoperitoneum.
Cardiovascular: Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure,
hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block,
pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.
Digestive: Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.
Hematologic and Lymphatic: Although thrombosis was not reported more frequently in aprotinin
versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials,
compassionate use trials, and spontaneous post-marketing reporting. These reports of
thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary
thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep
thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events
reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes
disseminated intravascular coagulation), decreased prothombin.
Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.
Musculoskeletal: Arthralgia.
Nervous: Agitation, dizziness, anxiety, convulsion.
Respiratory: Pneumonia, apnea, increased cough, lung edema.
Skin: Skin discoloration.
Urogenital: Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis.
Myocardial Infarction: In the pooled analysis of all patients undergoing CABG surgery, there
was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in
Trasylol® treated patients as compared to placebo treated patients. However, because no uniform
criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was
addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and
Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a
blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this
method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients
versus 4.7% in the placebo treated patients. This difference in the incidence rates was not
statistically significant. Data from these three studies are summarized below.
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Incidence of Myocardial Infarctions by Treatment Group Population:
All CABG Patients Valid for Safety Anaylsis
Treatment
Definite MI
Definite or Probable MI
Definite, Probable or Possible MI
%
%
%
Pooled Data from Three Studies that Evaluated Regimen A
Trasylol®
Regimen A
4.6
10.7
14.1
n = 646
Placebo
4.7
11.3
13.4
n = 661
Pooled Data from Two Studies that Evaluated Regimen B and Pump Prime Regimen
Trasylol®
Regimen B
8.7
15.9
18.7
n = 241
Trasylol®
Pump Prime
6.3
15.7
18.1
Regimen
n = 239
Placebo
6.3
15.1
15.8
n = 240
Graft Patency: In a recently completed multi-center, multi-national study to determine the effects
of Trasylol® Regimen A vs. placebo on saphenous vein graft patency in patients undergoing
primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13
study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel
(2)). The results of this study are summarized below.
Incidence of Graft Closure, Myocardial Infarction and Death by Treatment Group
Overall Closure Rates*
Incidence of MI**
Incidence of Death***
All Centers
U.S. Centers
All Centers
All Centers
n = 703
n = 381
n = 831
n = 870
%
%
%
%
Trasylol®
15.4
9.4
2.9
1.4
Placebo
10.9
9.5
3.8
1.6
CI for the
Difference (%)
(Drug - Placebo)
(1.3, 9.6)†
(-3.8, 5.9)†
-3.3 to 1.5‡
-1.9 to 1.4‡
* Population: all patients with assessable saphenous vein grafts
** Population: all patients assessable by blinded consultant
*** All patients
† 90%; per protocol
‡ 95%; not specified in protocol
Although there was a statistically significantly increased risk of graft closure for Trasylol® treated
patients compared to patients who received placebo (p=0.035), further analysis showed a
significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When
the analysis of graft closures was repeated for U.S. centers only, there was no statistically
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significant difference in graft closure rates in patients who received Trasylol® vs. placebo. These
results are the same whether analyzed as the proportion of patients who experienced at least one
graft closure postoperatively or as the proportion of grafts closed. There were no differences
between treatment groups in the incidence of myocardial infarction as evaluated by the blinded
consultant (2.9% Trasylol® vs. 3.8% placebo) or of death (1.4% Trasylol® vs. 1.6% placebo) in
this study.
Hypersensitivity and Anaphylaxis: See WARNINGS.
Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled
clinical studies in patients with no prior exposure to Trasylol® (1/1424 patients or <0.1% on
Trasylol® vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of
hypersensitivity/anaphylactic reactions has been reported to reach the 5% level. A review of 387
European patient records involving re-exposure to Trasylol® showed that the incidence of
hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6 months and 0.9% for
re-exposure greater than 6 months.
Laboratory Findings
Serum Creatinine: Data pooled from all patients undergoing CABG surgery in U.S. placebo-
controlled trials showed no statistically or clinically significant increase in the incidence of
postoperative renal dysfunction in patients treated with Trasylol®. The incidence of serum
creatinine elevations > 0.5 mg/dL above pre-treatment levels was 9% in the Trasylol® group vs.
8% in the placebo group (p=0.248), while the incidence of elevations >2.0 mg/dL above baseline
was only 1% in each group (p=0.883). In the majority of instances, postoperative renal
dysfunction was not severe and was reversible. Patients with baseline elevations in serum
creatinine were not at increased risk of developing postoperative renal dysfunction following
Trasylol® treatment.
Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S.
placebo-controlled trials showed no evidence of an increase in the incidence of post-operative
hepatic dysfunction in patients treated with Trasylol®. The incidence of treatment-emergent
increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the
Trasylol® and placebo-treated patients (p=0.687), while the incidence of increases > 3 times the
upper limit of normal was 5% in both groups (p=0.847).
Other Laboratory Findings: The incidence of treatment-emergent elevations in plasma glucose,
AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably different
between Trasylol® and placebo treated patients undergoing CABG surgery. Significant elevations
in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are
expected in Trasylol® treated patients in the hours after surgery due to circulating concentrations
of Trasylol®, which are known to inhibit activation of the intrinsic clotting system by contact with a
foreign material (e.g., celite), a method used in these tests. (see Laboratory Monitoring of
Anticoagulation During Cardiopulmonary Bypass).
OVERDOSAGE
The maximum amount of Trasylol® that can be safely administered in single or multiple doses has
not been determined. Doses up to 17.5 million KIU have been administered within a 24 hour
period without any apparent toxicity. There is one poorly documented case, however, of a patient
who received a large, but not well determined, amount of Trasylol® (in excess of 15 million KIU) in
24 hours. The patient, who had pre-existing liver dysfunction, developed hepatic and renal failure
postoperatively and died. Autopsy showed hepatic necrosis and extensive renal tubular and
glomerular necrosis. The relationship of these findings to Trasylol® therapy is unclear.
DOSAGE AND ADMINISTRATION
Trasylol® given prophylactically in both Regimen A and Regimen B (half Regimen A) to patients
undergoing CABG surgery significantly reduced the donor blood transfusion requirement relative
to placebo treatment. In low risk patients there is no difference in efficacy between regimen A and
B. Therefore, the dosage used (A vs. B) is at the discretion of the practitioner.
Trasylol® is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All
intravenous doses of Trasylol® should be administered through a central line. DO NOT
ADMINISTER ANY OTHER DRUG USING THE SAME LINE. Both regimens include a 1 mL test
dose, a loading dose, a dose to be added while recirculating the priming fluid of the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
cardiopulmonary bypass circuit (“pump prime” dose), and a constant infusion dose. To avoid
physical incompatibility of Trasylol® and heparin when adding to the pump prime solution, each
agent must be added during recirculation of the pump prime to assure adequate dilution prior to
admixture with the other component. Regimens A and B (both incorporating a 1 mL test dose) are
described in the table below:
TEST
LOADING
“PUMP PRIME”
CONSTANT
DOSE
DOSE
DOSE
INFUSION DOSE
TRASYLOL®
1 mL
200 mL
200 mL
50 mL/hr
REGIMEN A
(1.4 mg, or
(280 mg, or
(280 mg, or
(70 mg/hr, or
10,000 KIU)
2.0 million KIU)
2.0 million KIU)
500,000 KIU/hr)
TRASYLOL®
1 mL
100 mL
100 mL
25 mL/hr
REGIMEN B
(1.4 mg, or
(140 mg, or
(140 mg, or
(35 mg/hr, or
10,000 KIU)
1.0 million KIU)
1.0 million KIU)
250,000 KIU/hr)
The 1 mL test dose should be administered intravenously at least 10 minutes before the loading
dose. With the patient in a supine position, the loading dose is given slowly over 20-30 minutes,
after induction of anesthesia but prior to sternotomy. In patients with known previous exposure to
Trasylol®, the loading dose should be given just prior to cannulation. When the loading dose is
complete, it is followed by the constant infusion dose, which is continued until surgery is complete
and the patient leaves the operating room. The “pump prime” dose is added to the recirculating
priming fluid of the cardiopulmonary bypass circuit, by replacement of an aliquot of the priming
fluid, prior to the institution of cardiopulmonary bypass. Total doses of more than 7 million KIU
have not been studied in controlled trials.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit. Discard any unused portion.
Renal and Hepatic Impairment: No formal studies of the pharmacokinetics of aprotinin in
patients with pre-existing renal insufficiency have been conducted. However, in the placebo-
controlled clinical trials conducted in the United States, patients with mildly elevated pretreatment
serum creatinine levels did not have a notably higher incidence of clinically significant post-
treatment elevations in serum creatinine following either Trasylol® Regimen A or Regimen B
compared to administration of the placebo regimen. Changes in aprotinin pharmacokinetics with
age or impaired renal function are not great enough to require any dose adjustment. No
pharmacokinetic data from patients with pre-existing hepatic disease treated with Trasylol® are
available.
HOW SUPPLIED
Size
Strength
NDC
100 mL vials
1,000,000 KIU
0026-8196-36
200 mL vials
2,000,000 KIU
0026-8197-63
STORAGE
Trasylol® should be stored between 2° and 25°C (36° - 77°F).
Protect from freezing.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Made in Germany
Rx Only
01298181
12/03
©2003 Bayer Pharmaceuticals Corporation
10350L
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
|
2025-02-12T13:47:25.392460
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020304s009lbl.pdf', 'application_number': 20304, 'submission_type': 'SUPPL ', 'submission_number': 9}
|
12,433
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Roche logo
KYTRIL®
(granisetron hydrochloride)
INJECTION
Rx only
DESCRIPTION
KYTRIL (granisetron hydrochloride) Injection is an antinauseant and antiemetic agent.
Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole
3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its
empirical formula is C18H24N4O•HCl, while its chemical structure is: Structural Formula
granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and
normal saline at 20°C. KYTRIL Injection is a clear, colorless, sterile, nonpyrogenic,
aqueous solution for intravenous administration.
KYTRIL 1 mg/1 mL is available in 1 mL single-use and 4 mL multi-use vials. KYTRIL
0.1 mg/1 mL is available in a 1 mL single-use vial.
1 mg/1 mL: Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to
granisetron, 1 mg; sodium chloride, 9 mg; citric acid, 2 mg; and benzyl alcohol, 10 mg,
as a preservative. The solution’s pH ranges from 4.0 to 6.0.
0.1 mg/1 mL: Each 1 mL contains 0.112 mg granisetron hydrochloride equivalent to
granisetron, 0.1 mg; sodium chloride, 9 mg; citric acid, 2 mg. Contains no preservative.
The solution’s pH ranges from 4.0 to 6.0.
CLINICAL PHARMACOLOGY
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or
no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for
alpha1-, alpha2- or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1;
benzodiazepine; picrotoxin or opioid receptors.
1
Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals
and centrally in the chemoreceptor trigger zone of the area postrema. During
chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin,
which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce
vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron
blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as
cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting
due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
In most human studies, granisetron has had little effect on blood pressure, heart rate or
ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has
been found in other studies.
KYTRIL Injection exhibited no effect on oro-cecal transit time in normal volunteers
given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral
doses slowed colonic transit in normal volunteers.
Pharmacokinetics
Chemotherapy-Induced Nausea and Vomiting
In adult cancer patients undergoing chemotherapy and in volunteers, mean
pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of KYTRIL
Injection are shown in Table 1.
Table 1
Pharmacokinetic Parameters in Adult Cancer Patients
Undergoing Chemotherapy and in Volunteers, Following a
Single Intravenous 40 mcg/kg Dose of KYTRIL Injection
Peak Plasma
Concentration
(ng/mL)
Terminal Phase
Plasma Half-Life
(h)
Total
Clearance
(L/h/kg)
Volume of
Distribution
(L/kg)
Cancer Patients
Mean
Range
63.8*
18.0 to 176
8.95*
0.90 to 31.1
0.38*
0.14 to 1.54
3.07*
0.85 to 10.4
Volunteers
21 to 42 years
Mean
Range
65 to 81 years
Mean
Range
64.3†
11.2 to 182
57.0†
14.6 to 153
4.91†
0.88 to 15.2
7.69†
2.65 to 17.7
0.79†
0.20 to 2.56
0.44†
0.17 to 1.06
3.04†
1.68 to 6.13
3.97†
1.75 to 7.01
*5-minute infusion.
†3-minute infusion.
Distribution
Plasma protein binding is approximately 65% and granisetron distributes freely between
plasma and red blood cells.
2
Metabolism
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed
by conjugation. In vitro liver microsomal studies show that granisetron’s major route of
metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the
cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites
may also have 5-HT3 receptor antagonist activity.
Elimination
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately
12% of the administered dose is eliminated unchanged in the urine in 48 hours. The
remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.
Subpopulations
Gender
There was high inter- and intra-subject variability noted in these studies. No difference in
mean AUC was found between males and females, although males had a higher Cmax
generally.
Elderly
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years),
given a single 40 mcg/kg intravenous dose of KYTRIL Injection, were generally similar
to those in younger healthy volunteers; mean values were lower for clearance and longer
for half-life in the elderly patients (see Table 1).
Pediatric Patients
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single
40 mcg/kg intravenous dose of KYTRIL Injection, showed that volume of distribution
and total clearance increased with age. No relationship with age was observed for peak
plasma concentration or terminal phase plasma half-life. When volume of distribution
and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are
similar in pediatric and adult cancer patients.
Renal Failure Patients
Total clearance of granisetron was not affected in patients with severe renal failure who
received a single 40 mcg/kg intravenous dose of KYTRIL Injection.
Hepatically Impaired Patients
A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver
involvement showed that total clearance was approximately halved compared to patients
without hepatic impairment. Given the wide variability in pharmacokinetic parameters
noted in patients, dosage adjustment in patients with hepatic functional impairment is not
necessary.
Postoperative Nausea and Vomiting
In adult patients (age range, 18 to 64 years) recovering from elective surgery and
receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single
3
1 mg dose of KYTRIL Injection administered intravenously over 30 seconds are shown
in Table 2.
Table 2
Pharmacokinetic Parameters in 16 Adult Surgical Patients
Following a Single Intravenous 1 mg Dose of KYTRIL
Injection
Terminal Phase
Total
Volume of
Plasma Half-Life
Clearance
Distribution
(h)
(L/h/kg)
(L/kg)
Mean
8.63
0.28
2.42
Range
1.77 to 17.73
0.07 to 0.71
0.71 to 4.13
The pharmacokinetics of granisetron in patients undergoing surgery were similar to those
seen in cancer patients undergoing chemotherapy.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting
Single-Day Chemotherapy
Cisplatin-Based Chemotherapy
In a double-blind, placebo-controlled study in 28 cancer patients, KYTRIL Injection,
administered as a single intravenous infusion of 40 mcg/kg, was significantly more
effective than placebo in preventing nausea and vomiting induced by cisplatin
chemotherapy (see Table 3).
Table 3
Prevention of Chemotherapy-Induced Nausea and Vomiting
— Single-Day Cisplatin Therapy1
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No More Than Mild Nausea
KYTRIL
Injection
14
93%
93%
93%
Placebo
14
7%
14%
7%
P-Value
<0.001
<0.001
<0.001
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m2 in the KYTRIL
Injection group and 80 mg/m2 in the placebo group.
2 No vomiting and no moderate or severe nausea.
KYTRIL Injection was also evaluated in a randomized dose response study of cancer
patients receiving cisplatin ≥75 mg/m2. Additional chemotherapeutic agents included:
anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine,
nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca
alkaloids. KYTRIL Injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in
preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly
superior to 10 mcg/kg (see Table 4).
4
Table 4
Prevention of Chemotherapy-Induced Nausea and Vomiting
— Single-Day High-Dose Cisplatin Therapy1
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 2 mcg/kg)
2
10
40
10
40
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No More Than Mild Nausea
52
31%
38%
58%
52
62%
65%
75%
53
68%
74%
79%
<0.002
<0.001
NS
<0.001
<0.001
0.007
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m2.
2 No vomiting and no moderate or severe nausea.
KYTRIL Injection was also evaluated in a double-blind, randomized dose response study
of 353 patients stratified for high (≥80 to 120 mg/m2) or low (50 to 79 mg/m2) cisplatin
dose. Response rates of patients for both cisplatin strata are given in Table 5.
Table 5
Prevention of Chemotherapy-Induced Nausea and Vomiting
— Single-Day High-Dose and Low-Dose Cisplatin Therapy1
KYTRIL Injection
(mcg/kg)
P-Value
(vs. 5 mcg/kg)
5
10
20
40
10
20
40
High-Dose Cisplatin
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No Nausea
40
18%
28%
15%
49
41%
47%
35%
48
40%
44%
38%
47
47%
53%
43%
0.018
NS
0.036
0.025
NS
0.019
0.004
0.016
0.005
Low-Dose Cisplatin
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No Nausea
42
29%
36%
29%
41
56%
63%
56%
40
58%
65%
38%
46
41%
43%
33%
0.012
0.012
0.012
0.009
0.008
NS
NS
NS
NS
1 Cisplatin administration began within 10 minutes of KYTRIL Injection infusion and
continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and
high strata.
2 No vomiting and no use of rescue antiemetic.
For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more
effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of
chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher
doses.
5
Moderately Emetogenic Chemotherapy
KYTRIL Injection, 40 mcg/kg, was compared with the combination of chlorpromazine
(50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately
emetogenic chemotherapy, including primarily carboplatin >300 mg/m2, cisplatin 20 to
50 mg/m2 and cyclophosphamide >600 mg/m2. KYTRIL Injection was superior to the
chlorpromazine regimen in preventing nausea and vomiting (see Table 6).
Table 6
Prevention of Chemotherapy-Induced Nausea and
Vomiting—Single-Day Moderately Emetogenic
Chemotherapy
Number of Patients
Response Over 24 Hours
Complete Response2
No Vomiting
No More Than Mild Nausea
KYTRIL
Injection
133
68%
73%
77%
Chlorpromazine1
133
47%
53%
59%
P-Value
<0.001
<0.001
<0.001
1
Patients also received dexamethasone, 12 mg.
2
No vomiting and no moderate or severe nausea.
In other studies of moderately emetogenic chemotherapy, no significant difference in
efficacy was found between KYTRIL doses of 40 mcg/kg and 160 mcg/kg.
Repeat-Cycle Chemotherapy
In an uncontrolled trial, 512 cancer patients received KYTRIL Injection, 40 mcg/kg,
prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four
cycles, and 108 patients received it for at least six cycles. KYTRIL Injection efficacy
remained relatively constant over the first six repeat cycles, with complete response rates
(no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. No patients
were studied for more than 15 cycles.
Pediatric Studies
A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer
patients (age 2 to 16 years) to KYTRIL Injection 10, 20 or 40 mcg/kg. Patients were
treated with cisplatin ≥60 mg/m2, cytarabine ≥3 g/m2, cyclophosphamide ≥1 g/m2 or
nitrogen mustard ≥6 mg/m2 (see Table 7).
Table 7
Prevention of Chemotherapy-Induced Nausea and Vomiting
in Pediatric Patients
1
KYTRIL Injection Dose (mcg/kg)
10
20
40
Number of Patients
Median Number of Vomiting Episodes
Complete Response Over 24 Hours1
29
2
21%
26
3
31%
25
1
32%
No vomiting and no moderate or severe nausea.
6
A second pediatric study compared KYTRIL Injection 20 mcg/kg to chlorpromazine plus
dexamethasone in 88 patients treated with ifosfamide ≥3 g/m2/day for two or three days.
KYTRIL Injection was administered on each day of ifosfamide treatment. At 24 hours,
22% of KYTRIL Injection patients achieved complete response (no vomiting and no
moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine
regimen. The median number of vomiting episodes with KYTRIL Injection was 1.5; with
chlorpromazine it was 7.0.
Postoperative Nausea and Vomiting
Prevention of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for prevention of postoperative nausea and vomiting
was evaluated in 868 patients, of which 833 were women, 35 men, 484 Caucasians, 348
Asians, 18 Blacks, 18 Other, with 61 patients 65 years or older. KYTRIL was evaluated
in two randomized, double-blind, placebo-controlled studies in patients who underwent
elective gynecological surgery or cholecystectomy and received general anesthesia.
Patients received a single intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg)
or placebo either 5 minutes before induction of anesthesia or immediately before reversal
of anesthesia. The primary endpoint was the proportion of patients with no vomiting for
24 hours after surgery. Episodes of nausea and vomiting and use of rescue antiemetic
therapy were recorded for 24 hours after surgery. In both studies, KYTRIL Injection (1
mg) was more effective than placebo in preventing postoperative nausea and vomiting
(see Table 8). No additional benefit was seen in patients who received the 3 mg dose.
7
Table 8
Prevention of Postoperative Nausea and Vomiting in Adult
Patients
Study and Efficacy Endpoint
Placebo
KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 1
Number of Patients
No Vomiting
133
132
134
128
0 to 24 hours
No Nausea
34%
45%
63%**
62%**
0 to 24 hours
No Nausea or Vomiting
22%
28%
50%**
42%**
0 to 24 hours
No Use of Rescue Antiemetic
Therapy
18%
27%
49%**
42%**
0 to 24 hours
60%
67%
75%*
77%*
Study 2
Number of Patients
No Vomiting
117
–
110
114
0 to 24 hours
No Nausea
56%
–
77%**
75%*
0 to 24 hours
37%
–
59%**
56%*
*P<0.05
**P<0.001 versus placebo
Note: No Vomiting = no vomiting and no use of rescue antiemetic therapy; No Nausea =
no nausea and no use of rescue antiemetic therapy
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in
either population.
Treatment of Postoperative Nausea and Vomiting
The efficacy of KYTRIL Injection for treatment of postoperative nausea and vomiting
was evaluated in 844 patients, of which 731 were women, 113 men, 777 Caucasians, 6
Asians, 41 Blacks, 20 Other, with 107 patients 65 years or older. KYTRIL Injection was
evaluated in two randomized, double-blind, placebo-controlled studies of adult surgical
patients who received general anesthesia with no prophylactic antiemetic agent, and who
experienced nausea or vomiting within 4 hours postoperatively. Patients received a single
intravenous dose of KYTRIL Injection (0.1 mg, 1 mg or 3 mg) or placebo after
experiencing postoperative nausea or vomiting. Episodes of nausea and vomiting and use
of rescue antiemetic therapy were recorded for 24 hours after administration of study
medication. KYTRIL Injection was more effective than placebo in treating postoperative
nausea and vomiting (see Table 9). No additional benefit was seen in patients who
received the 3 mg dose.
8
Table 9
Treatment of Postoperative Nausea and Vomiting in Adult
Patients
Study and Efficacy Endpoint
Placebo
KYTRIL
0.1 mg
KYTRIL
1 mg
KYTRIL
3 mg
Study 3
Number of Patients
No Vomiting
0 to 6 hours
0 to 24 hours
No Nausea
0 to 6 hours
0 to 24 hours
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
0 to 24 hours
133
26%
20%
17%
13%
–
33%
128
53%***
38%***
40%***
27%**
–
51%**
133
58%***
46%***
41%***
30%**
–
61%***
125
60%***
49%***
42%***
37%***
–
61%***
Study 4
Number of Patients (All
Patients)
No Vomiting
0 to 6 hours
0 to 24 hours
No Nausea
0 to 6 hours
0 to 24 hours
No Nausea or Vomiting
0 to 6 hours
0 to 24 hours
No Use of Rescue Antiemetic
Therapy
0 to 6 hours
0 to 24 hours
162
20%
14%
13%
9%
13%
9%
–
24%
163
32%*
23%*
18%
14%
18%
14%
–
34%*
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Number of Patients (Treated
for Vomiting)1
No Vomiting
86
103
–
–
0 to 6 hours
21%
27%
–
–
0 to 24 hours
14%
20%
–
–
*P<0.05
**P<0.01
***P<0.001 versus placebo
1 Protocol Specified Analysis: Patients who had vomiting prior to treatment
Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea =
no nausea and no use of rescue antiemetic therapy
9
Gender/Race
There were too few male and Black patients to adequately assess differences in effect in
either population.
INDICATIONS AND USAGE
KYTRIL Injection is indicated for:
• The prevention of nausea and/or vomiting associated with initial and repeat courses of
emetogenic cancer therapy, including high-dose cisplatin.
• The prevention and treatment of postoperative nausea and vomiting in adults. As with
other antiemetics, routine prophylaxis is not recommended in patients in whom there
is little expectation that nausea and/or vomiting will occur postoperatively. In patients
where nausea and/or vomiting must be avoided during the postoperative period,
KYTRIL Injection is recommended even where the incidence of postoperative nausea
and/or vomiting is low.
CONTRAINDICATIONS
KYTRIL Injection is contraindicated in patients with known hypersensitivity to the drug
or to any of its components.
WARNINGS
Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to
other selective 5-HT3 receptor antagonists.
PRECAUTIONS
KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used
instead of nasogastric suction. The use of KYTRIL in patients following abdominal
surgery or in patients with chemotherapy-induced nausea and vomiting may mask a
progressive ileus and/or gastric distention.
An adequate QT assessment has not been conducted, but QT prolongation has been
reported with KYTRIL. Therefore, Kytril should be used with caution in patients with
pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical
consequences.
Patients with cardiac disease, on cardio-toxic chemotherapy, with
concomitant electrolyte abnormalities and/or on concomitant medications that prolong
the QT interval are particularly at risk.
Drug Interactions
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme
system in vitro. There have been no definitive drug-drug interaction studies to examine
pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans,
KYTRIL
Injection
has
been
safely
administered
with
drugs
representing
benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with
antiemetic treatments. KYTRIL Injection also does not appear to interact with
emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic
cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes
may change the clearance and, hence, the half-life of granisetron. No specific interaction
10
studies have been conducted in anesthetized patients. In addition, the activity of the
cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main
narcotic analgesic agents) is not modified by KYTRIL in vitro.
In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of KYTRIL.
However, the clinical significance of in vivo pharmacokinetic interactions with
ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction
with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous
KYTRIL. The clinical significance of this change is not known.
QT prolongation has been reported with KYTRIL. Use of Kytril in patients concurrently
treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may
result in to clinical consequences.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or
50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to
25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of
average height (1.46 m2 body surface area), these doses represent 16, 81 and 405 times
the recommended clinical dose (0.37 mg/m2, iv) on a body surface area basis. There was
a statistically significant increase in the incidence of hepatocellular carcinomas and
adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended
human dose based on body surface area) and above, and in females treated with
25 mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on body
surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day
(6 mg/m2/day, 16 times the recommended human dose based on body surface area) in
males and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on
body surface area) in females. In a 12-month oral toxicity study, treatment with
granisetron 100 mg/kg/day (600 mg/m2/day, 1622 times the recommended human dose
based on body surface area) produced hepatocellular adenomas in male and female rats
while no such tumors were found in the control rats. A 24-month mouse carcinogenicity
study of granisetron did not show a statistically significant increase in tumor incidence,
but the study was not conclusive.
Because of the tumor findings in rat studies, KYTRIL Injection should be prescribed only
at the dose and for the indication recommended (see INDICATIONS AND USAGE and
DOSAGE AND ADMINISTRATION).
Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell
forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat
hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa
cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro
human lymphocyte chromosomal aberration test.
Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the
recommended human dose based on body surface area) was found to have no effect on
fertility and reproductive performance of male and female rats.
11
Pregnancy
Teratogenic Effects
Pregnancy Category B.
Reproduction studies have been performed in pregnant rats at intravenous doses up to
9 mg/kg/day (54 mg/m2/day, 146 times the recommended human dose based on body
surface area) and pregnant rabbits at intravenous doses up to 3 mg/kg/day
(35.4 mg/m2/day, 96 times the recommended human dose based on body surface area)
and have revealed no evidence of impaired fertility or harm to the fetus due to
granisetron. 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.
Benzyl alcohol may cross the placenta. KYTRIL Injection 1 mg/1 mL is preserved with
benzyl alcohol and should be used in pregnancy only if the benefit outweighs the
potential risk.
Nursing Mothers
It is not known whether granisetron is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when KYTRIL Injection is
administered to a nursing woman.
Pediatric Use
See DOSAGE AND ADMINISTRATION for use in chemotherapy-induced nausea and
vomiting in pediatric patients 2 to 16 years of age. Safety and effectiveness in pediatric
patients under 2 years of age have not been established. Safety and effectiveness of
KYTRIL Injection have not been established in pediatric patients for the prevention or
treatment of postoperative nausea or vomiting.
Benzyl alcohol, a component of KYTRIL 1 mg/1 mL, has been associated with serious
adverse events and death, particularly in neonates. The “gasping syndrome,”
characterized by central nervous system depression, metabolic acidosis, gasping
respirations, and high levels of benzyl alcohol and metabolites in blood and urine, has
been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low birth-
weight neonates. Additional symptoms may include gradual neurological deterioration,
seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic
and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although
normal therapeutic doses of this product deliver amounts of benzyl alcohol that are
substantially lower than those reported in association with the “gasping syndrome,” the
minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature
and low birth-weight infants, as well as patients receiving high dosages, may be more
likely to develop toxicity. Practitioners administering this and other medications
containing benzyl alcohol should consider the combined daily metabolic load of benzyl
alcohol from all sources.
12
Geriatric Use
During chemotherapy clinical trials, 713 patients 65 years of age or older received
KYTRIL Injection. Effectiveness and safety were similar in patients of various ages.
During postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or
older, of which 47 were 75 years of age or older, received KYTRIL Injection. Clinical
studies of KYTRIL Injection did not include sufficient numbers of subjects aged 65 years
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients.
ADVERSE REACTIONS
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
Chemotherapy-Induced Nausea and Vomiting
The following have been reported during controlled clinical trials or in the routine
management of patients. The percentage figures are based on clinical trial experience
only. Table 10 gives the comparative frequencies of the five most commonly reported
adverse events (≥3%) in patients receiving KYTRIL Injection, in single-day
chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and
intravenous fluids during the 24-hour period following KYTRIL Injection administration.
Events were generally recorded over seven days post-KYTRIL Injection administration.
In the absence of a placebo group, there is uncertainty as to how many of these events
should be attributed to KYTRIL, except for headache, which was clearly more frequent
than in comparison groups.
Table 10
Principal Adverse Events in Clinical Trials — Single-Day
Chemotherapy
Percent of Patients With Event
KYTRIL Injection
40 mcg/kg
(n=1268)
Comparator1
(n=422)
Headache
Asthenia
Somnolence
Diarrhea
Constipation
14%
5%
4%
4%
3%
6%
6%
15%
6%
3%
Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
In over 3,000 patients receiving KYTRIL Injection (2 to 160 mcg/kg) in single-day and
multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than
those in Table 10, were observed; attribution of many of these events to KYTRIL is
uncertain.
Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and
ALT (>2 times the upper limit of normal) following administration of KYTRIL Injection
13
1
occurred in 2.8% and 3.3% of patients, respectively. These frequencies were not
significantly different from those seen with comparators (AST: 2.1%; ALT: 2.4%).
Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia,
atrial fibrillation, varying degrees of A-V block, ventricular ectopy including non-
sustained tachycardia, and ECG abnormalities have been observed rarely.
Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in
less than 2% of patients. Extrapyramidal syndrome occurred rarely and only in the
presence of other drugs associated with this syndrome.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg,
anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative
studies, fever occurred more frequently with KYTRIL Injection (8.6%) than with
comparative drugs (3.4%, P<0.014), which usually included dexamethasone.
Postoperative Nausea and Vomiting
The adverse events listed in Table 11 were reported in ≥2% of adults receiving KYTRIL
Injection 1 mg during controlled clinical trials.
Table 11
Adverse Events ≥2%
Percent of Patients With Event
KYTRIL Injection
1 mg
(n=267)
Placebo
(n=266)
Pain
10.1
8.3
Constipation
9.4
12.0
Anemia
9.4
10.2
Headache
8.6
7.1
Fever
7.9
4.5
Abdominal Pain
6.0
6.0
Hepatic Enzymes Increased
5.6
4.1
Insomnia
4.9
6.0
Bradycardia
4.5
5.3
Dizziness
4.1
3.4
Leukocytosis
3.7
4.1
Anxiety
3.4
3.8
Hypotension
3.4
3.8
Diarrhea
3.4
1.1
Flatulence
3.0
3.0
Infection
3.0
2.3
Dyspepsia
3.0
1.9
Hypertension
2.6
4.1
Urinary Tract Infection
2.6
3.4
Oliguria
2.2
1.5
Coughing
2.2
1.1
14
In a clinical study conducted in Japan, the types of adverse events differed notably from
those reported above in Table 11. The adverse events in the Japanese study that occurred
in ≥2% of patients and were more frequent with KYTRIL 1 mg than with placebo were:
fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%).
Postmarketing Experience
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
OVERDOSAGE
There is no specific antidote for KYTRIL Injection overdosage. In case of overdosage,
symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron
hydrochloride injection has been reported without symptoms or only the occurrence of a
slight headache.
DOSAGE AND ADMINISTRATION
NOTE:
KYTRIL
1
MG/1
ML
CONTAINS
BENZYL
ALCOHOL
(see
PRECAUTIONS).
Prevention of Chemotherapy-Induced Nausea and Vomiting
The recommended dosage for KYTRIL Injection is 10 mcg/kg administered
intravenously within 30 minutes before initiation of chemotherapy, and only on the
day(s) chemotherapy is given.
Infusion Preparation
KYTRIL Injection may be administered intravenously either undiluted over 30 seconds,
or diluted with 0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes.
Stability
Intravenous infusion of KYTRIL Injection should be prepared at the time of
administration. However, KYTRIL Injection has been shown to be stable for at least 24
hours when diluted in 0.9% Sodium Chloride or 5% Dextrose and stored at room
temperature under normal lighting conditions.
As a general precaution, KYTRIL Injection should not be mixed in solution with other
drugs. Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
Pediatric Patients
The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg (see
CLINICAL TRIALS). Pediatric patients under 2 years of age have not been studied.
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
15
Prevention and Treatment of Postoperative Nausea and Vomiting
The recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of
KYTRIL, undiluted, administered intravenously over 30 seconds, before induction of
anesthesia or immediately before reversal of anesthesia.
The recommended dosage for the treatment of nausea and/or vomiting after surgery is 1
mg of KYTRIL, undiluted, administered intravenously over 30 seconds.
Pediatric Patients
Safety and effectiveness of KYTRIL Injection have not been established in pediatric
patients for the prevention or treatment of postoperative nausea or vomiting.
Geriatric Patients, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
HOW SUPPLIED
KYTRIL Injection, 1 mg/1 mL (free base), is supplied in 1 mL Single-Use Vials and 4
mL Multi-Use Vials. CONTAINS BENZYL ALCOHOL.
NDC 0004-0239-09 (package of 1 Single-Use Vial)
NDC 0004-0240-09 (package of 1 Multi-Use Vial)
KYTRIL Injection, 0.1 mg/1 mL (free base), is supplied in 1 mL Single-Use Vials.
CONTAINS NO PRESERVATIVE.
NDC 0004-0242-08 (package of 5 Single-Use Vials)
Storage
Store single-use vials and multi-use vials at 25°C (77°F); excursions permitted to 15° to
30°C (59° to 86°F). [See USP Controlled Room Temperature]
Once the multi-use vial is penetrated, its contents should be used within 30 days.
Do not freeze. Protect from light.
Distributed by: logo
XXXXXXXX
Revised: September 2009
Copyright © 1998-2009 by Roche Laboratories Inc. All rights reserved.
16
Roche logo
KYTRIL®
(granisetron hydrochloride)
TABLETS
ORAL SOLUTION
Rx only
DESCRIPTION
KYTRIL Tablets and KYTRIL Oral Solution contain granisetron hydrochloride, an
antinauseant and antiemetic agent. Chemically it is endo-N-(9-methyl-9-azabicyclo
[3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular
weight of 348.9 (312.4 free base). Its empirical formula is C18H24N4O•HCl, while its
chemical structure is: Structural Formula
granisetron hydrochloride
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and
normal saline at 20ºC.
Tablets for Oral Administration
Each white, triangular, biconvex, film-coated KYTRIL Tablet contains 1.12 mg
granisetron hydrochloride equivalent to granisetron, 1 mg. Inactive ingredients are:
hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
Oral Solution
Each 10 mL of clear, orange-colored, orange-flavored KYTRIL Oral Solution contains
2.24 mg of granisetron hydrochloride equivalent to 2 mg granisetron. Inactive
ingredients: citric acid anhydrous, FD&C Yellow No. 6, orange flavor, purified water,
sodium benzoate, and sorbitol.
CLINICAL PHARMACOLOGY
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or
no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for
1
KYTRIL® (granisetron hydrochloride)
alpha1-, alpha2-, or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1;
benzodiazepine; picrotoxin or opioid receptors.
Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals
and centrally in the chemoreceptor trigger zone of the area postrema. During
chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin,
which stimulates 5-HT3 receptors. This evokes vagal afferent discharge, inducing
vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron
blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as
cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting
due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
In most human studies, granisetron has had little effect on blood pressure, heart rate or
ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has
been found in other studies.
Following single and multiple oral doses, KYTRIL Tablets slowed colonic transit in
normal volunteers. However, KYTRIL had no effect on oro-cecal transit time in normal
volunteers when given as a single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg.
Pharmacokinetics
In healthy volunteers and adult cancer patients undergoing chemotherapy, administration
of KYTRIL Tablets produced mean pharmacokinetic data shown in Table 1.
Table 1
Pharmacokinetic Parameters (Median [range]) Following
KYTRIL Tablets (granisetron hydrochloride)
Peak Plasma
Concentration
(ng/mL)
Terminal Phase
Plasma Half-Life
(h)
Volume of
Distribution
(L/kg)
Total
Clearance
(L/h/kg)
Cancer Patients
1 mg bid, 7 days
(n=27)
5.99
[0.63 to 30.9]
N.D.1
N.D.
0.52
[0.09 to 7.37]
Volunteers
single 1 mg dose
(n=39)
3.63
[0.27 to 9.14]
6.23
[0.96 to 19.9]
3.94
[1.89 to 39.4]
0.41
[0.11 to 24.6]
Not determined after oral administration; following a single intravenous dose of 40
mcg/kg, terminal phase half-life was determined to be 8.95 hours.
N.D. Not determined.
A 2 mg dose of KYTRIL Oral Solution is bioequivalent to the corresponding dose of
KYTRIL Tablets (1 mg x 2) and may be used interchangeably.
1
2
KYTRIL® (granisetron hydrochloride)
Absorption
When KYTRIL Tablets were administered with food, AUC was decreased by 5% and
Cmax increased by 30% in non-fasted healthy volunteers who received a single dose of 10
mg.
Distribution
Plasma protein binding is approximately 65% and granisetron distributes freely between
plasma and red blood cells.
Metabolism
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed
by conjugation. In vitro liver microsomal studies show that granisetron’s major route of
metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the
cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites
may also have 5-HT3 receptor antagonist activity.
Elimination
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately
11% of the orally administered dose is eliminated unchanged in the urine in 48 hours.
The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the
feces.
Subpopulations
Gender
The effects of gender on the pharmacokinetics of KYTRIL Tablets have not been studied.
However, after intravenous infusion of KYTRIL, no difference in mean AUC was found
between males and females, although males had a higher Cmax generally.
In elderly and pediatric patients and in patients with renal failure or hepatic impairment,
the pharmacokinetics of granisetron was determined following administration of
intravenous KYTRIL.
Elderly
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years),
given a single 40 mcg/kg intravenous dose of KYTRIL Injection, were generally similar
to those in younger healthy volunteers; mean values were lower for clearance and longer
for half-life in the elderly.
Renal Failure Patients
Total clearance of granisetron was not affected in patients with severe renal failure who
received a single 40 mcg/kg intravenous dose of KYTRIL Injection.
Hepatically Impaired Patients
A pharmacokinetic study with intravenous KYTRIL in patients with hepatic impairment
due to neoplastic liver involvement showed that total clearance was approximately halved
compared to patients without hepatic impairment. Given the wide variability in
3
KYTRIL® (granisetron hydrochloride)
pharmacokinetic parameters noted in patients, dosage adjustment in patients with hepatic
functional impairment is not necessary.
Pediatric Patients
A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single
40 mcg/kg intravenous dose of KYTRIL Injection, showed that volume of distribution
and total clearance increased with age. No relationship with age was observed for peak
plasma concentration or terminal phase plasma half-life. When volume of distribution
and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are
similar in pediatric and adult cancer patients.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting
KYTRIL Tablets prevent nausea and vomiting associated with initial and repeat courses
of emetogenic cancer therapy, as shown by 24-hour efficacy data from studies using both
moderately- and highly-emetogenic chemotherapy.
Moderately Emetogenic Chemotherapy
The first trial compared KYTRIL Tablets doses of 0.25 mg to 2 mg twice a day, in 930
cancer patients receiving, principally, cyclophosphamide, carboplatin, and cisplatin (20
mg/m2 to 50 mg/m2). Efficacy was based on complete response (ie, no vomiting, no
moderate or severe nausea, no rescue medication), no vomiting, and no nausea. Table 2
summarizes the results of this study.
Table 2
Prevention of Nausea and Vomiting 24 Hours Post
Chemotherapy1
Percentages of Patients
KYTRIL Tablet Dose
Efficacy Measures
0.25 mg
twice a day
(n=229)
%
0.5 mg twice
a day
(n=235)
%
1 mg twice a
day
(n=233)
%
2 mg twice a
day
(n=233)
%
Complete Response2
No Vomiting
No Nausea
61
66
48
70*
77*
57
81*†
88*
63*
72*
79*
54
1
Chemotherapy included oral and injectable cyclophosphamide, carboplatin, cisplatin
(20 mg/m2 to 50 mg/m2), dacarbazine, doxorubicin, epirubicin.
2
No vomiting, no moderate or severe nausea, no rescue medication.
*Statistically significant (P<0.01) vs. 0.25 mg bid.
†Statistically significant (P<0.01) vs. 0.5 mg bid.
4
KYTRIL® (granisetron hydrochloride)
Results from a second double-blind, randomized trial evaluating KYTRIL Tablets 2 mg
once a day and KYTRIL Tablets 1 mg twice a day were compared to prochlorperazine 10
mg twice a day derived from a historical control. At 24 hours, there was no statistically
significant difference in efficacy between the two KYTRIL Tablet regimens. Both
regimens were statistically superior to the prochlorperazine control regimen (see
Table 3).
Table 3
Prevention of Nausea and Vomiting 24 Hours Post
Chemotherapy1
Efficacy Measures
Percentages of Patients
KYTRIL
Tablets
1 mg twice a
day (n = 354)
%
KYTRIL
Tablets
2 mg once a
day
(n = 343)
%
Prochlorperazine2
10 mg twice daily
(n=111)
%
Complete Response3
No Vomiting
No Nausea
Total Control4
69*
82*
51*
51*
64*
77*
53*
50*
41
48
35
33
1
Moderately emetogenic chemotherapeutic agents included cisplatin (20 mg/m2 to 50
mg/m2), oral and intravenous cyclophosphamide, carboplatin, dacarbazine,
doxorubicin.
2
Historical control from a previous double-blind KYTRIL trial.
3
No vomiting, no moderate or severe nausea, no rescue medication.
4
No vomiting, no nausea, no rescue medication.
*Statistically significant (P<0.05) vs. prochlorperazine historical control.
Results from a KYTRIL Tablets 2 mg daily alone treatment arm in a third double-blind,
randomized trial, were compared to prochlorperazine (PCPZ), 10 mg bid, derived from a
historical control. The 24-hour results for KYTRIL Tablets 2 mg daily were statistically
superior to PCPZ for all efficacy parameters: complete response (58%), no vomiting
(79%), no nausea (51%), total control (49%). The PCPZ rates are shown in Table 3.
Cisplatin-Based Chemotherapy
The first double-blind trial compared KYTRIL Tablets 1 mg bid, relative to placebo
(historical control), in 119 cancer patients receiving high-dose cisplatin (mean dose 80
mg/m2). At 24 hours, KYTRIL Tablets 1 mg bid was significantly (P<0.001) superior to
placebo (historical control) in all efficacy parameters: complete response (52%), no
5
KYTRIL® (granisetron hydrochloride)
vomiting (56%) and no nausea (45%). The placebo rates were 7%, 14%, and 7%,
respectively, for the three efficacy parameters.
Results from a KYTRIL Tablets 2 mg once a day alone treatment arm in a second
double-blind, randomized trial, were compared to both KYTRIL Tablets 1 mg twice a
day and placebo historical controls. The 24-hour results for KYTRIL Tablets 2 mg once a
day were: complete response (44%), no vomiting (58%), no nausea (46%), total control
(40%). The efficacy of KYTRIL Tablets 2 mg once a day was comparable to KYTRIL
Tablets 1 mg twice a day and statistically superior to placebo. The placebo rates were
7%, 14%, 7%, and 7%, respectively, for the four parameters.
No controlled study comparing granisetron injection with the oral formulation to prevent
chemotherapy-induced nausea and vomiting has been performed.
Radiation-Induced Nausea and Vomiting
Total Body Irradiation
In a double-blind randomized study, 18 patients receiving KYTRIL Tablets, 2 mg daily,
experienced significantly greater antiemetic protection compared to patients in a
historical negative control group who received conventional (non-5-HT3 antagonist)
antiemetics. Total body irradiation consisted of 11 fractions of 120 cGy administered
over 4 days, with three fractions on each of the first 3 days, and two fractions on the
fourth day. KYTRIL Tablets were given one hour before the first radiation fraction of
each day.
Twenty-two percent (22%) of patients treated with KYTRIL Tablets did not experience
vomiting or receive rescue antiemetics over the entire 4-day dosing period, compared to
0% of patients in the historical negative control group (P<0.01).
In addition, patients who received KYTRIL Tablets also experienced significantly fewer
emetic episodes during the first day of radiation and over the 4-day treatment period,
compared to patients in the historical negative control group. The median time to the first
emetic episode was 36 hours for patients who received KYTRIL Tablets.
Fractionated Abdominal Radiation
The efficacy of KYTRIL Tablets, 2 mg daily, was evaluated in a double-blind, placebo-
controlled randomized trial of 260 patients. KYTRIL Tablets were given 1 hour before
radiation, composed of up to 20 daily fractions of 180 to 300 cGy each. The exceptions
were patients with seminoma or those receiving whole abdomen irradiation who initially
received 150 cGy per fraction. Radiation was administered to the upper abdomen with a
field size of at least 100 cm2.
The proportion of patients without emesis and those without nausea for KYTRIL Tablets,
compared to placebo, was statistically significant (P<0.0001) at 24 hours after radiation,
irrespective of the radiation dose. KYTRIL was superior to placebo in patients receiving
up to 10 daily fractions of radiation, but was not superior to placebo in patients receiving
20 fractions.
6
KYTRIL® (granisetron hydrochloride)
Patients treated with KYTRIL Tablets (n=134) had a significantly longer time to the first
episode of vomiting (35 days vs. 9 days, P<0.001) relative to those patients who received
placebo (n=126), and a significantly longer time to the first episode of nausea (11 days
vs. 1 day, P<0.001). KYTRIL provided significantly greater protection from nausea and
vomiting than placebo.
INDICATIONS AND USAGE
KYTRIL (granisetron hydrochloride) is indicated for the prevention of:
• Nausea and vomiting associated with initial and repeat courses of emetogenic cancer
therapy, including high-dose cisplatin.
• Nausea and vomiting associated with radiation, including total body irradiation and
fractionated abdominal radiation.
CONTRAINDICATIONS
KYTRIL is contraindicated in patients with known hypersensitivity to the drug or any of
its components.
PRECAUTIONS
KYTRIL is not a drug that stimulates gastric or intestinal peristalsis. It should not be used
instead of nasogastric suction. The use of KYTRIL in patients following abdominal
surgery or in patients with chemotherapy-induced nausea and vomiting may mask a
progressive ileus and/or gastric distention.
An adequate QT assessment has not been conducted, but QT prolongation has been
reported with KYTRIL. Therefore, Kytril should be used with caution in patients with
pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical
consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with
concomitant electrolyte abnormalities and/or on concomitant medications that prolong
the QT interval are particularly at risk.
Drug Interactions
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme
system in vitro. There have been no definitive drug-drug interaction studies to examine
pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans,
KYTRIL
Injection
has
been
safely
administered
with
drugs
representing
benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with
antiemetic treatments. KYTRIL Injection also does not appear to interact with
emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic
cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes
may change the clearance and, hence, the half-life of granisetron. No specific interaction
studies have been conducted in anesthetized patients. In addition, the activity of the
cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main
narcotic analgesic agents) is not modified by KYTRIL in vitro.
In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of KYTRIL.
However, the clinical significance of in vivo pharmacokinetic interactions with
ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction
7
KYTRIL® (granisetron hydrochloride)
with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous
KYTRIL. The clinical significance of this change is not known.
QT prolongation has been reported with KYTRIL. Use of Kytril in patients concurrently
treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may
result in clinical consequences.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50
mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25
mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of
average height (1.46 m2 body surface area), these doses represent 4, 20, and 101 times the
recommended clinical dose (1.48 mg/m2, oral) on a body surface area basis. There was a
statistically significant increase in the incidence of hepatocellular carcinomas and
adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 20 times the recommended
human dose based on body surface area) and above, and in females treated with 25
mg/kg/day (150 mg/m2/day, 101 times the recommended human dose based on body
surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6
mg/m2/day, 4 times the recommended human dose based on body surface area) in males
and 5 mg/kg/day (30 mg/m2/day, 20 times the recommended human dose based on body
surface area) in females. In a 12-month oral toxicity study, treatment with granisetron
100 mg/kg/day (600 mg/m2/day, 405 times the recommended human dose based on body
surface area) produced hepatocellular adenomas in male and female rats while no such
tumors were found in the control rats. A 24-month mouse carcinogenicity study of
granisetron did not show a statistically significant increase in tumor incidence, but the
study was not conclusive.
Because of the tumor findings in rat studies, KYTRIL (granisetron hydrochloride) should
be prescribed only at the dose and for the indication recommended (see INDICATIONS
AND USAGE, and DOSAGE AND ADMINISTRATION).
Granisetron was not mutagenic in in vitro Ames test and mouse lymphoma cell forward
mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat
hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa
cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro
human lymphocyte chromosomal aberration test.
Granisetron at oral doses up to 100 mg/kg/day (600 mg/m2/day, 405 times the
recommended human dose based on body surface area) was found to have no effect on
fertility and reproductive performance of male and female rats.
Pregnancy
Teratogenic Effects
Pregnancy Category B.
Reproduction studies have been performed in pregnant rats at oral doses up to 125
mg/kg/day (750 mg/m2/day, 507 times the recommended human dose based on body
surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2/day, 255
8
KYTRIL® (granisetron hydrochloride)
times the recommended human dose based on body surface area) and have revealed no
evidence of impaired fertility or harm to the fetus due to granisetron. 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 granisetron is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when KYTRIL is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
During clinical trials, 325 patients 65 years of age or older received KYTRIL Tablets;
298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety
were maintained with increasing age.
ADVERSE REACTIONS
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
Chemotherapy-Induced Nausea and Vomiting
Over 3700 patients have received KYTRIL Tablets in clinical trials with emetogenic
cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens.
In patients receiving KYTRIL Tablets 1 mg bid for 1, 7 or 14 days, or 2 mg daily for 1
day, adverse experiences reported in more than 5% of the patients with comparator and
placebo incidences are listed in Table 4.
9
KYTRIL® (granisetron hydrochloride)
Table 4
Principal Adverse Events in Clinical Trials
Percent of Patients With Event
KYTRIL1
Tablets
1 mg twice a
day
(n=978)
KYTRIL1
Tablets
2 mg once a
day
(n=1450)
Comparator2
(n=599)
Placebo
(n=185)
Headache3
Constipation
Asthenia
Diarrhea
Abdominal pain
Dyspepsia
21%
18%
14%
8%
6%
4%
20%
14%
18%
9%
4%
6%
13%
16%
10%
10%
6%
5%
12%
8%
4%
4%
3%
4%
1
Adverse events were recorded for 7 days when KYTRIL Tablets were given on a
single day and for up to 28 days when KYTRIL Tablets were administered for 7 or 14
days.
2
Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone
alone; prochlorperazine.
Other adverse events reported in clinical trials were:
Gastrointestinal: In single-day dosing studies in which adverse events were collected for
7 days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24
hour efficacy assessment period.
Hepatic: In comparative trials, elevation of AST and ALT (>2 times the upper limit of
normal) following the administration of KYTRIL Tablets occurred in 5% and 6% of
patients, respectively. These frequencies were not significantly different from those seen
with comparators (AST: 2%; ALT: 9%).
Cardiovascular: Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and
syncope have been observed rarely.
Central Nervous System: Dizziness (5%), insomnia (5%), anxiety (2%), somnolence
(1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms has
been reported in a patient treated with KYTRIL Tablets.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg,
anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
Other: Fever (5%). Events often associated with chemotherapy also have been reported:
leukopenia
(9%),
decreased
appetite
(6%),
anemia
(4%),
alopecia
(3%),
thrombocytopenia (2%).
10
KYTRIL® (granisetron hydrochloride)
Over 5000 patients have received injectable KYTRIL in clinical trials.
Table 5 gives the comparative frequencies of the five commonly reported adverse events
(≥3%) in patients receiving KYTRIL Injection, 40 mcg/kg, in single-day chemotherapy
trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids
during the 24-hour period following KYTRIL Injection administration.
Table 5
Principal Adverse Events in Clinical Trials — Single-Day
Chemotherapy
Percent of Patients with Event
KYTRIL Injection1
40 mcg/kg
(n=1268)
Comparator2
(n=422)
Headache
Asthenia
Somnolence
Diarrhea
Constipation
14%
5%
4%
4%
3%
6%
6%
15%
6%
3%
1
Adverse events were generally recorded over 7 days post-KYTRIL Injection
administration.
2
Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
In the absence of a placebo group, there is uncertainty as to how many of these events
should be attributed to KYTRIL, except for headache, which was clearly more frequent
than in comparison groups.
Radiation-Induced Nausea and Vomiting
In controlled clinical trials, the adverse events reported by patients receiving KYTRIL
Tablets and concurrent radiation were similar to those reported by patients receiving
KYTRIL Tablets prior to chemotherapy. The most frequently reported adverse events
were diarrhea, asthenia, and constipation. Headache, however, was less prevalent in this
patient population.
Postmarketing Experience
QT prolongation has been reported with KYTRIL (see PRECAUTIONS and Drug
Interactions).
OVERDOSAGE
There is no specific treatment for granisetron hydrochloride overdosage. In case of
overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of
granisetron hydrochloride injection has been reported without symptoms or only the
occurrence of a slight headache.
11
KYTRIL® (granisetron hydrochloride)
DOSAGE AND ADMINISTRATION
Emetogenic Chemotherapy
The recommended adult dosage of oral KYTRIL (granisetron hydrochloride) is 2 mg
once daily or 1 mg twice daily. In the 2 mg once-daily regimen, two 1 mg tablets or 10
mL of KYTRIL Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are
given up to 1 hour before chemotherapy. In the 1 mg twice-daily regimen, the first 1 mg
tablet or one teaspoonful (5 mL) of KYTRIL Oral Solution is given up to 1 hour before
chemotherapy, and the second tablet or second teaspoonful (5 mL) of KYTRIL Oral
Solution, 12 hours after the first. Either regimen is administered only on the day(s)
chemotherapy is given. Continued treatment, while not on chemotherapy, has not been
found to be useful.
Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Radiation (Either Total Body Irradiation or Fractionated Abdominal
Radiation)
The recommended adult dosage of oral KYTRIL is 2 mg once daily. Two 1 mg tablets or
10 mL of KYTRIL Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are
taken within 1 hour of radiation.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Use in the Elderly
No dosage adjustment is recommended.
HOW SUPPLIED
Tablets
White, triangular, biconvex, film-coated tablets; tablets are debossed K1 on one face.
1 mg Unit of Use 2’s: NDC 0004-0241-33
1 mg Single Unit Package 20’s: NDC 0004-0241-26 (intended for institutional use only)
Storage
Store between 15º and 30ºC (59º and 86ºF). Keep container closed tightly. Protect from
light.
12
KYTRIL® (granisetron hydrochloride)
Oral Solution
Clear, orange-colored, orange-flavored, 2 mg/10 mL, in 30 mL amber glass bottles with
child-resistant closures: NDC 0004-0237-09
Storage
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature]. Keep bottle closed tightly and stored in an upright
position. Protect from light.
Distributed by: logo
XXXXXXXX
Revised: September 2009
Copyright © 1999-2009 by Roche Laboratories Inc. All rights reserved.
13
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custom-source
|
2025-02-12T13:47:25.654811
|
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|
12,432
|
TRASYLOL tI
(aprotinin injection)
01298181
11/06
Trasyloi(j administration may cause fatal anaphylactic or anaphylactoid reactions.
Fatal reactions have occurred with an initial (test) dose as well as with any of the
components of the dose regimen. Fatal reactions have also occurred in situations
where the initial (test) dose was tolerated. The risk for anaphylactic or
anaphylactoid reactions is increased among patients with prior aprotinin exposure
and a history of any prior aprotinin exposure must be sought prior to Trasyloi(j
administration. The risk for a fatal reaction appears to be greater upon re-
exposure within 12 months of the most recent prior aprotinin exposure. Trasyloi(j
should be administered only in operative settings where cardiopulmonary bypass
can be rapidly initiated. The benefit of Trasyloi(j to patients undergoing primary
CABG surgery should be weighed against the risk of anaphylaxis associated with
any subsequent exposure to aprotinin. (See CONTRAINDICA TIONS, WARNINGS
and PRECAUTIONS).
DESCRIPTION
Trasyloi(j (aprotinin injection), C284H432N84079S7, is a natural proteinase inhibitor obtained
from bovine lung. Aprotinin (molecular weight of 6512 daltons), consists of 58 amino acid
residues that are arranged in a single polypeptide chain, cross-linked by three disulfide
bridges. It is supplied as a clear, colorless, sterile isotonic solution for intravenous
administration. Each millliter contains 10,000 KIU (Kallikrein Inhibitor Units) (1.4 mg/mL)
and 9 mg sodium chloride in water for injection. Hydrochloric acid and/or sodium hydroxide
is used to adjust the pH to 4.5-6.5.
CLINICAL PHARMACOLOGY
Mechanism of Action: Aprotinin is a broad spectrum protease inhibitor which
modulates
the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB)
surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and
humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators (e.g.,
kallkrein, plasmin) results in the attenuation of inflammatory responses, fibrinolysis, and
thrombin generation.
Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein
homeostasis. In platelets, aprotinin reduces glycoprotein
loss (e.g., GpIb, GpIIb/IIa), while in
granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g.,
CDllb).
The effects of aprotinin use in CPB involves a reduction in inflammatory response which
translates into a decreased need for àllogeneic blood transfusions, reduced bleeding, and
decreased mediastinal re-exploration for bleeding.
Pharmacokinetics: The studies comparing the pharmacokinetics of aprotinin in healthy
volunteers, cardiac patients undergoing surgery with cardiopulmonary bypass, and women
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undergoing hysterectomy suggest linear pharmacokinetics over the dose range of 50,000 KIU
to 2 milion KIU. After intravenous (IV) injection, rapid distribution of aprotinin occurs into
the total extracellular space, leading to a rapid initial decrease in plasma aprotinin
concentration. Following this distribution phase, a plasma half-life of about 150 minutes is
observed. At later time points, (i.e., beyond 5 hours after dosing) there is a terminal
elimination phase with a half-life of about 10 hours.
Average steady state intraoperative plasma concentrations were 13 7 KIU/mL (n= 10) after
administration of the following dosage regimen: 1 milion KIU iV loading dose, 1 milion
KIU into the pump prime volume, 250,000 KIU per hour of operation as continuous
intravenous infusion (Regimen B). Average steady state intraoperative plasma concentrations
were 250 KIU/mL in patients (n=20) treated with aprotinin during cardiac surgery by
administration of
Regimen A (exactly double Regimen B): 2 millon KIU IV loading dose, 2
milion KIU into the pump prime volume, 500,000 KIU per hour of operation as continuous
intravenous infusion.
Following a single iV dose of radiolabelled aprotinin, approximately 25-40% of the
radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 milion
KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused
over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of
the dose. Animal studies have shown that aprotinin is accumulated primarily in the kidney.
Aprotinin, after being filtered by the glomeruli, is actively reabsorbed by the proximal tubules in
which it is stored in phagolysosomes. Aprotinin is slowly degraded by lysosomal enzymes. The
physiological renal handling of aprotinin is similar to that of other small proteins, e.g., insulin.
CLINICAL TRIALS
Repeat Coronary Artery Bypass Graft Patients:
Four placebo-controlled, double-blind studies of Trasyloi(j were conducted in the United
States; of 540 randomized patients undergoing repeat coronary artery bypass graft (CAB
G)
surgery, 480 were valid for efficacy analysis. The following treatment regimens were used in
the studies:
Trasyloi(j Regimen A (2 milion KIU iV loading dose, 2 milion KID into the pump prime
volume, and 500,000 KIU per hour of surgery as a continuous intravenous infusion);
Trasyloi(j Regimen B (1 million KIU IV loading dose, 1 millon KIU into the pump prime
volume, and 250,000 KIU per hour of surgery as a continuous intravenous infusion); a pump
prime regimen (2 milion KIU into the pump prime volume only); and a placebo regimen
(normal saline). All patients valid for effcacy in the above studies were pooled by treatment
regimen for analyses of efficacy.
In this pooled analysis, fewer patients receiving Trasyloi(j, either Regimen A or Regimen B,
required any donor blood compared to the pump prime only or placebo regimens. The
number of units of donor blood required by patients, the volume (milliliters) of donor blood
transfused, the number of units of donor blood products transfused, the thoracic drainage rate,
and the total thoracic drainage volumes were also reduced in patients receiving Trasyloi(j as
compared to placebo.
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Efficacy Variables: Repeat CABG Patients
Mean (S.D.) or % of Patients
Trasylol(ß
Trasyloi(j
Trasyloi(j
PLACEBO
PUMP PRIME
REGIMEN
REGIMEN
VARIABLE
REGIMEN
REGIMENt
B**
A**
N=156
N=68
N=113
N=143
'"
% OF REPEAT CABG
76.3%
72.1%
48.7%
46.9%
PATIENTS WHO
REQUIRED
DONOR BLOOD
UNITS OF
3.7 (4.4)
2.5 (2.4)
2.2 (5.0)*
1.6 (2.9)*
DONOR BLOOD
TRANSFUSED
mLOF
1132 (1443)
756 (807)
723 (1779)*
515 (999)*
DONOR BLOOD
TRANSFUSED
PLATELETS
5.0 (10.0)
2.1 (4.6)*
1.3 (4.6)*
0.9 (4.3)*
TRANSFUSED (Donor Units)
CRYOPRECIPITATE
0.9 (3.5)
0.0 (0.0)*
0.5 (4.0)
0.1 (0.8)*
TRANSFUSED (Donor Units)
FRESH FROZEN
1.3 (2.5)
0.5 (1.4)*
0.3 (1. 1)*
0.2 (0.9)*
PLASMA TRANSFUSED
(Donor Units)
THORACIC DRAINAGE
89 (77)
73 (69)
66 (244)
40 (36)*
RATE (mL/hr)
TOTAL THORACIC
1659 (1226)
1561 (1370)
1103 (2001)*
960 (849)*
DRAINAGE VOLUME (mLt
REOPERA TION FOR
1.9%
2.9%
0%
0%
DIFFUSE BLEEDING
t The pump prime regimen was evaluated in only one study in patients undergoing repeat
CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p..0.05
(Transfusion variables analyzed via ANOV A on ranks)
** Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and
safety are not statistically significant.
a Excludes patients who required reoperation
Primary Coronary Artery Bypass Graft Patients:
Four placebo-controlled, double-blind studies of Trasyloi(j were conducted in the United
States; of 1745 randomized patients undergoing primary CABG surgery, 1599 were valid for
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efficacy analysis. The dosage regimens used in these studies were identical to those used in
the repeat CABO studies described above (Regimens A, B, pump prime, and placebo). All
patients valid for efficacy were pooled by treatment regimen.
In this pooled analysis, fewer patients receiving Trasyloi(j Regimens A, B, and pump prime
required any donor blood in comparison to the placebo regimen. The number of units of
donor blood required by patients, the volume of donor blood transfused, the number of units
of donor blood products transfused, the thoracic drainage rate, and total thoracic drainage
volumes were also reduced in patients receiving Trasyloi(j as compared to placebo.
Efficacy Variables. Primary CABG Patients
Mean (S.D.) or % of Patients
TrasylolCI
Trasyloi(j
Trasyloi(j
PLACEBO
PUMP PRIME
REGIMEN
REGIMEN
VARIABLE
REGIMEN
REGIMENt
B**
A**
N=624
N=159
N=175
N=641
% OF PRIMARY CABG
53.5%
32.7%*
37.1 %*
36.8%*
PATIENTS WHO
REQUIRED
DONOR BLOOD
UNITS OF
1 7 (2.4)
0.9 (1.6)*
1.0 (1.6)*
0.9 (1.4)*
DONOR BLOOD
TRANSFUSED
mLOF
584 (840)
286 (518)*
313 (505)*
295 (503)*
DONOR BLOOD
TRANSFUSED
PLATELETS
1.3 (3.7)
0.5 (2.4)*
0.3 (1.6)*
0.3 (1.5)*
TRANSFUSED
(Donor Units)
CR YOPRECIPIT ATE
0.5 (2.2)
0.0 (0.0)*
0.1 (0.8)*
0.0 (0.0)*
TRANSFUSED
(Donor Units)
FRESH FROZEN
0.6 (1.7)
0.2 (1 7)*
0.2 (0.8)*
0.2 (0.9)*
PLASMA TRANSFUSED
(Donor Units)
THORACIC DRAINAGE
87 (67)
51 (36)*
45 (31)*
39 (32)*
RATE (mL/hr)
TOTAL THORACIC
1232 (711)
852 (653)*
792 (465)*
705 (493)*
DRAAGE VOLUME (mL)
REOPERA TION FOR
1.4%
0.6%
0%
0%*
DIFFUSE BLEEDING
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t The pump prime regimen was evaluated in only one study in patients undergoing primary
CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p":0.05
(Transfusion variables analyzed via ANOV A on ranks)
* * Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and
safety are not statistically significant.
Additional subgroup analyses showed no diminution in benefit with increasing age. Male and
female patients benefited from Trasyloi(ß with a reduction in the average number of units of
donor blood transfused. Although male patients did better than female patients in terms of the
percentage of patients who required any donor blood transfusions, the number of female
patients studied was small.
A double-blind, randomized, Canadian study compared Trasyloi(j Regien A (n=28) and placebo
(n=23) in primar cardiac surgery patients (mainly CAB
G) requiring cardiopulmonar bypass who
were treated with aspirin within 48 hours of surgery. The mean total blood loss (1209.7 mL vs.
2532.3 mL) and the mean number of unts of packed red blood cells transfused (1.6 unts vs 4.3
unts) were signficantly less (p":0.008) in the Trasylol(ß group compared to the placebo group.
In a U.S. randomized study of Trasyloi(j Regimen A and Regimen B versus the placebo
regimen in 212 patients undergoing primary aortic and/or mitral valve replacement or repair,
no benefit was found for Trasyloi(j in terms of the need for transfusion or the number of units
uf ùlood required.
INDICATIONS AND USAGE
Trasyloi(j is indicated for prophylactic use to reduce perioperative blood loss and the need for
blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary
artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.
CONTRAINDICA TIONS
Hypersensitivity to aprotinin.
Administration of Trasyloi(j to patients with a known or suspected previous aprotmm
exposure during the last 12 months is contraindicated. For patients with known or suspected
history of exposure to aprotinin greater than 12 months previously, see WARNINGS.
Aprotinin may also be a component of some fibrin sealant products and the use of these
products should be included in the patient history.
WARNINGS
Anaphylactic or anaphylactoid reactions have occurred with Trasyloi(j administration,
including fatal reactions in association with the initial (test) dose. The initial (test) dose
does not fully predict a patient's risk for a hypersensitivity reaction, including a fatal
reaction. Fatal hypersensitivity reactions have occurred among patients who tolerated
an initial (test) dose.
Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with
hypotension the most frequently reported sign of the hypersensitivity reaction. The
hypersensitivity reaction can progress to anaphylactic shock with circulatory failure. If a
hypersensitivity reaction occurs during injection or infusion of Trasyloi(j, administration
should be stopped immediately and emergency treatment should be initiated. Even when a
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second exposure to aprotmm has been tolerated without symptoms, a subsequent
administration may result in severe hypersensitivity/anaphylactic reactions.
Trasyloi(j should be administered only in operative settings where cardiopulmonary bypass
can be rapidly initiated. Before initiating treatment with Trasyloi(j, the recommendations
below should be followed to manage a potential hypersensitivity or anaphylactic reaction: 1)
Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily
available in the operating room (e.g., epinephrine, corticosteroids). 2) Administration of the
initial (test) dose and loading dose should be done only when the patient is intubated and when
conditions for rapid canulation and initiation of cardiopulmonary bypass are present. 3) Delay
the addition of Trasyloi(j into the pump prime solution until after the loading dose has been
safely
administered.
Re-exposure to aprotinin: Administration of aprotinin, especially to patients who have
received aprotinin in the past, requires a careful risk/benefit assessment because an allergic
reaction may occur (see CONTRAINDICA TIONS). Although the majority of cases of
anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of
anaphylaxis occurring upon re-exposure after more than 12 months.
In a retrospective review of 387 European patient records with documented re-exposure to
Trasylol\I, the incidence of hypersensitivity/anaphylactic reactions was 2.7%. Two patients
who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and 5
days after Sl'rgery, respectively. The relationship of these 2 deaths to Trasyloi(( is unclear.
This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic
reaction following re-exposure is increased when the re-exposure occurs within 6 months of
the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposure
greater than 6 months). Other smaller studies have shown that in case of re-exposure, the
incidence of
hypersensitivity/anaphylactic reactions may reach the five percent leveL.
An analysis of all spontaneous reports from the Bayer Global database covering a period from
1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of
hypersensitivity (fatal: n=52 and non-fatal: n=239), 47% (138/291) of hypersensitivity cases
had documented previous exposure to Trasyloi(j. Ofthe 138 cases with documented previous
exposure, 110 had information on the time of the previous exposure. Ninety-nine of the 110
cases had previous exposure within the prior 12 months.
Renal Dysfunction: Trasyloi(j administration increases the risk for renal dysfunction and
may increase the need for dialysis in the perioperative period. This risk may be especially
increased for patients with pre-existing renal impairent or those who receive amno
glycoside
antibiotics or drugs that alter renal function. Data from Bayer's global pool of placebo-
controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery
showed that the incidence of serum creatinine elevations ::0.5 mg/dL above pre-treatment
levels was statistically higher at 9.0% (185/2047) in the high-dose aprotinin (Regimen A)
group compared with 6.6% (129/1957) in the placebo group. In the majority of instances,
post-operative renal dysfunction was not severe and was reversible. However, renal
dysfunction may progress to renal failure and the incidence of serum creatinine elevations
::2.0 mg/dL above baseline was slightly higher in the high-dose aprotinin group (1 1% vs.
0.8%). Careful consideration of
the balance of
benefits versus potential risks is advised before
admistering Trasyloi(j to patients with impaired renal fuction (creatinine clearance .. 60 mL/min)
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or those with other risk factors for renal dysfunction (such as peri
operative administration of
amno
glycoside or products that alter renal function). (See PRECAUTIONS and ADVERSE
REACTIONS: Laboratory Findings: Serum Creatinine.)
PRECAUTIONS
General: Inital (Test) Dose: All patients treated with Trasyloi(j should first receive an
initial (test) dose to minimize the extent of
Trasyloi(j exposure and to help assess the potential
for allergic reactions. Initiation of this initial (test) dose should occur only in operative
settings where cardiopulmonary bypass can be rapidly initiated. The initial (test) dose of 1 mL
Trasyloi(j should be administered intravenously at least 10 minutes prior to the loading dose
and the patient should be observed for manifestations of possible hypersensitivity reaction.
However, even after the uneventful administration of the 1 mL initial (test) dose, any
subsequent dose may cause an anaphylactic reaction. If this happens, the infusion of
Trasyloi(j should immediately be stopped and standard emergency treatment for anaphylaxis
applied. It should be noted that serious, even fatal, hypersensitivity/anaphylactic reactions can
also occur with administration of
the initial (test) dose (see WARNINGS).
Allemic Reactions: Patients with a history of allergic reactions to drugs or other agents may
be at greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to
Trasyloi(j. (see WARNINGS)
Loadinq Dose: The loading dose of Trasyloi(j should be given intravenously to patients in
the supine position over a 20-30 minute . Rapid intravenous administration of
TrasylolQj can cause a transient fall in blood pressure (see DOSAGE AND
ADMINISTRATION).
Renal Dvsfunction: Bayer's global pool of placebo-controlled studies in patients undergoing
CABG showed aprotinin administration was associated with elevations of serum creatinine
values? 0.5 mg/dL above baseline. Careful consideration ofthe balance of
benefits and risks
is advised before administering aprotinin to patients with pre-existing impaired renal function
or those with other risk factors for renal dysfunction. Serum creatinine should be monitored
regularly following Trasyloi(j administration (see WARNINGS: Renal Dysfunction).
Use of TrasvlofI in patients undemoinq deep hypothermic circulatory arrest: Two U.S.
case control studies have reported contradictory results in patients receiving TrasylolQj while
undergoing deep hypothermic circulatory arrest in connection with surgery of the aortic arch.
The first study showed an increase in both renal failure and mortality compared to age-
matched historical controls. Similar results were not observed, however, in a second case
control study. The strength of this association is uncertain because there are no data from
randomized studies to confirm or refute these findings.
Drug Interactions: Trasyloi(j is known to have antifibrinolytic activity and, therefore, may
inhibit the effects of fibrinolytic agents.
In study of nine patients with untreated hypertension, Trasyloi(j infused intravenously in a
dose of 2 million KIU over two hours blocked the acute hypotensive effect of 100mg of
captopriL.
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Trasyloi(j, in the presence of heparin, has been found to prolong the activated clotting time
(ACT) as measured by a celite surface activation method. The kaolin activated clotting time
appears to be
much less affected. However, Trasyloi(j should not be viewed as a heparin
sparing agent (see Laboratory Monitoring of Anticoagulation During
Cardiopulmonary Bypass).
Carcinogenesis, Mutagenesis, Impairment of Fertilty: Long-term animal studies to
evaluate the carcinogenic potential of
Trasyloi(j or studies to determine the effect of
TrasylolCI
on fertility have not been performed.
Results of microbial in vitro tests using Salmonella typhimurium and Bacilus subtils indicate
that Trasyloi(j is not a mutagen.
Pregnancy: Teratogenic Effects: Pregnancy Category B: Reproduction studies have
been performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in
rabbits at intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the
human dose on a mg/kg basis and 0.37 and 0.36 times the human mg/m2 dose. They have
revealed no evidence of impaired fertility or harm to the fetus due to Trasyloi(j. 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 Mother: Not applicable.
Pediatric Use: Safety and II pediatric patient(s) have not been established.
Geriatric Use: Of the total of 3083 subjects in clinical studies of TrasylolCI, 1100 (357
percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and
older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B.
No overall differences in safety or effectiveness were observed between these subjects and
younger subjects for either dose regimen, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients.
Laboratory Monitoring of Anticoagulation during Cardiopulmonary Bypass:
Trasyloi(j prolongs whole blood clotting times by a different mechanism than heparin. In the
presence of aprotinin, prolongation is dependent on the type of whole blood clotting test
employed. If an activated clotting time (ACT) is used to determine the effectiveness of
heparin anticoagulation, the prolongation of the ACT by aprotinin may lead to an
overestimation of the degree of anticoagulation, thereby leading to inadequate
anticoagulation. During extended extracorporeal circulation, patients may require additional
heparin, even in the presence of ACT levels that appear adequate.
In patients undergoing CPB with Trasyloi(j therapy, one of the following methods may be
employed to maintain adequate anticoagulation:
1) ACT - An ACT is not a standardized coagulation test, and different formulations of the
assay are affected differently by the presence of aprotinin. The test is further influenced by
variable dilution effects and the temperature experienced during cardiopulmonary bypass. It
has been observed that Kaolin-based ACTs are not increased to the same degree by aprotinin
as are diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite ACT
of 750 seconds or kaolin-ACT of 480 seconds, independent ofthe effects of
hemodilution and
hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the
ACT test regarding the interpretation of
the assay in the presence of
Trasyloi(j.
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2) Fixed Heparin Dosing - A standard loading dose of heparin, administered prior to
cannulation of the heart, plus the quantity of heparin added to the prime volume of the CPB
circuit, should total at least 350 IU/kg. Additional heparin should be administered in a fixed-
dose regimen based on patient weight and duration of CPB.
3) Heparin Titration - Protamine titration, a method that is not affected by aprotinin, can be
used to measure heparin levels. A heparin dose response, assessed by protamine titration,
should be performed prior to administration of aprotinin to determine the heparin loading
dose. Additional heparin should be administered on the basis of heparin levels measured by
protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7
U/mL (2.0 mg/kg) or below the level indicated by heparin dose response testing performed
prior to administration of aprotinin.
Protamine Administration - In patients treated with Trasyloi(j, the amount of protamine
administered to reverse heparin activity should be based on the actual amount of heparin
administered, and not on the ACT values.
ADVERSE REACTIONS
Studies of patients undergoing CABO surgery, either primary or repeat, indicate that
Trasyloi(j is generally well tolerated. The adverse events reported are frequent sequelae of
cardiac surgery and are not necessarily attributable to Trasyloi(j therapy. Adverse events
reported, up to the time of hospital discharge, from patients in US placebo-controlled trials
are listed in the following table. The table lists only those events that were reported in 2% or
more of the TrasylollI treated patients without regard to causal relationship.
INCIDENCE RATES OF ADVERSE EVENTS (:: = 2%) BY BODY SYSTEM AND TREATMENT
FOR ALL PATIENTS FROM US PLACEBO-CONTROLLED CLINICAL TRIALS
Aprotinin Placebo
(n = 2002) (n = 1084)
Adverse Event values in % values in %
Any Event
76
77
Body as a Whole
Fever
15
14
Infection
6
7
Chest Pain
2
2
Asthenia
2
2
Cardiovascular
Atrial Fibrilation
21
23
Hypotension
8
10
Myocardial Infarct
6
6
Atrial Flutter
6
5
Ventricular Extrasystoles
6
4
Tachycardia
6
7
Ventricular Tachycardia
5
4
Heart Failure
5
4
Pericarditis
5
5
Peripheral Edema
5
5
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Hypertension
4
5
Arrhythmia
4
3
Supraventricular Tachycardia
4
3
Atrial Arrhythmia
3
3
Digestive
Nausea
11
9
Constipation
4
5
Vomiting
3
4
Diarrhea
3
2
Liver Function Tests Abnormal
3
2
Hemic and Lymphatic
Anemia
2
8
Metabolic & Nutritional
Creatine Phosphokinase Increased
2
1
Musculoskeletal
Any Event
2
3
Nervous
Confusion
4
4
Insomnia
3
4
Respiratory
Lung Disorder
8
8
Pleural Effusion
7
9
Atelectasis
5
6
Dyspnea
4
4
Pneumothorax
4
4
Asthma
2
3
Hypoxia
2
1
Skin and Appendages
Rash
2
2
Urogenital
Kidney Function Abnormal
3
2
Urinary Retention
3
3
Urinary Tract Infection
2
2
In comparison to the placebo group, no increase in mortality in patients treated with Trasyloi(j
was observed. Additional events of particular interest from controlled US trials with an
incidence of less than 2%, are listed below:
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EVENT Percentage of patients Percentage of patients
treated with Trasylol(j treated with Placebo
N = 2002 N = 1084
Thrombosis 1.0 0.6
Shock 0.7 0.4
Cerebrovascular Accident 0.7 2.1
Thrombophlebitis 0.2 0.5
Deep Thrombophlebitis 0.7 1.0
Lung Edema 1.3 1.5
Pulmonary Embolus 0.3 0.6
Kidney Failure 1.0 0.6
Acute Kidney Failure 0.5 0.6
Kidney Tubular Necrosis 0.8 0.4
Listed below are additional events, from controlled US trials with an incidence between 1 and
2%, and also from uncontrolled, compassionate use trials and spontaneous post-marketing
reports. Estimates of frequency cannot be made for spontaneous post-marketing reports
(italicized) .
Body as a Whole: Sepsis, death, multi-system organ failure, immune system disorder,
hemoperitoneum.
Cardiovascular: Ventricular fibrilation, hcart arrcst, bradycardia, congestive heart
hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block,
pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.
Digestive: Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.
Hematologic and Lymphatic: Although thrombosis was not reported more frequently in
aprotinin versus placebo-treated patients in controlled trials, it has been reported in
uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting.
These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial
thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus,
thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other
hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder
(which includes disseminated intravascular coagulation), decreased prothrombin.
Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.
Musculoskeletal: Arthralgia.
Nervous: Agitation, dizziness, anxiety, convulsion.
Respiratory: Pneumonia, apnea, increased cough, lung edema.
Skin. Skin discoloration.
Urogenital: Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis.
Myocardial Infarction: In the pooled analysis of all patients undergoing CABO surgery,
there was no significant difference in the incidence of investigator-reported myocardial
infarction (MI) in Trasyloi(j treated patients as compared to placebo treated patients.
However, because no uniform criteria for the diagnosis of myocardial infàrction were utilized
by investigators, this issue was addressed prospectively in three later studies (two studies
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evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only
Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for
possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial
infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated
patients. This difference in the incidence rates was not statistically significant. Data from
these three studies are summarized below.
Incidence of Myocardial
Infarctions by Treatment Group Population.
All CABG Patients Valid for Safety Analysis
Treatment
Definite MI
Definite or Probable MI
Definite, Probable or Possible MI
%
%
%
Pooled Data from Three Studies that Evaluated Regimen A
Trasyloi(j
Regimen A
4.6
10.7
14.1
n = 646
Placebo
4.7
11.3
13.4
n = 661
Pooled Data from Two Studies that Evaluated Regimen 8 and Pump Prime Regimen
Trasyloi(j
Regimen B
8.7
15.9
18.7
n = 241
Trasyloi(j
Pump Prime
6.3
15.7
i 8. 1
Regimen
n = 239
Placebo
6.3
15.1
15.8
n = 240
Graft Patency: In a recently completed multi-center, multi-national study to determine the
effects of Trasyloi(j Regimen A vs. placebo on saphenous vein graft patency in patients
undergoing primary CABG surgery, patients were subjected to routine postoperative
angiography. Of the 13 study sites, 10 were in the United States and three were non-U:S.
centers (Denmark (1), Israel (2)). The results of
this study are summarized below.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Incidence of Graft Closure, Myocardial
Infarction and Death by Treatment Group
Overall Closure Rates*
Incidence of MI**
Incidence of Death***
All Centers
U.S. Centers
All Centers
All Centers
n = 703
n = 381
n = 831
n = 870
%
%
%
%
Trasyloi(j
15.4
9.4
2.9
1.4
Placebo
10.9
9.5
3.8
1.6
CI for the
Difference (%)
(Drug - Placebo)
(1.3,9.6)t
(-3.8,5.9)t
-3.3 to 1.5:1
1.9 to 1.4:1
* Population: all patients with assessable saphenous vein grafts
* * Population: all patients assessable by blinded consultant
* * * All patients
t 90%; per protocol
:I 95%; not specified in protocol
Although there was a statistically significantly increased risk of graft closure for TrasylolQD
treated patients compared to patients who received placebo (p=0.035), further analysis
showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S.
centers. When the analysis of graft closures was repeated for U.S. centers only, there was no
statistically significant difference in graft closure rates in patients who received Trasyloi(j vs.
placebo. These results are the same whether analyzed as the proportion of patients who
experienced at least one graft closure postoperatively or as the proportion of grafts closed.
There were no differences between treatment groups in the incidence of myocardial infarction
as evaluated by the blinded consultant (2.9% Trasyloi(j vs. 3.8% placebo) or of death (1.4%
Trasyloi(j vs. 1 .6% placebo) in this study.
Hypersensitivity and Anaphylaxis: See CONTRAINDICATIONS and WARNINGS.
Hypersensitivity and anaphylactic reactions during surgery were rarely reported in u.s.
controlled clinical studies in patients with no prior exposure to Trasyloi(j (1/1424 patients or
0:0.1 % on Trasyloi(j vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the
incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% leveL.
A review of 387 European patient records involving re-exposure to Trasyloi(j showed that the
incidence of hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6
months and 0.9% for re-exposure greater than 6 months.
Laboratory Findings
Serum Creatinine: Trasyloi(j administration is associated with a risk for renal dysfunction
(see WARNINGS: Renal Dysfunction).
Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S.
placebo-controlled trials showed no evidence of an increase in the incidence of postoperative
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hepatic dysfunction in patients treated with Trasyloi(j The incidence of treatment-emergent
increases in ALT (formerly SGPT)? 1.8 times the upper limit of
normal was 14% in both the
Trasyloi(j and placebo-treated patients (p=0.687), while the incidence of increases? 3 times
the upper limit of
normal was 5% in both groups (p=0.847).
Other Laboratory Findings: The incidence of treatment-emergent elevations in plasma
glucose, AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably
different between Trasyloi(j and placebo treated patients undergoing CABG surgery.
Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting
Time (celite ACT) are expected in Trasyloi(i treated patients in the hours after surgery due to
circulating concentrations of Trasyloi(j, which are known to inhibit activation of the intrinsic
clotting system by contact with a foreign material (e.g., celite), a method used in these tests
(see Laboratory Monitoring of Anticoagulation During Cardiopulmonary
Bypass).
OVERDOSAGE
The maximum amount of Trasyloi(j that can be safely administered in single or multiple
doses has not been determined. Doses up to 17.5 milion KIU have been administered within
a 24 hour period without any apparent toxicity. There is one poorly documented case,
however, of a patient who received a large, but not well determined, amount of Trasyloi(j (in
excess of 15 milion KIU) in 24 hours. The patient, who had pre-existing liver dysfunction,
developed hepatic and renal failure postoperatively and died. Autopsy showed hepatic
necrosis and extensive renal tubular and glomerular necrosis. The relationship of these
findings to Trasyloi(j therapy is unclear.
DOSAGE AND ADMINISTRATION
TrasyloltI given prophylactically in both Regimen A and Regimen B (half Regimen A) to
patients undergoing CABG surgery significantly reduced the donor blood transfusion
requirement relative to placebo treatment. In low risk patients there is no difference in
efficacy between regimen A and B. Therefore, the dosage used (A vs. B) is at the discretion
of the practitioner.
Trasyloi(j is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL.
All intravenous doses of Trasyloi(j should be administered through a central line. DO NOT
ADMINISTER ANY OTHER DRUG USING THE SAME LINE. Both regimens include
a 1 mL initial (test) dose, a loading dose, a dose to be added while recirculating the priming
fluid of the cardiopulmonary bypass circuit ("pump prime" dose), and a constant infusion
dose. To avoid physical incompatibility of Trasyloi(j and heparin when adding to the pump
prime solution, each agent must be added during recirculation of the pump prime to assure
adequate dilution prior to admixture with the other component. Regimens A and B, both
incorporating a 1 mL initial (test) dose, are described in the table below:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
INITIAL (TEST)
LOADING
"PUMP PRIME"
.CONST ANT
DOSE
DOSE
DOSE
INFUSION DOSE
TRASYLOL (j
1 rn
200 mL
200 rn
50 rn/h
REGIMN A
(1.4 mg, or
(280 mg, or
(280 mg, or
(70 mg/, or
10,000 Ki
2.0 millon KI)
2.0 millon Ki
500,000 KI/h)
TRASYLOL (j
1 rn
100 mL
100 rn
25 rn/h
REGIMN B
(1.4 mg, or
(140 mg, or
(140 mg, or
(35 mg/, or
10,000 KIU)
1.0 milion KIU)
1.0 milion KIU)
250,000 KIU/hr)
The 1 mL initial (test) dose should be administered intravenously at least 10 minutes before the
loading dose. With the patient in a supine position, the loading dose is given slowly over 20-30
minutes, after induction of anesthesia but prior to sternotomy. In patients with known previous
exposure to Trasyloi(j, the loading dose should be given just prior to cannulation. When the
loading dose is complete, it is followed by the constant infsion dose, which is continued until
surgery is complete and the patient leaves the operating room. The "pump prime" dose is added
to the recirculatin2 priming fluid of the cardiopulmonar bypass circuit, by replacement of an
aliquot of the priming fluid, prior to the institution of cardiopulmonary bypass. Total doses of
more than 7 milion KIU have not been studied in controlled trials.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior administration whenever solution and container permit. Discard any unused portion.
Renal and Hepatic Impairment: Trasyloi(j administration is associated with a risk for
renal dysfunction (see WARNINGS: Renal Dysfunction). Changes in aprotinin
pharmacokinetics with age or impaired renal function are not great enough to require any
dose adjustment. Pharmacokinetic data from patients with pre-existing hepatic disease treated
with Trasyloi(j are
not available.
HOW SUPPLIED
Strength
1,000,000 KIU
2,000,000 KIU
STORAGE
Trasyloi(j should be stored between 2° and 25°C (36° - 77°F).
Protect from freezing.
~j;~
r~
Size
100 mL vials
200 mL vials
NDC
0026-8196-36
0026-8197 -63
Bayer HealthCare
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Made in Germany
Rx Only
01298181 11/06 cg2006 Bayer Pharaceuticals Corporation 13116 Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020304s022lbl.pdf', 'application_number': 20304, 'submission_type': 'SUPPL ', 'submission_number': 22}
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20306_FLUDEOXYGLUCOSE_prntlbl.pdf', 'application_number': 20306, 'submission_type': 'SUPPL ', 'submission_number': 5}
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ORTHO-CEPT® TABLETS
(DESOGESTREL AND ETHINYL ESTRADIOL)
WARNING: 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-CEPT, 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
ORTHO-CEPT® Tablets provide an oral contraceptive regimen of 21 light orange round tablets
each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en
20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne
3,17,diol). Inactive ingredients include colloidal silicone dioxide, corn starch, ferric oxide,
hypromellose, lactose, polyethylene glycol, povidone, stearic acid, talc, titanium dioxide, and
vitamin E. Each green tablet contains the following inactive ingredients: FD&C Blue No.1
Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate, polyethylene glycol,
pregelatinized starch, talc and titanium dioxide. structural formula
CLINICAL PHARMACOLOGY
Pharmacodynamics
Combined oral contraceptives act by suppression of gonadotropins. Although the primary
mechanism of this action is inhibition of ovulation, other alterations include changes in the
Reference ID: 3854047
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For current labeling information, please visit https://www.fda.gov/drugsatfda
cervical mucus, which increase the difficulty of sperm entry into the uterus, and changes in the
endometrium which reduce the likelihood of implantation.
Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the
biologically active metabolite of desogestrel, combines high progestational activity with
minimal intrinsic androgenicity.91,92 The relevance of this latter finding in humans is unknown.
Pharmacokinetics
Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel,
its biologically active metabolite. Following oral administration, the relative bioavailability of
desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.
In the third cycle of use after a single dose of ORTHO-CEPT®, maximum concentrations of 3
keto-desogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are reached at 1.4 ± 0.8 hours. The area
under the curve (AUC0-∞) is 33,858 ± 11,043 pg/mL∙hr after a single dose. At steady state,
attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are
reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are
1,400 ± 560 pg/mL. The AUC0-24 at steady state is 52,299 ± 17,878 pg/mL∙hr. The mean
AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at
steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an
increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle,
attributed to increased sex hormone-binding globulin levels which are induced by the daily
administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly
in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).
The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state.
In addition to 3-keto-desogestrel, other phase I metabolites are 3α-OH-desogestrel,
3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to
have any pharmacologic effects, and are further converted in part by conjugation (phase II
metabolism) into polar metabolites, mainly sulfates and glucuronides.
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a
single dose of ORTHO-CEPT®, the relative bioavailability is approximately 83%.
In the third cycle of use after a single dose of ORTHO-CEPT®, maximum concentrations of
ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours. The AUC0-∞ is 1,471 ± 268
pg/mL∙hr after a single dose. At steady state, attained from at least day 19 onwards, maximum
ethinyl estradiol concentrations of 141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The
minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC0-24 at
steady state is 1,117 ± 302 pg/mL∙hr. The mean AUC0-∞ for ethinyl estradiol following a single
dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady
state. This finding indicates linear kinetics for ethinyl estradiol.
Reference ID: 3854047
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The elimination half-life is 26 ± 6.8 hours at steady state. Ethinyl estradiol is subject to a
significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping
gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II
metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl
estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites,
which are excreted in bile, can undergo enterohepatic circulation.
INDICATIONS AND USAGE
ORTHO-CEPT® Tablets are indicated for the prevention of pregnancy in women who elect to
use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for
users of combined 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 these methods can
result in lower failure rates.
In a clinical trial with ORTHO-CEPT®, 1,195 subjects completed 11,656 cycles and a total of
10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy)
pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the
drug correctly.
Table 1:
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 Year*
Method
Typical Use†
Perfect Use‡
(1)
(2)
(3)
(4)
Chance#
85
85
SpermicidesÞ
26
6
40
Periodic abstinence
25
63
Calendar
9
Ovulation Method
3
Sympto-Thermalß
2
Post-Ovulation
1
Withdrawal
19
4
Capà
Parous Women
40
26
42
Nulliparous Women
20
9
56
Sponge
Parous Women
40
20
42
Nulliparous Women
20
9
56
Diaphragmà
20
6
56
3
Reference ID: 3854047
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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
0.1
0.1
81
Depo-Provera
0.3
0.3
70
Norplant® and Norplant-2®
0.05
0.05
88
Female Sterilization
0.5
0.5
100
Male Sterilization
0.15
0.10
100
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of
pregnancy by at least 75%.§
Lactation 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, Kowel 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 FDA 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 4 yellow pills).
¶ However, to maintain effective protection against pregnancy, another method of contraception must be used as soon
as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the
baby reaches 6 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.
ß 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-CEPT® has not been studied for and is not indicated for use in emergency
contraception.
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the following conditions:
Thrombophlebitis or thromboembolic disorders
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For current labeling information, please visit https://www.fda.gov/drugsatfda
A past history of deep vein thrombophlebitis or thromboembolic disorders
Known thrombophilic conditions
Cerebral vascular or coronary artery disease (current or 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-CEPT, 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 formulations of higher doses of estrogens and
progestogens than those in common use today. The effect of long-term use of the oral
Reference ID: 3854047
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
contraceptives with formulations of lower doses 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 Disorder and Other Vascular Problems
a. 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 non-users 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
gradually disappears after combined oral contraceptive (COC) use is stopped.2 VTE risk is
highest in the first year of use and when restarting hormonal contraception after a break of four
weeks or longer.
Several epidemiologic studies indicate that third generation oral contraceptives, including those
containing desogestrel, are associated with a higher risk of venous thromboembolism than
certain second generation oral contraceptives. In general, these studies indicate an approximate
2-fold increased risk, which corresponds to an additional 1-2 cases of venous
thromboembolism per 10,000 women-years of use. However, data from additional studies have
not shown this 2-fold increase in risk.
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 breastfeed.
Reference ID: 3854047
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For current labeling information, please visit https://www.fda.gov/drugsatfda
b. 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 in women 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.)
Figure 1:.
Circulatory Disease Mortality Rates per 100,000 Women-Years by Age, Smoking Status and
Oral Contraceptive Use graph
(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.
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. Receptor binding and animal studies have shown that desogestrel or its
active metabolite has minimal androgenic activity (see CLINICAL PHARMACOLOGY),
although these findings have not been confirmed in adequate and well-controlled clinical trials.
Reference ID: 3854047
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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 nature and
absolute amount of progestogens used in the contraceptives. The 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 old 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 0.050 mg or higher of estrogens.
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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 2). 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 risk 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 2:
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 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
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.
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The risk of having breast cancer diagnosed may be slightly increased among current and recent
users of combined oral contraceptives (COC). 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 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.
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.
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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
concerned,55,56,58,59
reduction defects are
when oral contraceptives are 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 In
general, progestogens increase insulin secretion and create insulin resistance, this effect varying
with different progestational agents.17,66 In the nondiabetic woman, oral contraceptives appear
to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic
and diabetic women 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 1.a. and 1.d.), changes in serum triglycerides and
lipoprotein levels have been reported in oral contraceptive users.
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 and
concentrations of progestogens.
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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,69 and
there is no difference in the occurrence of hypertension among former and never users.68,70,71
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. Nonhormonal 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 pre-existent.
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,
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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 oral contraceptives, 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
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.
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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 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
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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.
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, 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 oral contraceptives but to use other forms of
contraception until she has completely weaned her child.
13. Pediatric Use
Safety and efficacy of ORTHO-CEPT® 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. 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.
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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
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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, and 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
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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 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 of 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
Effects from long-term use:
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
To achieve maximum contraceptive effectiveness, ORTHO-CEPT® must be taken exactly as
directed and at intervals not exceeding 24 hours. ORTHO-CEPT® is available in a blister card
with a tablet dispenser which is preset for a Sunday Start. Day 1 Start is also provided.
Day 1 Start
The dosage of ORTHO-CEPT® for the initial cycle of therapy is one light orange "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". Tablets are taken without interruption as follows:
One light orange "active" tablet daily for 21 days, then one green "reminder" tablet daily for 7
days. After 28 tablets have been taken, a new course is started and a light orange "active" tablet
is taken the next day.
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The use of ORTHO-CEPT® 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.) If the patient starts on ORTHO-CEPT®
postpartum, and has not yet had a period, she should be instructed to use another method of
contraception until a light orange "active" tablet has been taken daily for 7 days. The possibility
of ovulation and conception prior to initiation of medication should be considered. If the patient
misses one (1) light orange "active" tablet in Weeks 1, 2, or 3, the light orange "active" tablet
should be taken as soon as she remembers. If the patient misses two (2) light orange "active"
tablets in Week 1 or Week 2, the patient should take two (2) light orange "active" tablets the
day she remembers and two (2) light orange "active" tablets the next day; and then continue
taking one (1) light orange "active" 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) light orange
"active" tablets in the third week or misses three (3) or more light orange "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.
Sunday Start
When taking ORTHO-CEPT®, the first light orange "active" tablet should be taken on the first
Sunday after menstruation begins. If the period begins on Sunday, the first light orange "active"
tablet is taken on that day. If switching directly from another oral contraceptive, the first light
orange "active" tablet should be taken on the first Sunday after the last ACTIVE tablet of the
previous product. Tablets are taken without interruption as follows: One light orange "active"
tablet daily for 21 days, then one green "reminder" tablet daily for 7 days. After 28 tablets have
been taken, a new course is started and a light orange "active" tablet is taken the next day
(Sunday). When initiating a Sunday start regimen, another method of contraception should be
used until after the first 7 consecutive days of administration.
The use of ORTHO-CEPT® for contraception may be initiated 4 weeks postpartum. 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.) If the patient starts on ORTHO-CEPT® postpartum, and
has not yet had a period, she should be instructed to use another method of contraception until a
light orange "active" tablet has been taken daily for 7 days. The possibility of ovulation and
conception prior to initiation of medication should be considered. If the patient misses one (1)
light orange active tablet in Weeks 1, 2, or 3, the light orange "active" tablet should be taken as
soon as she remembers. If the patient misses two (2) light orange "active" tablets in Week 1 or
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Week 2, the patient should take two (2) light orange "active" tablets the day she remembers and
two (2) light orange "active" tablets the next day; and then continue taking one (1) light orange
"active" 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) light orange "active" tablets in the third
week or misses three (3) or more light orange "active" tablets in a row, the patient should
continue taking one light orange "active" 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.
ADDITIONAL INSTRUCTIONS FOR ALL DOSING REGIMENS
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.
HOW SUPPLIED
ORTHO-CEPT® Tablets are available in a blister card (NDC 50458-196-01) with a tablet
dispenser (unfilled). The blister card contains 28 tablets, as follows: 21 light orange, round,
convex, beveled edged, coated tablets imprinted "ORTHO" on one side and "D 150" on the
other side containing 0.15 mg desogestrel together with 0.03 mg ethinyl estradiol, and 7 green,
round, convex, beveled edged, coated tablets imprinted "ORTHO P" on both sides containing
inert ingredients. ORTHO-CEPT® Tablets are packaged in a carton (NDC 50458-196-15)
containing 6 blister cards and 6 unfilled tablet dispensers.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
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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 and Gynecol 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
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9. Vessey MP. Female hormones and vascular disease-an epidemiological overview. Br
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13. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors
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51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives.
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52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC.
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53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular
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55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980;
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56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives
analyzed in a national malformation register. Am J Obstet Gynecol 1981;
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57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J
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58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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61. Royal College of General Practitioners: Oral contraceptives and health. New York,
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62. Layde PM, Vessey MP, Yeates D. Risk of gall bladder disease: a cohort study of
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63. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO):
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64. Strom BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK.
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66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In
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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
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72. Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the
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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
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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
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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,
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81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F,
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82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral
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83. Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the Royal
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84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal
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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.
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Reference ID: 3854047
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BRIEF SUMMARY PATIENT PACKAGE INSERT
ORTHO-CEPT® (desogestrel and ethinyl estradiol) Tablets
This product (like all oral contraceptives) is intended to prevent pregnancy. It 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, and when taken correctly without missing any pills, have a failure rate of
approximately 1% per year. The typical failure rate is approximately 5% per year 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.
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 life-threatening 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.
Do not use ORTHO-CEPT® 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 such effects are nausea,
vomiting, bleeding between menstrual periods, weight gain, breast tenderness, headache, 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:
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1. Blood clots in the legs (thrombophlebitis) or 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 patient
labeling 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.
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 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
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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.
The detailed patient information labeling gives you further information which you should read
and discuss with your healthcare professional.
This product (like all oral contraceptives) is intended to prevent pregnancy. It does 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, 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.
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.
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It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK:
The pill pack has 21 light orange "active" pills (with hormones) to take for 3 weeks,
followed by 1 week of green "reminder" pills (without hormones).
3. ALSO FIND:
1)
where on the pack to start taking pills,
2) in what order to take the pills,
3) check picture of pill pack and additional instructions for using this package
below.
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-CEPT® is
available in a blister card with a 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.
DAY 1 START:
1. Take the first light orange "active" pill of the first pack during the first 24 hours of your
period.
2. 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.
SUNDAY START:
1. Take the first light orange "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.
2. 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).
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS
EMPTY.
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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 green "reminder" pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 light orange "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 light orange "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 light orange "active" pills in a row in THE 3RD WEEK:
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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 light orange "active" pills in a row (during the first 3 weeks):
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter:
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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.
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 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 LIGHT ORANGE "ACTIVE" PILL EACH DAY until you can reach
your healthcare professional.
INSTRUCTIONS FOR USE
1. Open the compact. Place the blister into the compact, with the tablets facing up, so that
the V notch in the blister card matches up with the V shaped post at the top of the
compact. Press down firmly on each edge of the blister card and make sure that the
edge of the blister card is firmly seated under each of the nibs inside the compact (see
picture).
There are 21 light orange “active” pills and 7 green “reminder” pills.
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2. If you are to start pill-taking on Sunday, take your first light orange pill on the first
Sunday after your menstrual period begins. If your period begins on Sunday, take your
first pill that day. Remove the first pill at the top of the dispenser (Sunday) by pressing
the pill through the hole in the bottom of the dispenser.
3. If you are to start pill-taking on “Day 1”, choose a light orange pill that corresponds with
the day of the week on which you are taking the first pill. Remove that light orange pill
by pressing the pill through the hole in the bottom of the dispenser.
4. Continue taking one pill daily, clockwise, until no pills remain in the outer ring.
5. The next day take the green pill from the inner ring that corresponds with the day of the
week it happens to be. Take a green pill each day until all seven pills are taken. During
this time your period should begin.
6. After you have taken all the green pills, begin a new blister card (see Step 1 above in
“Instructions for Use”) and take the first light orange “active” pill on the next day, even
if your period is not yet over.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
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DETAILED PATIENT LABELING
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not
protect against HIV infection (AIDS) and other sexually transmitted diseases.
PLEASE NOTE: This labeling is revised from time to time as important new medical
information becomes available. Therefore, please review this labeling carefully.
The following oral contraceptive product contains a combination of a progestogen and
estrogen, the two kinds of female hormones:
ORTHO-CEPT® (desogestrel and ethinyl estradiol) Tablets
Each light orange tablet contains 0.15 mg desogestrel and 0.03 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
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% (1
pregnancy per 100 women per year of use). Typical failure rates, including women who do not
always take the pills exactly as directed, are approximately 5% per year. The chance of
becoming pregnant increases with each missed pill during a menstrual cycle.
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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%
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Do not use ORTHO-CEPT® 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
Liver tumor (benign or cancerous)
Known or suspected pregnancy
If you plan to have surgery with prolonged bed rest
Tell your healthcare professional if you have ever had any of these conditions. Your healthcare
professional can recommend another method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have or have had:
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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. 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
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. The risks of these side
effects may be greater with desogestrel-containing oral contraceptives, such as
ORTHO-CEPT®, than with certain other low-dose pills. 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 three
to 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.)
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The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose
pills. The risk of venous thromboembolic disease associated with oral contraceptives does not
increase with length of use and disappears after pill use is stopped. 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.
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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 pills 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 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
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 (7-26 deaths per 100,000 women, depending
on age). Among pill users who do not smoke, the risk of death is always lower than that
associated with pregnancy for any age group, although over the age of 40, the risk increases to
32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. 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
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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
1. 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.
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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 before
doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you
may be pregnant. 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 oral contraceptives if pregnancy is confirmed.
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, oral contraceptives may decrease the amount and quality of your
milk. If possible, do not use 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
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of time. You should consider starting 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-CEPT® less effective.
Some medicines and grapefruit juice may increase your level of the hormone ethinyl estradiol if
used together, including:
acetaminophen
ascorbic acid
medicines that affect how your liver breaks down other medicines (itraconazole,
ketoconazole, voriconazole, and fluconazole)
certain HIV medicines (atazanavir, indinavir)
atorvastatin
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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
This product (like all oral contraceptives) is intended to prevent pregnancy. It does 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, 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.
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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 light orange "active" pills (with hormones) to take for 3 weeks,
followed by 1 week of green "reminder" pills (without hormones).
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.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO-CEPT® is
available in a blister card with a 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.
DAY 1 START:
1. Take the first light orange "active" pill of the first pack during the first 24 hours of your
period.
2. 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.
SUNDAY START:
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1. Take the first light orange "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.
2. 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).
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 green "reminder" pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 light orange "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 light orange "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 light orange "active" pills in a row in THE 3RD WEEK:
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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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 light orange "active" pills in a row (during the first 3 weeks):
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
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.
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 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 LIGHT ORANGE "ACTIVE" PILL EACH DAY until you can
reach your healthcare professional.
PREGNANCY DUE TO PILL FAILURE
When taken correctly without missing any pills, oral contraceptives are highly effective;
however the typical failure rate of large numbers of pill users is 5% per year when women who
miss pills are included. If failure does occur, the risk to the fetus is minimal.
Reference ID: 3854047
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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.
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 combined 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: 3854047
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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.
STORAGE: Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).
Keep out of reach of children.
Product of The Netherlands
Jointly Manufactured by
Janssen Ortho, LLC
Manati, Puerto Rico 00674 and
NV Organon
Oss, The Netherlands
Manufactured for
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised November 2015
Reference ID: 3854047
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:25.888248
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020301s036lbl.pdf', 'application_number': 20301, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
12,438
|
univasc® tablets
(moexipril hydrochloride)
Rx only
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
•
When pregnancy is detected, discontinue univasc® 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
univasc® (moexipril hydrochloride), the hydrochloride salt of moexipril, has the empirical
formula C27H34N2O7•HCl and a molecular weight of 535.04. It is chemically described as [3S
[2[R*(R*)],3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4
tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, monohydrochloride. It is a non
sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor
moexiprilat and its structural formula is: structural formula
Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to
volume) in distilled water at room temperature.
univasc® is supplied as scored, coated tablets containing 7.5 mg and 15 mg of moexipril
hydrochloride for oral administration. In addition to the active ingredient, moexipril
hydrochloride, the tablet core contains the following inactive ingredients: lactose, magnesium
oxide, crospovidone, magnesium stearate and gelatin. The film coating contains hydroxypropyl
cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate, titanium dioxide, and
ferric oxide.
Reference ID: 3189130
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Mechanism of Action
Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and
animals. The mechanism through which moexiprilat lowers blood pressure is believed to be
primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion
of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II.
Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by
the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to
kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator.
Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II.
Inhibition of ACE results in decreased angiotensin II formation, leading to decreased
vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The
latter results in diuresis and natriuresis and a small increase in serum potassium concentration
(mean increases of about 0.25 mEq/L were seen when moexipril was used alone, see
PRECAUTIONS).
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the
therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of
moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone
system, ACE inhibitors have some effect on blood pressure even in apparent low-renin
hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of
moexipril is considerably smaller in black patients, a predominantly low-renin population, than
in non-black hypertensive patients.
Pharmacokinetics and Metabolism
Pharmacokinetics: Moexipril’s antihypertensive activity is almost entirely due to its
deesterified metabolite, moexiprilat. Bioavailability of oral moexipril is about 13% compared to
intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly
affected by food, which reduces the peak plasma level (Cmax) and AUC (see Absorption).
Moexipril should therefore be taken in a fasting state. The time of peak plasma concentration
(Tmax) of moexiprilat is about 1½ hours and elimination half-life (t½) is estimated at 2 to 9 hours
in various studies, the variability reflecting a complex elimination pattern that is not simply
exponential. Like all ACE inhibitors, moexiprilat has a prolonged terminal elimination phase,
presumably reflecting slow release of drug bound to the ACE. Accumulation of moexiprilat with
repeated dosing is minimal, about 30%, compatible with a functional elimination t½ of about
12 hours. Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose
proportional.
Absorption: Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about
13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC by
about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50%
respectively after the ingestion of a high-fat breakfast.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Distribution: The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min
with a t½ of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The
volume of distribution of moexiprilat is about 183 liters.
Metabolism and Excretion: Moexipril is relatively rapidly converted to its active metabolite
moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t½ is over
one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to
diketopiperazine derivatives and unidentified metabolites. After I.V. administration of
moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with
small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as
moexiprilat. After oral administration, only about 7% of the dose appears in urine as
moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of
the dose is recovered in feces as moexiprilat and 1% as moexipril.
Special Populations:
Decreased Renal Function: The effective elimination t½ and AUC of both moexipril and
moexiprilat are increased with decreasing renal function. There is insufficient information
available to characterize this relationship fully, but at creatinine clearances in the range of 10 to
40 mL/min, the t½ of moexiprilat is increased by a factor of 3 to 4.
Decreased Hepatic Function: In patients with mild to moderate cirrhosis given single 15 mg
doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by
about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased
by almost 300%.
Elderly Patients: In elderly male subjects (65-80 years old) with clinically normal renal and
hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger
subjects (19-42 years old).
Pharmacokinetic Interactions With Other Drugs:
No clinically important pharmacokinetic interactions occurred when univasc® was administered
concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
Pharmacodynamics and Clinical Effect
Single and multiple doses of 15 mg or more of univasc® gives sustained inhibition of plasma
ACE activity of 80-90%, beginning within 2 hours and lasting 24 hours (80%).
In controlled trials, the peak effects of orally administered moexipril increased with the dose
administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were
first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing.
Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to
dose and the antihypertensive effect tended to diminish during the 24-hour dosing interval when
the drug was administered once a day.
Reference ID: 3189130
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In multiple dose studies in the dose range of 7.5 to 30 mg once daily, univasc® lowered sitting
diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more
than placebo, respectively. There was a tendency toward increased response with higher doses
over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of
adequate size comparing moexipril with other antihypertensive agents.
The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in
various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood
pressure effect still present at trough. During dose titration, any decision as to the adequacy of a
dosing regimen should be based on trough blood pressure measurements. If diastolic blood
pressure control is not adequate at the end of the dosing interval, the dose can be increased or
given as a divided (BID) regimen.
During chronic therapy, the antihypertensive effect of any dose of univasc® is generally evident
within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects
of univasc® have been proven to continue during therapy for up to 24 months.
univasc®, like other ACE inhibitors, is less effective in decreasing trough blood pressures in
blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects
in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in
non-blacks of -4 to -6 mmHg.
The effectiveness of univasc® was not significantly influenced by patient age, gender, or weight.
univasc® has been shown to have antihypertensive activity in both pre- and postmenopausal
women who have participated in placebo-controlled clinical trials.
Formal interaction studies with moexipril have not been carried out with antihypertensive agents
other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its
effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta
adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.
INDICATIONS AND USAGE
univasc® is indicated for treatment of patients with hypertension. It may be used alone or in
combination with thiazide diuretics.
In using univasc®, consideration should be given to the fact that another ACE inhibitor,
captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-
vascular disease. Available data are insufficient to show that univasc® does not have a similar
risk (see WARNINGS).
In considering use of univasc®, it should be noted that in controlled trials ACE inhibitors have an
effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE
inhibitors (for which adequate data are available) cause a higher rate of angioedema in black
than in non-black patients (see WARNINGS, Angioedema).
Reference ID: 3189130
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
univasc® is contraindicated in patients who are hypersensitive to this product and in patients with
a history of angioedema related to previous treatment with an ACE inhibitor.
Do not co-administer aliskiren with Univasc in patients with diabetes (see PRECAUTIONS,
Drug Interactions).
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 univasc®, may be subject to a variety of adverse reactions, some of them
serious.
Head and Neck Angioedema: Angioedema involving the face, extremities, lips, tongue,
glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including
univasc®. Symptoms suggestive of angioedema or facial edema occurred in <0.5% of moexipril
treated patients in placebo-controlled trials. None of the cases were considered life-threatening
and all resolved either without treatment or with medication (antihistamines or glucocorticoids).
One patient treated with hydrochlorothiazide alone experienced laryngeal edema. No instances
of angioedema were reported in placebo-treated patients.
In cases of angioedema, treatment should be promptly discontinued and the patient carefully
observed until the swelling disappears. 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 involvement of the tongue, glottis, or larynx, may be fatal due
to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution
1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly
provided (see ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors
were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently
readministered.
Reference ID: 3189130
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hypotension
univasc® can cause symptomatic hypotension, although, as with other ACE inhibitors, this is
unusual in uncomplicated hypertensive patients treated with univasc® alone. Symptomatic
hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy
in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been
salt- and volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction,
dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general,
diuretics stopped, before initiating therapy with univasc® (see PRECAUTIONS, Drug
Interactions, and ADVERSE REACTIONS).
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or
progressive azotemia, and rarely, with acute renal failure and death. In these patients, univasc®
therapy should be started under close medical supervision, and patients should be followed
closely for the first two weeks of treatment and whenever the dose of moexipril or an
accompanying diuretic is increased. Care in avoiding hypotension should also be taken in
patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an
excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated
with an intravenous infusion of normal saline. univasc® treatment usually can be continued
following restoration of blood pressure and volume.
Neutropenia/Agranulocytosis
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow
depression, rarely in patients with uncomplicated hypertension, but more frequently in
hypertensive patients with renal impairment, especially if they also have a collagen-vascular
disease such as systemic lupus erythematosus or scleroderma. Although there were no instances
of severe neutropenia (absolute neutrophil count <500/mm3) among patients given univasc®, as
with other ACE inhibitors, monitoring of white blood cell counts should be considered for
patients who have collagen-vascular disease, especially if the disease is associated with impaired
renal function. Available data from clinical trials of univasc® are insufficient to show that
univasc® does not cause agranulocytosis at rates similar to captopril.
Reference ID: 3189130
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 univasc® as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third
trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure 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 to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue univasc®, 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
univasc® for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to
90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a
mg/m2 basis.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibition of the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. There is no
clinical experience of univasc® in the treatment of hypertension in patients with renal failure.
Some hypertensive patients with no apparent preexisting renal vascular disease have developed
increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially
when univasc® has been given concomitantly with a thiazide diuretic. This is more likely to
occur in patients with preexisting renal impairment. There may be a need for dose adjustment of
univasc® and/or the discontinuation of the thiazide diuretic.
Reference ID: 3189130
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Evaluation of hypertensive patients should always include assessment of renal function (see
DOSAGE AND ADMINISTRATION).
Hypertensive Patients With Congestive Heart Failure: In hypertensive patients with severe
congestive heart failure, whose renal function may depend on the activity of the renin
angiotensin-aldosterone system, treatment with ACE inhibitors, including univasc®, may be
associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death.
Hypertensive Patients With Renal Artery Stenosis: In hypertensive patients with unilateral
or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been
observed in some patients following ACE inhibitor therapy. These increases were almost always
reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients,
renal function should be monitored during the first few weeks of therapy.
Hyperkalemia: In clinical trials, persistent hyperkalemia (serum potassium above 5.4 mEq/L)
occurred in approximately 1.3% of hypertensive patients receiving univasc®. Risk factors for the
development of hyperkalemia with ACE inhibitors include renal insufficiency, diabetes mellitus,
and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or
potassium-containing salt substitutes, which should be used cautiously, if at all, with univasc®
(see PRECAUTIONS, Drug Interactions).
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents
that produce hypotension, moexipril may block the effects of compensatory renin release. If
hypotension occurs in this setting and is considered to be due to this mechanism, it can be
corrected by volume expansion.
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. In controlled trials with moexipril, cough was present in 6.1% of
moexipril patients and 2.2% of patients given placebo.
Information for Patients
Food: Patients should be advised to take moexipril one hour before meals (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Angioedema: Angioedema, including laryngeal edema, may occur with treatment with ACE
inhibitors, usually occurring early in therapy (within the first month). Patients should be so
advised and told to report immediately any signs or symptoms suggesting angioedema (swelling
of the face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more univasc®
until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur with
univasc®, especially during the first few days of therapy. If fainting occurs, the patient should
stop taking univasc® and consult the prescribing physician.
Reference ID: 3189130
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 their physician if they develop these conditions.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore
throat, fever) that could be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to univasc® 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
Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy
when ACE inhibitors are started. The possibility of hypotensive effects with univasc® can be
minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake
before initiation of treatment with univasc®. If this is not possible, the starting dose of moexipril
should be reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION).
Potassium Supplements and Potassium-Sparing Diuretics: univasc® can increase serum
potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics
(spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE
inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is
indicated, they should be given with caution and the patient’s serum potassium should be
monitored.
Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically
important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. These drugs should be
coadministered with caution, and frequent monitoring of serum lithium levels is recommended.
If a diuretic is also used, the risk of lithium toxicity may be increased.
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 univasc®.
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
Reference ID: 3189130
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
COX-2 inhibitors, with ACE inhibitors, including moexipril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving moexipril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including moexipril, may be attenuated by
NSAIDS.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with
angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of
hypotension, hyperkalemia, and changes in renal function (including acute renal failure)
compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in
patients on univasc® and other agents that affect the RAS.
Do not co-administer aliskiren with univasc® in patients with diabetes. Avoid use of aliskiren
with univasc® in patients with renal impairment (GFR <60 mL/min).
Other Agents: No clinically important pharmacokinetic interactions occurred when univasc®
was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
univasc® has been used in clinical trials concomitantly with calcium-channel-blocking agents,
diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents.
There was no evidence of clinically important adverse interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to
14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis.
No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and
without metabolic activation, or in an in vivo nucleus anomaly test. However, increased
chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic
activation conditions at a 20-hour harvest time.
Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on
a mg/m2 basis, and in rats up to 90.9 times the MRHD on a mg/m2 basis. No indication of
impaired fertility, reproductive toxicity, or teratogenicity was observed.
Nursing Mothers
It is not known whether univasc® is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when univasc® is given to a nursing mother.
Pediatric Use
Neonates with a history of in utero exposure to univasc®:
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.
Reference ID: 3189130
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Safety and effectiveness of univasc® in pediatric patients have not been established.
Geriatric Use
Clinical studies of univasc® 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
univasc® has been evaluated for safety in more than 2500 patients with hypertension; more than
250 of these patients were treated for approximately one year. The overall incidence of reported
adverse events was only slightly greater in patients treated with univasc® than patients treated
with placebo.
Reported adverse experiences were usually mild and transient, and there were no differences in
adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage
within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse
experiences was required in 3.4% of patients treated with univasc® and in 1.8% of patients
treated with placebo. The most common reasons for discontinuation in patients treated with
univasc® were cough (0.7%) and dizziness (0.4%).
All adverse experiences considered at least possibly related to treatment that occurred at any
dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with
univasc® alone and that were at least as frequent in the univasc® group as in the placebo group
are shown in the following table:
ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES
ADVERSE
EVENT
UNIVASC
(N=674)
PLACEBO
(N=226)
N
(%)
N
(%)
Cough Increased
41 (6.1)
5 (2.2)
Dizziness
29 (4.3)
5 (2.2)
Diarrhea
21 (3.1)
5 (2.2)
Flu Syndrome
21 (3.1)
0 (0)
Fatigue
16 (2.4)
4 (1.8)
Pharyngitis
12 (1.8)
2 (0.9)
Flushing
11 (1.6)
0 (0)
Rash
11 (1.6)
2 (0.9)
Myalgia
9 (1.3)
0 (0)
Other adverse events occurring in more than 1% of patients on moexipril that were at least as
frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia,
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nausea, peripheral edema, sinusitis, chest pain, and urinary frequency. See WARNINGS and
PRECAUTIONS for discussion of anaphylactoid reactions, angioedema, hypotension,
neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality,
hyperkalemia, and cough.
Other potentially important adverse experiences reported in controlled or uncontrolled clinical
trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors
include the following:
Cardiovascular: Symptomatic hypotension, postural hypotension, or syncope were seen in
9/1750 (0.51%) patients; these reactions led to discontinuation of therapy in controlled trials in
3/1254 (0.24%) patients who had received univasc® monotherapy and in 1/344 (0.3%) patients
who had received univasc® with hydrochlorothiazide (see PRECAUTIONS and WARNINGS).
Other adverse events included angina/myocardial infarction, palpitations, rhythm disturbances,
and cerebrovascular accident.
Renal: Of hypertensive patients with no apparent preexisting renal disease, 1% of patients
receiving univasc® alone and 2% of patients receiving univasc® with hydrochlorothiazide
experienced increases in serum creatinine to at least 140% of their baseline values (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Gastrointestinal: Abdominal pain, constipation, vomiting, appetite/weight change, dry
mouth, pancreatitis, hepatitis.
Respiratory: Bronchospasm, dyspnea, eosinophilic pneumonitis.
Urogenital: Renal insufficiency, oliguria.
Dermatologic: Apparent hypersensitivity reactions manifested by urticaria, rash, pemphigus,
pruritus, photosensitivity, alopecia.
Neurological and Psychiatric: Drowsiness, sleep disturbances, nervousness, mood changes,
anxiety.
Other: Angioedema (see WARNINGS), taste disturbances, tinnitus, sweating, malaise,
arthralgia, hemolytic anemia.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine and Blood Urea Nitrogen: As with other ACE inhibitors, minor increases in blood
urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in
approximately 1% of patients with essential hypertension who were treated with univasc®.
Increases are more likely to occur in patients receiving concomitant diuretics and in patients with
compromised renal function (see PRECAUTIONS, General).
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Other (causal relationship unknown): Clinically important changes in standard laboratory
tests were rarely associated with univasc® administration.
Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of
moexipril-treated patients discontinued univasc® treatment because of laboratory abnormalities.
The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-
treated group.
OVERDOSAGE
Human overdoses of moexipril have not been reported. In case reports of overdoses with other
ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of
2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated
single oral doses of up to 3 g/kg.
No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH
of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of
moexipril is not known.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities.
Because the hypotensive effect of moexipril is achieved through vasodilation and effective
hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution.
In addition, renal function and serum potassium should be monitored.
DOSAGE AND ADMINISTRATION
Hypertension
The recommended initial dose of univasc® in patients not receiving diuretics is 7.5 mg, one hour
prior to meals, once daily. Dosage should be adjusted according to blood pressure response.
The antihypertensive effect of univasc® may diminish towards the end of the dosing interval.
Blood pressure should, therefore, be measured just prior to dosing to determine whether
satisfactory blood pressure control is obtained. If control is not adequate, increased dose or
divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in
one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not
been studied in hypertensive patients.
In patients who are currently being treated with a diuretic, symptomatic hypotension may
occasionally occur following the initial dose of univasc®. The diuretic should, if possible, be
discontinued for 2 to 3 days before therapy with univasc® is begun, to reduce the likelihood of
hypotension (see WARNINGS). If the patient’s blood pressure is not controlled with univasc®
alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an
initial dose of 3.75 mg of univasc® should be used with medical supervision until blood pressure
has stabilized (see WARNINGS and PRECAUTIONS, Drug Interactions).
Dosage Adjustment in Renal Impairment
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For patients with a creatinine clearance ≤40 mL/min/1.73 m2, an initial dose of 3.75 mg once
daily should be given cautiously. Doses may be titrated upward to a maximum daily dose of
15 mg.
HOW SUPPLIED
univasc® (moexipril hydrochloride) 7.5 mg tablets are pink colored, biconvex, film-coated and
scored with engraved code 707 on the unscored side and SP above and 7.5 below the score.
They are supplied as follows:
Bottles of 90 (Unit-of-Use)
NDC 0091-3707-09
Bottles of 100
NDC 0091-3707-01
univasc® (moexipril hydrochloride) 15 mg tablets are salmon colored, biconvex, film-coated,
and scored with engraved code 715 on the unscored side and SP above and 15 below the score.
They are supplied as follows:
Bottles of 90 (Unit-of-Use)
NDC 0091-3715-09
Bottles of 100
NDC 0091-3715-01
Store, tightly closed, at controlled room temperature 20° to 25°C (68° to 77°F). Protect from
excessive moisture.
If product package is subdivided, dispense in tight containers as described in USP-NF.
Manufactured for:
UCB, Inc.
Smyrna, GA 30080
Rev. 5E xx/2012
Reference ID: 3189130
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020312s035lbl.pdf', 'application_number': 20312, 'submission_type': 'SUPPL ', 'submission_number': 35}
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DOCUMENT INFORMATION PAGE
DARRTS COMMUNICATION
This page is for FDA internal use only. Do NOT send this page with the letter.
Application #(s):
NDA 20312/S-031
CommunicationType:
Correspondence
Communication Group:
sNDA Action
Communication Name: Approval
Communication ID:
COR-SNDAACTION-05
Drafted by:
MEP-F, 01.04.2009
Clearance History by:
M. Monteleone, 01.04.2010; E. Fromm, 01.05.2010; N. Xu, 01.04.2010; T.
Marciniak, 01.05.2010; N. Stockbridge, 01.05.2010; MR Southworth, 01.05.2010
Finalized:
January 12, 2010
Filename:
Notes:
INSTRUCTION TO PM:
USE THIS LETTER (COR-SNDAACTION-05) FOR EFFICACY SUPPLEMENT
AND NON-FDAAA LABELING SUPPLEMENT APPROVALS ONLY.
USE COR-SNDAACTION-06 FOR sNDA CMC APPROVALS
USE COR-SNDAACTION-09 FOR sNDA TENTATIVE APPROVALS
USE COR-SNDAACTION-XX FOR sNDA FDAAA SAFETY LABELING
CHANGES (Note: This letter is still under creation.)
Version: DARRTS 8/25/09, v.2
END OF DOCUMENT INFORMATION PAGE
The letter begins on the next page.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring MD 20993
NDA 20312/S-031
SUPPLEMENT APPROVAL
Schwarz Pharma
Attention: Donna Multhauf
Director, Regulatory Affairs
P.O. Box 2038
Milwaukee, WI 53201
Dear Ms. Multhauf:
Please refer to your supplemental new drug application dated 15 September 2009, submitted
under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Univasc
(moexipril hydrochloride) 7.5 and 15 mg Tablets.
This “Changes Being Effected” supplemental new drug application provides for revisions to the
PRECAUTIONS, Drug Interactions section of the package insert in response to our letter dated
March 8, 2008. As requested, you made the following change:
Under PRECAUTIONS, Drug Interactions, the following new subsection was added:
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 Univasc.
We have completed our review of this application. It is approved, effective on the date of this
letter, for use as recommended in the enclosed, agreed upon labeling text, which is identical to
the content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format
submitted on 15 September 2009.
LETTERS TO HEALTH CARE PROFESSIONALS
If you issue a letter communicating important safety related information about this drug product
(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
the letter to both this NDA and to the following address:
MedWatch
Food and Drug Administration
5600 Fishers Lane, Room 12B05
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NDA 20312/S-031
Page 2
Rockville, MD 20857
REPORTING REQUIREMENTS
We remind you that you must comply with reporting requirements for an approved NDA
(21 CFR 314.80 and 314.81).
If you have any questions, please call:
Michael Monteleone, MS
Regulatory Project Manager
(301) 796-1952
Sincerely,
{See appended electronic signature page}
Mary Ross Southworth, Pharm. D.
Deputy Director for Safety
Office of Drug Evaluation I
Center for Drug Evaluation and Research
Cc:
UCB, Incorporated
Attention: Kimberly Christopher
Director, US Marketed Products
1950 Lake Park Drive
Smyrna, GA, 30080
Enclosure
Approved labeling text
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20312/S-031
Page 3
Univasc tablets
(moexipril hydrochloride)
Rx only
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, Univasc should
be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
DESCRIPTION
Univasc (moexipril hydrochloride), the hydrochloride salt of moexipril, has the empirical
formula C27H34N2O7•HCl and a molecular weight of 535.04. It is chemically described as [3S-
[2[R*(R*)],3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-
tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, monohydrochloride. It is a non-
sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor
moexiprilat and its structural formula is:
Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to-
volume) in distilled water at room temperature.
Univasc is supplied as scored, coated tablets containing 7.5 mg and 15 mg of moexipril
hydrochloride for oral administration. In addition to the active ingredient, moexipril
hydrochloride, the tablet core contains the following inactive ingredients: lactose, magnesium
oxide, crospovidone, magnesium stearate and gelatin. The film coating contains hydroxypropyl
cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate, titanium dioxide, and
ferric oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and
animals. The mechanism through which moexiprilat lowers blood pressure is believed to be
primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion
of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II.
Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by
the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to
kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator.
Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II.
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NDA 20312/S-031
Page 4
Inhibition of ACE results in decreased angiotensin II formation, leading to decreased
vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter
results in diuresis and natriuresis and a small increase in serum potassium concentration (mean
increases of about 0.25 mEq/L were seen when moexipril was used alone, see PRECAUTIONS).
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the
therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of
moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone
system, ACE inhibitors have some effect on blood pressure even in apparent low-renin
hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of
moexipril is considerably smaller in black patients, a predominantly low-renin population, than
in non-black hypertensive patients.
Pharmacokinetics and Metabolism
Pharmacokinetics: Moexipril’s antihypertensive activity is almost entirely due to its deesterified
metabolite, moexiprilat. Bioavailability of oral moexipril is about 13% compared to intravenous
(I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly affected by food,
which reduces the peak plasma level (Cmax) and AUC (see Absorption). Moexipril should
therefore be taken in a fasting state. The time of peak plasma concentration (Tmax) of moexiprilat
is about 1½ hours and elimination half-life (t½) is estimated at 2 to 9 hours in various studies, the
variability reflecting a complex elimination pattern that is not simply exponential. Like all ACE
inhibitors, moexiprilat has a prolonged terminal elimination phase, presumably reflecting slow
release of drug bound to the ACE. Accumulation of moexiprilat with repeated dosing is
minimal, about 30%, compatible with a functional elimination t½ of about
12 hours. Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose
proportional.
Absorption: Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about
13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC by
about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50%
respectively after the ingestion of a high-fat breakfast.
Distribution: The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min
with a t½ of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The
volume of distribution of moexiprilat is about 183 liters.
Metabolism and Excretion: Moexipril is relatively rapidly converted to its active metabolite
moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t½ is over
one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to
diketopiperazine derivatives and unidentified metabolites. After I.V. administration of
moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with
small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as
moexiprilat. After oral administration, only about 7% of the dose appears in urine as
moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the
dose is recovered in feces as moexiprilat and 1% as moexipril.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20312/S-031
Page 5
Special Populations:
Decreased Renal Function: The effective elimination t½ and AUC of both moexipril and
moexiprilat are increased with decreasing renal function. There is insufficient information
available to characterize this relationship fully, but at creatinine clearances in the range of 10 to
40 mL/min, the t½ of moexiprilat is increased by a factor of 3 to 4.
Decreased Hepatic Function: In patients with mild to moderate cirrhosis given single 15 mg
doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by
about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased
by almost 300%.
Elderly Patients: In elderly male subjects (65-80 years old) with clinically normal renal and
hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger
subjects (19-42 years old).
Pharmacokinetic Interactions With Other Drugs:
No clinically important pharmacokinetic interactions occurred when Univasc was administered
concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
Pharmacodynamics and Clinical Effect
Single and multiple doses of 15 mg or more of Univasc gives sustained inhibition of plasma
ACE activity of 80-90%, beginning within 2 hours and lasting 24 hours (80%).
In controlled trials, the peak effects of orally administered moexipril increased with the dose
administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were
first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing.
Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to
dose and the antihypertensive effect tended to diminish during the 24-hour dosing interval when
the drug was administered once a day.
In multiple dose studies in the dose range of 7.5 to 30 mg once daily, Univasc lowered sitting
diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more
than placebo, respectively. There was a tendency toward increased response with higher doses
over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of
adequate size comparing moexipril with other antihypertensive agents.
The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in
various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood
pressure effect still present at trough. During dose titration, any decision as to the adequacy of a
dosing regimen should be based on trough blood pressure measurements. If diastolic blood
pressure control is not adequate at the end of the dosing interval, the dose can be increased or
given as a divided (BID) regimen.
During chronic therapy, the antihypertensive effect of any dose of Univasc is generally evident
within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects
of Univasc have been proven to continue during therapy for up to 24 months.
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NDA 20312/S-031
Page 6
Univasc, like other ACE inhibitors, is less effective in decreasing trough blood pressures in
blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects
in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in
non-blacks of -4 to -6 mmHg.
The effectiveness of Univasc was not significantly influenced by patient age, gender, or weight.
Univasc has been shown to have antihypertensive activity in both pre- and postmenopausal
women who have participated in placebo-controlled clinical trials.
Formal interaction studies with moexipril have not been carried out with antihypertensive agents
other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its
effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta-
adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.
INDICATIONS AND USAGE
Univasc is indicated for treatment of patients with hypertension. It may be used alone or in
combination with thiazide diuretics.
In using Univasc, consideration should be given to the fact that another ACE inhibitor, captopril,
has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular
disease. Available data are insufficient to show that Univasc does not have a similar risk (see
WARNINGS).
In considering use of Univasc, it should be noted that in controlled trials ACE inhibitors have an
effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE
inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than
in non-black patients (see WARNINGS, Angioedema).
CONTRAINDICATIONS
Univasc is contraindicated in patients who are hypersensitive to this product and in patients with
a history of angioedema related to previous treatment with an ACE inhibitor.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors, including Univasc, may be subject to a variety of adverse reactions, some of them
serious.
Head and Neck Angioedema: Angioedema involving the face, extremities, lips, tongue, glottis,
and/or larynx has been reported in patients treated with ACE inhibitors, including Univasc.
Symptoms suggestive of angioedema or facial edema occurred in <0.5% of moexipril-treated
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20312/S-031
Page 7
patients in placebo-controlled trials. None of the cases were considered life-threatening and all
resolved either without treatment or with medication (antihistamines or glucocorticoids). One
patient treated with hydrochlorothiazide alone experienced laryngeal edema. No instances of
angioedema were reported in placebo-treated patients.
In cases of angioedema, treatment should be promptly discontinued and the patient carefully
observed until the swelling disappears. 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 involvement of the tongue, glottis, or larynx, may be fatal due
to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution
1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly
provided (see ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors
were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently
readministered.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hypotension
Univasc can cause symptomatic hypotension, although, as with other ACE inhibitors, this is
unusual in uncomplicated hypertensive patients treated with Univasc alone. Symptomatic
hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy
in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been
salt- and volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction,
dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general,
diuretics stopped, before initiating therapy with Univasc (see PRECAUTIONS, Drug
Interactions, and ADVERSE REACTIONS).
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20312/S-031
Page 8
progressive azotemia, and rarely, with acute renal failure and death. In these patients, Univasc
therapy should be started under close medical supervision, and patients should be followed
closely for the first two weeks of treatment and whenever the dose of moexipril or an
accompanying diuretic is increased. Care in avoiding hypotension should also be taken in
patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an
excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated
with an intravenous infusion of normal saline. Univasc treatment usually can be continued
following restoration of blood pressure and volume.
Neutropenia/Agranulocytosis
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow
depression, rarely in patients with uncomplicated hypertension, but more frequently in
hypertensive patients with renal impairment, especially if they also have a collagen-vascular
disease such as systemic lupus erythematosus or scleroderma. Although there were no instances
of severe neutropenia (absolute neutrophil count <500/mm3) among patients given Univasc, as
with other ACE inhibitors, monitoring of white blood cell counts should be considered for
patients who have collagen-vascular disease, especially if the disease is associated with impaired
renal function. Available data from clinical trials of Univasc are insufficient to show that
Univasc does not cause agranulocytosis at rates similar to captopril.
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 were caused by the ACE
inhibitor exposure.
Fetal and neonatal morbidity do not appear to have resulted from intrauterine ACE inhibitor
exposure limited to the first trimester. Mothers who have used ACE inhibitors only during the
first trimester should be informed of this. Nonetheless, when patients become pregnant,
physicians should make every effort to discontinue the use of moexipril 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.
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Page 9
If oligohydramnios is observed, moexipril should be discontinued unless it is considered life-
saving 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 be detected 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 peritoneal dialysis may
be required as means of reversing hypotension and/or substituting for disordered renal function.
Theoretically, the ACE inhibitor could be removed from the neonatal circulation by exchange
transfusion, but no experience with this procedure has been reported.
No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to
90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a
mg/m2 basis.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibition of the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. There is no
clinical experience of Univasc in the treatment of hypertension in patients with renal failure.
Some hypertensive patients with no apparent preexisting renal vascular disease have developed
increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially
when Univasc has been given concomitantly with a thiazide diuretic. This is more likely to
occur in patients with preexisting renal impairment. There may be a need for dose adjustment of
Univasc and/or the discontinuation of the thiazide diuretic.
Evaluation of hypertensive patients should always include assessment of renal function (see
DOSAGE AND ADMINISTRATION).
Hypertensive Patients With Congestive Heart Failure: In hypertensive patients with severe
congestive heart failure, whose renal function may depend on the activity of the renin-
angiotensin-aldosterone system, treatment with ACE inhibitors, including Univasc, may be
associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death.
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Hypertensive Patients With Renal Artery Stenosis: In hypertensive patients with unilateral or
bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been
observed in some patients following ACE inhibitor therapy. These increases were almost always
reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients,
renal function should be monitored during the first few weeks of therapy.
Hyperkalemia: In clinical trials, persistent hyperkalemia (serum potassium above 5.4 mEq/L)
occurred in approximately 1.3% of hypertensive patients receiving Univasc. Risk factors for the
development of hyperkalemia with ACE inhibitors include renal insufficiency, diabetes mellitus,
and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or
potassium-containing salt substitutes, which should be used cautiously, if at all, with Univasc
(see PRECAUTIONS, Drug Interactions).
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, moexipril may block the effects of compensatory renin release. If
hypotension occurs in this setting and is considered to be due to this mechanism, it can be
corrected by volume expansion.
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. In controlled trials with moexipril, cough was present in 6.1% of
moexipril patients and 2.2% of patients given placebo.
Information for Patients
Food: Patients should be advised to take moexipril one hour before meals (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Angioedema: Angioedema, including laryngeal edema, may occur with treatment with ACE
inhibitors, usually occurring early in therapy (within the first month). Patients should be so
advised and told to report immediately any signs or symptoms suggesting angioedema (swelling
of the face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more Univasc
until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur with
Univasc, especially during the first few days of therapy. If fainting occurs, the patient should
stop taking Univasc and consult 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 their physician if they develop these conditions.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician.
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Page 11
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore
throat, fever) that could be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
second- and third-trimester exposure to ACE inhibitors and 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. Patients should be asked to report pregnancies to their
physicians as soon as possible.
Drug Interactions
Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy
when ACE inhibitors are started. The possibility of hypotensive effects with Univasc can be
minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake
before initiation of treatment with Univasc. If this is not possible, the starting dose of moexipril
should be reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION).
Potassium Supplements and Potassium-Sparing Diuretics: Univasc can increase serum
potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics
(spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE
inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is
indicated, they should be given with caution and the patient’s serum potassium should be
monitored.
Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important
effect on the serum concentrations of the anticoagulant or on its anticoagulant effect.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. These drugs should be
coadministered with caution, and frequent monitoring of serum lithium levels is recommended.
If a diuretic is also used, the risk of lithium toxicity may be increased.
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 Univasc.
Other Agents: No clinically important pharmacokinetic interactions occurred when Univasc was
administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
Univasc has been used in clinical trials concomitantly with calcium-channel-blocking agents,
diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents.
There was no evidence of clinically important adverse interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to
14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis.
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Page 12
No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and
without metabolic activation, or in an in vivo nucleus anomaly test. However, increased
chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic
activation conditions at a 20-hour harvest time.
Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on
a mg/m2 basis, and in rats up to 90.9 times the MRHD on a mg/m2 basis. No indication of
impaired fertility, reproductive toxicity, or teratogenicity was observed.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether Univasc is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Univasc is given to a nursing mother.
Pediatric Use
Safety and effectiveness of Univasc in pediatric patients have not been established.
Geriatric Use
Clinical studies of Univasc 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
Univasc has been evaluated for safety in more than 2500 patients with hypertension; more than
250 of these patients were treated for approximately one year. The overall incidence of reported
adverse events was only slightly greater in patients treated with Univasc than patients treated
with placebo.
Reported adverse experiences were usually mild and transient, and there were no differences in
adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage
within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse
experiences was required in 3.4% of patients treated with Univasc and in 1.8% of patients treated
with placebo. The most common reasons for discontinuation in patients treated with Univasc
were cough (0.7%) and dizziness (0.4%).
All adverse experiences considered at least possibly related to treatment that occurred at any
dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with
Univasc alone and that were at least as frequent in the Univasc group as in the placebo group are
shown in the following table:
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Page 13
ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES
ADVERSE
EVENT
UNIVASC
(N=674)
PLACEBO
(N=226)
N
(%)
N
(%)
Cough Increased
41
(6.1)
5 (2.2)
Dizziness
29
(4.3)
5 (2.2)
Diarrhea
21
(3.1)
5 (2.2)
Flu Syndrome
21
(3.1)
0 (0)
Fatigue
16
(2.4)
4 (1.8)
Pharyngitis
12
(1.8)
2 (0.9)
Flushing
11
(1.6)
0 (0)
Rash
11
(1.6)
2 (0.9)
Myalgia
9
(1.3)
0 (0)
Other adverse events occurring in more than 1% of patients on moexipril that were at least as
frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia,
nausea, peripheral edema, sinusitis, chest pain, and urinary frequency. See WARNINGS and
PRECAUTIONS for discussion of anaphylactoid reactions, angioedema, hypotension,
neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality,
hyperkalemia, and cough.
Other potentially important adverse experiences reported in controlled or uncontrolled clinical
trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors
include the following:
Cardiovascular: Symptomatic hypotension, postural hypotension, or syncope were seen in
9/1750 (0.51%) patients; these reactions led to discontinuation of therapy in controlled trials in
3/1254 (0.24%) patients who had received Univasc monotherapy and in 1/344 (0.3%) patients
who had received Univasc with hydrochlorothiazide (see PRECAUTIONS and WARNINGS).
Other adverse events included angina/myocardial infarction, palpitations, rhythm disturbances,
and cerebrovascular accident.
Renal: Of hypertensive patients with no apparent preexisting renal disease, 1% of patients
receiving Univasc alone and 2% of patients receiving Univasc with hydrochlorothiazide
experienced increases in serum creatinine to at least 140% of their baseline values (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Gastrointestinal: Abdominal pain, constipation, vomiting, appetite/weight change, dry mouth,
pancreatitis, hepatitis.
Respiratory: Bronchospasm, dyspnea, eosinophilic pneumonitis.
Urogenital: Renal insufficiency, oliguria.
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Page 14
Dermatologic: Apparent hypersensitivity reactions manifested by urticaria, rash, pemphigus,
pruritus, photosensitivity, alopecia.
Neurological and Psychiatric: Drowsiness, sleep disturbances, nervousness, mood changes,
anxiety.
Other: Angioedema (see WARNINGS), taste disturbances, tinnitus, sweating, malaise,
arthralgia, hemolytic anemia.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine and Blood Urea Nitrogen: As with other ACE inhibitors, minor increases in blood
urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in
approximately 1% of patients with essential hypertension who were treated with Univasc.
Increases are more likely to occur in patients receiving concomitant diuretics and in patients with
compromised renal function (see PRECAUTIONS, General).
Other (causal relationship unknown): Clinically important changes in standard laboratory tests
were rarely associated with Univasc administration.
Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of
moexipril-treated patients discontinued Univasc treatment because of laboratory abnormalities.
The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-
treated group.
OVERDOSAGE
Human overdoses of moexipril have not been reported. In case reports of overdoses with other
ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of 2
g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated single
oral doses of up to 3 g/kg.
No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH
of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of
moexipril is not known.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities.
Because the hypotensive effect of moexipril is achieved through vasodilation and effective
hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution.
In addition, renal function and serum potassium should be monitored.
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Page 15
DOSAGE AND ADMINISTRATION
Hypertension
The recommended initial dose of Univasc in patients not receiving diuretics is 7.5 mg, one hour
prior to meals, once daily. Dosage should be adjusted according to blood pressure response.
The antihypertensive effect of Univasc may diminish towards the end of the dosing interval.
Blood pressure should, therefore, be measured just prior to dosing to determine whether
satisfactory blood pressure control is obtained. If control is not adequate, increased dose or
divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in
one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not
been studied in hypertensive patients.
In patients who are currently being treated with a diuretic, symptomatic hypotension may
occasionally occur following the initial dose of Univasc. The diuretic should, if possible, be
discontinued for 2 to 3 days before therapy with Univasc is begun, to reduce the likelihood of
hypotension (see WARNINGS). If the patient’s blood pressure is not controlled with Univasc
alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an
initial dose of 3.75 mg of Univasc should be used with medical supervision until blood pressure
has stabilized (see WARNINGS and PRECAUTIONS, Drug Interactions).
Dosage Adjustment in Renal Impairment
For patients with a creatinine clearance ≤40 mL/min/1.73 m2, an initial dose of 3.75 mg once
daily should be given cautiously. Doses may be titrated upward to a maximum daily dose of
15 mg.
HOW SUPPLIED
Univasc (moexipril hydrochloride) 7.5 mg tablets are pink colored, biconvex, film-coated and
scored with engraved code 707 on the unscored side and SP above and 7.5 below the score.
They are supplied as follows:
Bottles of 90 (Unit-of-Use)
NDC 0091-3707-09
Bottles of 100
NDC 0091-3707-01
Univasc (moexipril hydrochloride) 15 mg tablets are salmon colored, biconvex, film-coated,
and scored with engraved code 715 on the unscored side and SP above and 15 below the score.
They are supplied as follows:
Bottles of 90 (Unit-of-Use)
NDC 0091-3715-09
Bottles of 100
NDC 0091-3715-01
Store, tightly closed, at controlled room temperature. Protect from excessive moisture.
If product package is subdivided, dispense in tight containers as described in USP-NF.
Manufactured for:
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NDA 20312/S-031
Page 16
Schwarz Pharma, LLC
a subsidiary of UCB, Inc.
Smyrna, GA 30080
Rev. 1E 06/2009
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Application
Type/Number
Submission
Type/Number
Submitter Name
Product Name
--------------------
--------------------
--------------------
------------------------------------------
NDA-20312
SUPPL-31
SCHWARZ
PHARMA INC
UNIVASC (MOEXIPRIL HCL)
TABLETS
---------------------------------------------------------------------------------------------------------
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
01/13/2010
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|
custom-source
|
2025-02-12T13:47:26.232952
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020312s031lbl.pdf', 'application_number': 20312, 'submission_type': 'SUPPL ', 'submission_number': 31}
|
12,437
|
univasc® tablets
(moexipril hydrochloride)
Rx only
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
•
When pregnancy is detected, discontinue univasc® 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
univasc® (moexipril hydrochloride), the hydrochloride salt of moexipril, has the empirical
formula C27H34N2O7•HCl and a molecular weight of 535.04. It is chemically described as [3S
[2[R*(R*)],3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4
tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, monohydrochloride. It is a non
sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor
moexiprilat and its structural formula is: structural formula
Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to
volume) in distilled water at room temperature.
univasc® is supplied as scored, coated tablets containing 7.5 mg and 15 mg of moexipril
hydrochloride for oral administration. In addition to the active ingredient, moexipril
hydrochloride, the tablet core contains the following inactive ingredients: lactose, magnesium
oxide, crospovidone, magnesium stearate and gelatin. The film coating contains hydroxypropyl
cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate, titanium dioxide, and
ferric oxide.
1
Reference ID: 3073760
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CLINICAL PHARMACOLOGY
Mechanism of Action
Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and
animals. The mechanism through which moexiprilat lowers blood pressure is believed to be
primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion
of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II.
Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by
the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to
kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator.
Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II.
Inhibition of ACE results in decreased angiotensin II formation, leading to decreased
vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The
latter results in diuresis and natriuresis and a small increase in serum potassium concentration
(mean increases of about 0.25 mEq/L were seen when moexipril was used alone, see
PRECAUTIONS).
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the
therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of
moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone
system, ACE inhibitors have some effect on blood pressure even in apparent low-renin
hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of
moexipril is considerably smaller in black patients, a predominantly low-renin population, than
in non-black hypertensive patients.
Pharmacokinetics and Metabolism
Pharmacokinetics: Moexipril’s antihypertensive activity is almost entirely due to its
deesterified metabolite, moexiprilat. Bioavailability of oral moexipril is about 13% compared to
intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly
affected by food, which reduces the peak plasma level (Cmax) and AUC (see Absorption).
Moexipril should therefore be taken in a fasting state. The time of peak plasma concentration
(Tmax) of moexiprilat is about 1½ hours and elimination half-life (t½) is estimated at 2 to 9 hours
in various studies, the variability reflecting a complex elimination pattern that is not simply
exponential. Like all ACE inhibitors, moexiprilat has a prolonged terminal elimination phase,
presumably reflecting slow release of drug bound to the ACE. Accumulation of moexiprilat with
repeated dosing is minimal, about 30%, compatible with a functional elimination t½ of about
12 hours. Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose
proportional.
Absorption: Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about
13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC by
about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50%
respectively after the ingestion of a high-fat breakfast.
2
Reference ID: 3073760
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Distribution: The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min
with a t½ of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The
volume of distribution of moexiprilat is about 183 liters.
Metabolism and Excretion: Moexipril is relatively rapidly converted to its active metabolite
moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t½ is over
one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to
diketopiperazine derivatives and unidentified metabolites. After I.V. administration of
moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with
small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as
moexiprilat. After oral administration, only about 7% of the dose appears in urine as
moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of
the dose is recovered in feces as moexiprilat and 1% as moexipril.
Special Populations:
Decreased Renal Function: The effective elimination t½ and AUC of both moexipril and
moexiprilat are increased with decreasing renal function. There is insufficient information
available to characterize this relationship fully, but at creatinine clearances in the range of 10 to
40 mL/min, the t½ of moexiprilat is increased by a factor of 3 to 4.
Decreased Hepatic Function: In patients with mild to moderate cirrhosis given single 15 mg
doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by
about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased
by almost 300%.
Elderly Patients: In elderly male subjects (65-80 years old) with clinically normal renal and
hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger
subjects (19-42 years old).
Pharmacokinetic Interactions With Other Drugs:
No clinically important pharmacokinetic interactions occurred when univasc® was administered
concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
Pharmacodynamics and Clinical Effect
Single and multiple doses of 15 mg or more of univasc® gives sustained inhibition of plasma
ACE activity of 80-90%, beginning within 2 hours and lasting 24 hours (80%).
In controlled trials, the peak effects of orally administered moexipril increased with the dose
administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were
first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing.
Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to
dose and the antihypertensive effect tended to diminish during the 24-hour dosing interval when
the drug was administered once a day.
3
Reference ID: 3073760
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In multiple dose studies in the dose range of 7.5 to 30 mg once daily, univasc® lowered sitting
diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more
than placebo, respectively. There was a tendency toward increased response with higher doses
over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of
adequate size comparing moexipril with other antihypertensive agents.
The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in
various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood
pressure effect still present at trough. During dose titration, any decision as to the adequacy of a
dosing regimen should be based on trough blood pressure measurements. If diastolic blood
pressure control is not adequate at the end of the dosing interval, the dose can be increased or
given as a divided (BID) regimen.
During chronic therapy, the antihypertensive effect of any dose of univasc® is generally evident
within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects
of univasc® have been proven to continue during therapy for up to 24 months.
univasc®, like other ACE inhibitors, is less effective in decreasing trough blood pressures in
blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects
in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in
non-blacks of -4 to -6 mmHg.
The effectiveness of univasc® was not significantly influenced by patient age, gender, or weight.
univasc® has been shown to have antihypertensive activity in both pre- and postmenopausal
women who have participated in placebo-controlled clinical trials.
Formal interaction studies with moexipril have not been carried out with antihypertensive agents
other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its
effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta
adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.
INDICATIONS AND USAGE
univasc® is indicated for treatment of patients with hypertension. It may be used alone or in
combination with thiazide diuretics.
In using univasc®, consideration should be given to the fact that another ACE inhibitor,
captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-
vascular disease. Available data are insufficient to show that univasc® does not have a similar
risk (see WARNINGS).
In considering use of univasc®, it should be noted that in controlled trials ACE inhibitors have an
effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE
inhibitors (for which adequate data are available) cause a higher rate of angioedema in black
than in non-black patients (see WARNINGS, Angioedema).
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CONTRAINDICATIONS
univasc® is contraindicated in patients who are hypersensitive to this product and in patients with
a history of angioedema related to previous treatment with an ACE inhibitor.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors, including univasc®, may be subject to a variety of adverse reactions, some of them
serious.
Head and Neck Angioedema: Angioedema involving the face, extremities, lips, tongue,
glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including
univasc®. Symptoms suggestive of angioedema or facial edema occurred in <0.5% of moexipril
treated patients in placebo-controlled trials. None of the cases were considered life-threatening
and all resolved either without treatment or with medication (antihistamines or glucocorticoids).
One patient treated with hydrochlorothiazide alone experienced laryngeal edema. No instances
of angioedema were reported in placebo-treated patients.
In cases of angioedema, treatment should be promptly discontinued and the patient carefully
observed until the swelling disappears. 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 involvement of the tongue, glottis, or larynx, may be fatal due
to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution
1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly
provided (see ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors
were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently
readministered.
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Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hypotension
univasc® can cause symptomatic hypotension, although, as with other ACE inhibitors, this is
unusual in uncomplicated hypertensive patients treated with univasc® alone. Symptomatic
hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy
in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been
salt- and volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction,
dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general,
diuretics stopped, before initiating therapy with univasc® (see PRECAUTIONS, Drug
Interactions, and ADVERSE REACTIONS).
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or
progressive azotemia, and rarely, with acute renal failure and death. In these patients, univasc®
therapy should be started under close medical supervision, and patients should be followed
closely for the first two weeks of treatment and whenever the dose of moexipril or an
accompanying diuretic is increased. Care in avoiding hypotension should also be taken in
patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an
excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated
with an intravenous infusion of normal saline. univasc® treatment usually can be continued
following restoration of blood pressure and volume.
Neutropenia/Agranulocytosis
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow
depression, rarely in patients with uncomplicated hypertension, but more frequently in
hypertensive patients with renal impairment, especially if they also have a collagen-vascular
disease such as systemic lupus erythematosus or scleroderma. Although there were no instances
of severe neutropenia (absolute neutrophil count <500/mm3) among patients given univasc®, as
with other ACE inhibitors, monitoring of white blood cell counts should be considered for
patients who have collagen-vascular disease, especially if the disease is associated with impaired
renal function. Available data from clinical trials of univasc® are insufficient to show that
univasc® does not cause agranulocytosis at rates similar to captopril.
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Reference ID: 3073760
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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 univasc® as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third
trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
exposure 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 to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue univasc®, 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
univasc® for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to
90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a
mg/m2 basis.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibition of the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. There is no
clinical experience of univasc® in the treatment of hypertension in patients with renal failure.
Some hypertensive patients with no apparent preexisting renal vascular disease have developed
increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially
when univasc® has been given concomitantly with a thiazide diuretic. This is more likely to
occur in patients with preexisting renal impairment. There may be a need for dose adjustment of
univasc® and/or the discontinuation of the thiazide diuretic.
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Evaluation of hypertensive patients should always include assessment of renal function (see
DOSAGE AND ADMINISTRATION).
Hypertensive Patients With Congestive Heart Failure: In hypertensive patients with severe
congestive heart failure, whose renal function may depend on the activity of the renin
angiotensin-aldosterone system, treatment with ACE inhibitors, including univasc®, may be
associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death.
Hypertensive Patients With Renal Artery Stenosis: In hypertensive patients with unilateral
or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been
observed in some patients following ACE inhibitor therapy. These increases were almost always
reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients,
renal function should be monitored during the first few weeks of therapy.
Hyperkalemia: In clinical trials, persistent hyperkalemia (serum potassium above 5.4 mEq/L)
occurred in approximately 1.3% of hypertensive patients receiving univasc®. Risk factors for the
development of hyperkalemia with ACE inhibitors include renal insufficiency, diabetes mellitus,
and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or
potassium-containing salt substitutes, which should be used cautiously, if at all, with univasc®
(see PRECAUTIONS, Drug Interactions).
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents
that produce hypotension, moexipril may block the effects of compensatory renin release. If
hypotension occurs in this setting and is considered to be due to this mechanism, it can be
corrected by volume expansion.
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. In controlled trials with moexipril, cough was present in 6.1% of
moexipril patients and 2.2% of patients given placebo.
Information for Patients
Food: Patients should be advised to take moexipril one hour before meals (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Angioedema: Angioedema, including laryngeal edema, may occur with treatment with ACE
inhibitors, usually occurring early in therapy (within the first month). Patients should be so
advised and told to report immediately any signs or symptoms suggesting angioedema (swelling
of the face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more univasc®
until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur with
univasc®, especially during the first few days of therapy. If fainting occurs, the patient should
stop taking univasc® and consult the prescribing physician.
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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 their physician if they develop these conditions.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore
throat, fever) that could be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to univasc® 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
Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy
when ACE inhibitors are started. The possibility of hypotensive effects with univasc® can be
minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake
before initiation of treatment with univasc®. If this is not possible, the starting dose of moexipril
should be reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION).
Potassium Supplements and Potassium-Sparing Diuretics: univasc® can increase serum
potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics
(spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE
inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is
indicated, they should be given with caution and the patient’s serum potassium should be
monitored.
Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically
important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. These drugs should be
coadministered with caution, and frequent monitoring of serum lithium levels is recommended.
If a diuretic is also used, the risk of lithium toxicity may be increased.
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 univasc®.
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
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COX-2 inhibitors, with ACE inhibitors, including moexipril, may result in deterioration of renal
function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving moexipril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including moexipril, may be attenuated by
NSAIDS.
Other Agents: No clinically important pharmacokinetic interactions occurred when univasc®
was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
univasc® has been used in clinical trials concomitantly with calcium-channel-blocking agents,
diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents.
There was no evidence of clinically important adverse interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to
14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis.
No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and
without metabolic activation, or in an in vivo nucleus anomaly test. However, increased
chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic
activation conditions at a 20-hour harvest time.
Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on
a mg/m2 basis, and in rats up to 90.9 times the MRHD on a mg/m2 basis. No indication of
impaired fertility, reproductive toxicity, or teratogenicity was observed.
Nursing Mothers
It is not known whether univasc® is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when univasc® is given to a nursing mother.
Pediatric Use
Neonates with a history of in utero exposure to univasc®:
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.
Safety and effectiveness of univasc® in pediatric patients have not been established.
Geriatric Use
Clinical studies of univasc® 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
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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
univasc® has been evaluated for safety in more than 2500 patients with hypertension; more than
250 of these patients were treated for approximately one year. The overall incidence of reported
adverse events was only slightly greater in patients treated with univasc® than patients treated
with placebo.
Reported adverse experiences were usually mild and transient, and there were no differences in
adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage
within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse
experiences was required in 3.4% of patients treated with univasc® and in 1.8% of patients
treated with placebo. The most common reasons for discontinuation in patients treated with
univasc® were cough (0.7%) and dizziness (0.4%).
All adverse experiences considered at least possibly related to treatment that occurred at any
dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with
univasc® alone and that were at least as frequent in the univasc® group as in the placebo group
are shown in the following table:
ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES
ADVERSE
EVENT
UNIVASC
(N=674)
PLACEBO
(N=226)
N
(%)
N
(%)
Cough Increased
41 (6.1)
5 (2.2)
Dizziness
29 (4.3)
5 (2.2)
Diarrhea
21 (3.1)
5 (2.2)
Flu Syndrome
21 (3.1)
0 (0)
Fatigue
16 (2.4)
4 (1.8)
Pharyngitis
12 (1.8)
2 (0.9)
Flushing
11 (1.6)
0 (0)
Rash
11 (1.6)
2 (0.9)
Myalgia
9 (1.3)
0 (0)
Other adverse events occurring in more than 1% of patients on moexipril that were at least as
frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia,
nausea, peripheral edema, sinusitis, chest pain, and urinary frequency. See WARNINGS and
PRECAUTIONS for discussion of anaphylactoid reactions, angioedema, hypotension,
neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality,
hyperkalemia, and cough.
Other potentially important adverse experiences reported in controlled or uncontrolled clinical
trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors
include the following:
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Cardiovascular: Symptomatic hypotension, postural hypotension, or syncope were seen in
9/1750 (0.51%) patients; these reactions led to discontinuation of therapy in controlled trials in
3/1254 (0.24%) patients who had received univasc® monotherapy and in 1/344 (0.3%) patients
who had received univasc® with hydrochlorothiazide (see PRECAUTIONS and WARNINGS).
Other adverse events included angina/myocardial infarction, palpitations, rhythm disturbances,
and cerebrovascular accident.
Renal: Of hypertensive patients with no apparent preexisting renal disease, 1% of patients
receiving univasc® alone and 2% of patients receiving univasc® with hydrochlorothiazide
experienced increases in serum creatinine to at least 140% of their baseline values (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Gastrointestinal: Abdominal pain, constipation, vomiting, appetite/weight change, dry
mouth, pancreatitis, hepatitis.
Respiratory: Bronchospasm, dyspnea, eosinophilic pneumonitis.
Urogenital: Renal insufficiency, oliguria.
Dermatologic: Apparent hypersensitivity reactions manifested by urticaria, rash, pemphigus,
pruritus, photosensitivity, alopecia.
Neurological and Psychiatric: Drowsiness, sleep disturbances, nervousness, mood changes,
anxiety.
Other: Angioedema (see WARNINGS), taste disturbances, tinnitus, sweating, malaise,
arthralgia, hemolytic anemia.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine and Blood Urea Nitrogen: As with other ACE inhibitors, minor increases in blood
urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in
approximately 1% of patients with essential hypertension who were treated with univasc®.
Increases are more likely to occur in patients receiving concomitant diuretics and in patients with
compromised renal function (see PRECAUTIONS, General).
Other (causal relationship unknown): Clinically important changes in standard laboratory
tests were rarely associated with univasc® administration.
Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of
moexipril-treated patients discontinued univasc® treatment because of laboratory abnormalities.
The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-
treated group.
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OVERDOSAGE
Human overdoses of moexipril have not been reported. In case reports of overdoses with other
ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of
2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated
single oral doses of up to 3 g/kg.
No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH
of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of
moexipril is not known.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities.
Because the hypotensive effect of moexipril is achieved through vasodilation and effective
hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution.
In addition, renal function and serum potassium should be monitored.
DOSAGE AND ADMINISTRATION
Hypertension
The recommended initial dose of univasc® in patients not receiving diuretics is 7.5 mg, one hour
prior to meals, once daily. Dosage should be adjusted according to blood pressure response.
The antihypertensive effect of univasc® may diminish towards the end of the dosing interval.
Blood pressure should, therefore, be measured just prior to dosing to determine whether
satisfactory blood pressure control is obtained. If control is not adequate, increased dose or
divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in
one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not
been studied in hypertensive patients.
In patients who are currently being treated with a diuretic, symptomatic hypotension may
occasionally occur following the initial dose of univasc®. The diuretic should, if possible, be
discontinued for 2 to 3 days before therapy with univasc® is begun, to reduce the likelihood of
hypotension (see WARNINGS). If the patient’s blood pressure is not controlled with univasc®
alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an
initial dose of 3.75 mg of univasc® should be used with medical supervision until blood pressure
has stabilized (see WARNINGS and PRECAUTIONS, Drug Interactions).
Dosage Adjustment in Renal Impairment
For patients with a creatinine clearance ≤40 mL/min/1.73 m2, an initial dose of 3.75 mg once
daily should be given cautiously. Doses may be titrated upward to a maximum daily dose of
15 mg.
HOW SUPPLIED
univasc® (moexipril hydrochloride) 7.5 mg tablets are pink colored, biconvex, film-coated and
scored with engraved code 707 on the unscored side and SP above and 7.5 below the score.
They are supplied as follows:
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Bottles of 90 (Unit-of-Use)
NDC 0091-3707-09
Bottles of 100
NDC 0091-3707-01
univasc® (moexipril hydrochloride) 15 mg tablets are salmon colored, biconvex, film-coated,
and scored with engraved code 715 on the unscored side and SP above and 15 below the score.
They are supplied as follows:
Bottles of 90 (Unit-of-Use)
NDC 0091-3715-09
Bottles of 100
NDC 0091-3715-01
Store, tightly closed, at controlled room temperature. Protect from excessive moisture.
If product package is subdivided, dispense in tight containers as described in USP-NF.
Manufactured for:
UCB, Inc.
Smyrna, GA 30080
Rev. 4E XX/20XX
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|
custom-source
|
2025-02-12T13:47:26.306514
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020312s034lbl.pdf', 'application_number': 20312, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
12,436
|
univasc® tablets
(moexipril hydrochloride)
Rx only
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, univasc® should
be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
DESCRIPTION
univasc® (moexipril hydrochloride), the hydrochloride salt of moexipril, has the empirical
formula C27H34N2O7•HCl and a molecular weight of 535.04. It is chemically described as [3S
[2[R*(R*)],3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4
tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, monohydrochloride. It is a non-
sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor
moexiprilat and its structural formula is: structural formula
Moexipril hydrochloride is a fine white to off-white powder. It is soluble (about 10% weight-to
volume) in distilled water at room temperature.
univasc® is supplied as scored, coated tablets containing 7.5 mg and 15 mg of moexipril
hydrochloride for oral administration. In addition to the active ingredient, moexipril
hydrochloride, the tablet core contains the following inactive ingredients: lactose, magnesium
oxide, crospovidone, magnesium stearate and gelatin. The film coating contains hydroxypropyl
cellulose, hypromellose, polyethylene glycol 6000, magnesium stearate, titanium dioxide, and
ferric oxide.
Reference ID: 3004714
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Mechanism of Action
Moexipril hydrochloride is a prodrug for moexiprilat, which inhibits ACE in humans and
animals. The mechanism through which moexiprilat lowers blood pressure is believed to be
primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion
of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II.
Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by
the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to
kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator.
Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II.
Inhibition of ACE results in decreased angiotensin II formation, leading to decreased
vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter
results in diuresis and natriuresis and a small increase in serum potassium concentration (mean
increases of about 0.25 mEq/L were seen when moexipril was used alone, see PRECAUTIONS).
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the
therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of
moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone
system, ACE inhibitors have some effect on blood pressure even in apparent low-renin
hypertension. As is the case with other ACE inhibitors, however, the antihypertensive effect of
moexipril is considerably smaller in black patients, a predominantly low-renin population, than
in non-black hypertensive patients.
Pharmacokinetics and Metabolism
Pharmacokinetics: Moexipril’s antihypertensive activity is almost entirely due to its
deesterified metabolite, moexiprilat. Bioavailability of oral moexipril is about 13% compared to
intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly
affected by food, which reduces the peak plasma level (Cmax) and AUC (see Absorption).
Moexipril should therefore be taken in a fasting state. The time of peak plasma concentration
(Tmax) of moexiprilat is about 1½ hours and elimination half-life (t½) is estimated at 2 to 9 hours
in various studies, the variability reflecting a complex elimination pattern that is not simply
exponential. Like all ACE inhibitors, moexiprilat has a prolonged terminal elimination phase,
presumably reflecting slow release of drug bound to the ACE. Accumulation of moexiprilat with
repeated dosing is minimal, about 30%, compatible with a functional elimination t½ of about
12 hours. Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose
proportional.
Absorption: Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about
13%. Bioavailability varies with formulation and food intake which reduces Cmax and AUC by
about 70% and 40% respectively after the ingestion of a low-fat breakfast or by 80% and 50%
respectively after the ingestion of a high-fat breakfast.
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Distribution: The clearance (CL) for moexipril is 441 mL/min and for moexiprilat 232 mL/min
with a t½ of 1.3 and 9.8 hours, respectively. Moexiprilat is about 50% protein bound. The
volume of distribution of moexiprilat is about 183 liters.
Metabolism and Excretion: Moexipril is relatively rapidly converted to its active metabolite
moexiprilat, but persists longer than some other ACE inhibitor prodrugs, such that its t½ is over
one hour and it has a significant AUC. Both moexipril and moexiprilat are converted to
diketopiperazine derivatives and unidentified metabolites. After I.V. administration of
moexipril, about 40% of the dose appears in urine as moexiprilat, about 26% as moexipril, with
small amounts of the metabolites; about 20% of the I.V. dose appears in feces, principally as
moexiprilat. After oral administration, only about 7% of the dose appears in urine as
moexiprilat, about 1% as moexipril, with about 5% as other metabolites. Fifty-two percent of the
dose is recovered in feces as moexiprilat and 1% as moexipril.
Special Populations:
Decreased Renal Function: The effective elimination t½ and AUC of both moexipril and
moexiprilat are increased with decreasing renal function. There is insufficient information
available to characterize this relationship fully, but at creatinine clearances in the range of 10 to
40 mL/min, the t½ of moexiprilat is increased by a factor of 3 to 4.
Decreased Hepatic Function: In patients with mild to moderate cirrhosis given single 15 mg
doses of moexipril, the Cmax of moexipril was increased by about 50% and the AUC increased by
about 120%, while the Cmax for moexiprilat was decreased by about 50% and the AUC increased
by almost 300%.
Elderly Patients: In elderly male subjects (65-80 years old) with clinically normal renal and
hepatic function, the AUC and Cmax of moexiprilat is about 30% greater than those of younger
subjects (19-42 years old).
Pharmacokinetic Interactions With Other Drugs:
No clinically important pharmacokinetic interactions occurred when univasc® was administered
concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
Pharmacodynamics and Clinical Effect
Single and multiple doses of 15 mg or more of univasc® gives sustained inhibition of plasma
ACE activity of 80-90%, beginning within 2 hours and lasting 24 hours (80%).
In controlled trials, the peak effects of orally administered moexipril increased with the dose
administered over a dose range of 7.5 to 60 mg, given once a day. Antihypertensive effects were
first detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours after dosing.
Just before dosing (i.e., at trough), the antihypertensive effects were less prominently related to
dose and the antihypertensive effect tended to diminish during the 24-hour dosing interval when
the drug was administered once a day.
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In multiple dose studies in the dose range of 7.5 to 30 mg once daily, univasc® lowered sitting
diastolic and systolic blood pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more
than placebo, respectively. There was a tendency toward increased response with higher doses
over this range. These effects are typical of ACE inhibitors but, to date, there are no trials of
adequate size comparing moexipril with other antihypertensive agents.
The trough diastolic blood pressure effects of moexipril were approximately 3 to 6 mmHg in
various studies. Generally, higher doses of moexipril leave a greater fraction of the peak blood
pressure effect still present at trough. During dose titration, any decision as to the adequacy of a
dosing regimen should be based on trough blood pressure measurements. If diastolic blood
pressure control is not adequate at the end of the dosing interval, the dose can be increased or
given as a divided (BID) regimen.
During chronic therapy, the antihypertensive effect of any dose of univasc® is generally evident
within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects
of univasc® have been proven to continue during therapy for up to 24 months.
univasc®, like other ACE inhibitors, is less effective in decreasing trough blood pressures in
blacks than in non-blacks. Placebo-corrected trough group mean diastolic blood pressure effects
in blacks in the proposed dose range varied between +1 to -3 mmHg compared with responses in
non-blacks of -4 to -6 mmHg.
The effectiveness of univasc® was not significantly influenced by patient age, gender, or weight.
univasc® has been shown to have antihypertensive activity in both pre- and postmenopausal
women who have participated in placebo-controlled clinical trials.
Formal interaction studies with moexipril have not been carried out with antihypertensive agents
other than thiazide diuretics. In these studies, the added effect of moexipril was similar to its
effect as monotherapy. In general, ACE inhibitors have less than additive effects with beta-
adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.
INDICATIONS AND USAGE
univasc® is indicated for treatment of patients with hypertension. It may be used alone or in
combination with thiazide diuretics.
In using univasc®, consideration should be given to the fact that another ACE inhibitor,
captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-
vascular disease. Available data are insufficient to show that univasc® does not have a similar
risk (see WARNINGS).
In considering use of univasc®, it should be noted that in controlled trials ACE inhibitors have an
effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE
inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than
in non-black patients (see WARNINGS, Angioedema).
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CONTRAINDICATIONS
univasc® is contraindicated in patients who are hypersensitive to this product and in patients with
a history of angioedema related to previous treatment with an ACE inhibitor.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors, including univasc®, may be subject to a variety of adverse reactions, some of them
serious.
Head and Neck Angioedema: Angioedema involving the face, extremities, lips, tongue,
glottis, and/or larynx has been reported in patients treated with ACE inhibitors, including
univasc®. Symptoms suggestive of angioedema or facial edema occurred in <0.5% of moexipril
treated patients in placebo-controlled trials. None of the cases were considered life-threatening
and all resolved either without treatment or with medication (antihistamines or glucocorticoids).
One patient treated with hydrochlorothiazide alone experienced laryngeal edema. No instances
of angioedema were reported in placebo-treated patients.
In cases of angioedema, treatment should be promptly discontinued and the patient carefully
observed until the swelling disappears. 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 involvement of the tongue, glottis, or larynx, may be fatal due
to airway obstruction. Appropriate therapy, e.g., subcutaneous epinephrine solution
1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly
provided (see ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors
were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently
readministered.
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Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hypotension
univasc® can cause symptomatic hypotension, although, as with other ACE inhibitors, this is
unusual in uncomplicated hypertensive patients treated with univasc® alone. Symptomatic
hypotension was seen in 0.5% of patients given moexipril and led to discontinuation of therapy
in about 0.25%. Symptomatic hypotension is most likely to occur in patients who have been
salt- and volume-depleted as a result of prolonged diuretic therapy, dietary salt restriction,
dialysis, diarrhea, or vomiting. Volume- and salt-depletion should be corrected and, in general,
diuretics stopped, before initiating therapy with univasc® (see PRECAUTIONS, Drug
Interactions, and ADVERSE REACTIONS).
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or
progressive azotemia, and rarely, with acute renal failure and death. In these patients, univasc®
therapy should be started under close medical supervision, and patients should be followed
closely for the first two weeks of treatment and whenever the dose of moexipril or an
accompanying diuretic is increased. Care in avoiding hypotension should also be taken in
patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease, in whom an
excessive decrease in blood pressure could result in a myocardial infarction or a cerebrovascular
accident.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated
with an intravenous infusion of normal saline. univasc® treatment usually can be continued
following restoration of blood pressure and volume.
Neutropenia/Agranulocytosis
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow
depression, rarely in patients with uncomplicated hypertension, but more frequently in
hypertensive patients with renal impairment, especially if they also have a collagen-vascular
disease such as systemic lupus erythematosus or scleroderma. Although there were no instances
of severe neutropenia (absolute neutrophil count <500/mm3) among patients given univasc®, as
with other ACE inhibitors, monitoring of white blood cell counts should be considered for
patients who have collagen-vascular disease, especially if the disease is associated with impaired
renal function. Available data from clinical trials of univasc® are insufficient to show that
univasc® does not cause agranulocytosis at rates similar to captopril.
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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 were caused by the ACE
inhibitor exposure.
Fetal and neonatal morbidity do not appear to have resulted from intrauterine ACE inhibitor
exposure limited to the first trimester. Mothers who have used ACE inhibitors only during the
first trimester should be informed of this. Nonetheless, when patients become pregnant,
physicians should make every effort to discontinue the use of moexipril 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, moexipril should be discontinued unless it is considered life
saving 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 be detected 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 peritoneal dialysis may
be required as means of reversing hypotension and/or substituting for disordered renal function.
Theoretically, the ACE inhibitor could be removed from the neonatal circulation by exchange
transfusion, but no experience with this procedure has been reported.
No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to
90.9 and 0.7 times, respectively, the Maximum Recommended Human Dose (MRHD) on a
mg/m2 basis.
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Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibition of the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. There is no
clinical experience of univasc® in the treatment of hypertension in patients with renal failure.
Some hypertensive patients with no apparent preexisting renal vascular disease have developed
increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially
when univasc® has been given concomitantly with a thiazide diuretic. This is more likely to
occur in patients with preexisting renal impairment. There may be a need for dose adjustment of
univasc® and/or the discontinuation of the thiazide diuretic.
Evaluation of hypertensive patients should always include assessment of renal function (see
DOSAGE AND ADMINISTRATION).
Hypertensive Patients With Congestive Heart Failure: In hypertensive patients with severe
congestive heart failure, whose renal function may depend on the activity of the renin-
angiotensin-aldosterone system, treatment with ACE inhibitors, including univasc®, may be
associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death.
Hypertensive Patients With Renal Artery Stenosis: In hypertensive patients with unilateral
or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been
observed in some patients following ACE inhibitor therapy. These increases were almost always
reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients,
renal function should be monitored during the first few weeks of therapy.
Hyperkalemia: In clinical trials, persistent hyperkalemia (serum potassium above 5.4 mEq/L)
occurred in approximately 1.3% of hypertensive patients receiving univasc®. Risk factors for the
development of hyperkalemia with ACE inhibitors include renal insufficiency, diabetes mellitus,
and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or
potassium-containing salt substitutes, which should be used cautiously, if at all, with univasc®
(see PRECAUTIONS, Drug Interactions).
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents
that produce hypotension, moexipril may block the effects of compensatory renin release. If
hypotension occurs in this setting and is considered to be due to this mechanism, it can be
corrected by volume expansion.
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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. In controlled trials with moexipril, cough was present in 6.1% of
moexipril patients and 2.2% of patients given placebo.
Information for Patients
Food: Patients should be advised to take moexipril one hour before meals (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Angioedema: Angioedema, including laryngeal edema, may occur with treatment with ACE
inhibitors, usually occurring early in therapy (within the first month). Patients should be so
advised and told to report immediately any signs or symptoms suggesting angioedema (swelling
of the face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more univasc®
until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur with
univasc®, especially during the first few days of therapy. If fainting occurs, the patient should
stop taking univasc® and consult 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 their physician if they develop these conditions.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore
throat, fever) that could be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
second- and third-trimester exposure to ACE inhibitors and 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. Patients should be asked to report pregnancies to their
physicians as soon as possible.
Drug Interactions
Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy
when ACE inhibitors are started. The possibility of hypotensive effects with univasc® can be
minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake
before initiation of treatment with univasc®. If this is not possible, the starting dose of moexipril
should be reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION).
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Potassium Supplements and Potassium-Sparing Diuretics: univasc® can increase serum
potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics
(spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE
inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is
indicated, they should be given with caution and the patient’s serum potassium should be
monitored.
Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically
important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. These drugs should be
coadministered with caution, and frequent monitoring of serum lithium levels is recommended.
If a diuretic is also used, the risk of lithium toxicity may be increased.
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 univasc®.
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 moexipril, may result in
deterioration of renal function, including possible acute renal failure. These effects are usually
reversible. Monitor renal function periodically in patients receiving moexipril and NSAID
therapy.
The antihypertensive effect of ACE inhibitors, including moexipril, may be attenuated by
NSAIDS.
Other Agents: No clinically important pharmacokinetic interactions occurred when univasc®
was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine.
univasc® has been used in clinical trials concomitantly with calcium-channel-blocking agents,
diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents.
There was no evidence of clinically important adverse interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was detected in long-term studies in mice and rats at doses up to
14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m2 basis.
No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and
without metabolic activation, or in an in vivo nucleus anomaly test. However, increased
chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic
activation conditions at a 20-hour harvest time.
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Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on
a mg/m2 basis, and in rats up to 90.9 times the MRHD on a mg/m2 basis. No indication of
impaired fertility, reproductive toxicity, or teratogenicity was observed.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See
WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether univasc® is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when univasc® is given to a nursing mother.
Pediatric Use
Safety and effectiveness of univasc® in pediatric patients have not been established.
Geriatric Use
Clinical studies of univasc® 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
univasc® has been evaluated for safety in more than 2500 patients with hypertension; more than
250 of these patients were treated for approximately one year. The overall incidence of reported
adverse events was only slightly greater in patients treated with univasc® than patients treated
with placebo.
Reported adverse experiences were usually mild and transient, and there were no differences in
adverse reaction rates related to gender, race, age, duration of therapy, or total daily dosage
within the range of 3.75 mg to 60 mg. Discontinuation of therapy because of adverse
experiences was required in 3.4% of patients treated with univasc® and in 1.8% of patients
treated with placebo. The most common reasons for discontinuation in patients treated with
univasc® were cough (0.7%) and dizziness (0.4%).
All adverse experiences considered at least possibly related to treatment that occurred at any
dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with
univasc® alone and that were at least as frequent in the univasc® group as in the placebo group
are shown in the following table:
ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES
ADVERSE
UNIVASC
PLACEBO
EVENT
(N=674)
(N=226)
N
(%)
N
(%)
Cough Increased
41 (6.1)
5 (2.2)
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Dizziness
29 (4.3)
5 (2.2)
Diarrhea
21 (3.1)
5 (2.2)
Flu Syndrome
21 (3.1)
0 (0)
Fatigue
16 (2.4)
4 (1.8)
Pharyngitis
12 (1.8)
2 (0.9)
Flushing
11 (1.6)
0 (0)
Rash
11 (1.6)
2 (0.9)
Myalgia
9 (1.3)
0 (0)
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Other adverse events occurring in more than 1% of patients on moexipril that were at least as
frequent on placebo include: headache, upper respiratory infection, pain, rhinitis, dyspepsia,
nausea, peripheral edema, sinusitis, chest pain, and urinary frequency. See WARNINGS and
PRECAUTIONS for discussion of anaphylactoid reactions, angioedema, hypotension,
neutropenia/agranulocytosis, second and third trimester fetal/neonatal morbidity and mortality,
hyperkalemia, and cough.
Other potentially important adverse experiences reported in controlled or uncontrolled clinical
trials in less than 1% of moexipril patients or that have been attributed to other ACE inhibitors
include the following:
Cardiovascular: Symptomatic hypotension, postural hypotension, or syncope were seen in
9/1750 (0.51%) patients; these reactions led to discontinuation of therapy in controlled trials in
3/1254 (0.24%) patients who had received univasc® monotherapy and in 1/344 (0.3%) patients
who had received univasc® with hydrochlorothiazide (see PRECAUTIONS and WARNINGS).
Other adverse events included angina/myocardial infarction, palpitations, rhythm disturbances,
and cerebrovascular accident.
Renal: Of hypertensive patients with no apparent preexisting renal disease, 1% of patients
receiving univasc® alone and 2% of patients receiving univasc® with hydrochlorothiazide
experienced increases in serum creatinine to at least 140% of their baseline values (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Gastrointestinal: Abdominal pain, constipation, vomiting, appetite/weight change, dry
mouth, pancreatitis, hepatitis.
Respiratory: Bronchospasm, dyspnea, eosinophilic pneumonitis.
Urogenital: Renal insufficiency, oliguria.
Dermatologic: Apparent hypersensitivity reactions manifested by urticaria, rash, pemphigus,
pruritus, photosensitivity, alopecia.
Neurological and Psychiatric: Drowsiness, sleep disturbances, nervousness, mood changes,
anxiety.
Other: Angioedema (see WARNINGS), taste disturbances, tinnitus, sweating, malaise,
arthralgia, hemolytic anemia.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
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Creatinine and Blood Urea Nitrogen: As with other ACE inhibitors, minor increases in blood
urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in
approximately 1% of patients with essential hypertension who were treated with univasc®.
Increases are more likely to occur in patients receiving concomitant diuretics and in patients with
compromised renal function (see PRECAUTIONS, General).
Other (causal relationship unknown): Clinically important changes in standard laboratory
tests were rarely associated with univasc® administration.
Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of
moexipril-treated patients discontinued univasc® treatment because of laboratory abnormalities.
The incidence of abnormal laboratory values with moexipril was similar to that in the placebo-
treated group.
OVERDOSAGE
Human overdoses of moexipril have not been reported. In case reports of overdoses with other
ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of
2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated
single oral doses of up to 3 g/kg.
No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH
of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of
moexipril is not known.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities.
Because the hypotensive effect of moexipril is achieved through vasodilation and effective
hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution.
In addition, renal function and serum potassium should be monitored.
DOSAGE AND ADMINISTRATION
Hypertension
The recommended initial dose of univasc® in patients not receiving diuretics is 7.5 mg, one hour
prior to meals, once daily. Dosage should be adjusted according to blood pressure response.
The antihypertensive effect of univasc® may diminish towards the end of the dosing interval.
Blood pressure should, therefore, be measured just prior to dosing to determine whether
satisfactory blood pressure control is obtained. If control is not adequate, increased dose or
divided dosing can be tried. The recommended dose range is 7.5 to 30 mg daily, administered in
one or two divided doses one hour before meals. Total daily doses above 60 mg a day have not
been studied in hypertensive patients.
Reference ID: 3004714
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In patients who are currently being treated with a diuretic, symptomatic hypotension may
occasionally occur following the initial dose of univasc®. The diuretic should, if possible, be
discontinued for 2 to 3 days before therapy with univasc® is begun, to reduce the likelihood of
hypotension (see WARNINGS). If the patient’s blood pressure is not controlled with univasc®
alone, diuretic therapy may then be reinstituted. If diuretic therapy cannot be discontinued, an
initial dose of 3.75 mg of univasc® should be used with medical supervision until blood pressure
has stabilized (see WARNINGS and PRECAUTIONS, Drug Interactions).
Dosage Adjustment in Renal Impairment
For patients with a creatinine clearance ≤40 mL/min/1.73 m2, an initial dose of 3.75 mg once
daily should be given cautiously. Doses may be titrated upward to a maximum daily dose of
15 mg.
HOW SUPPLIED
univasc® (moexipril hydrochloride) 7.5 mg tablets are pink colored, biconvex, film-coated and
scored with engraved code 707 on the unscored side and SP above and 7.5 below the score.
They are supplied as follows:
Bottles of 90 (Unit-of-Use)
NDC 0091-3707-09
Bottles of 100
NDC 0091-3707-01
univasc® (moexipril hydrochloride) 15 mg tablets are salmon colored, biconvex, film-coated,
and scored with engraved code 715 on the unscored side and SP above and 15 below the score.
They are supplied as follows:
Bottles of 90 (Unit-of-Use)
NDC 0091-3715-09
Bottles of 100
NDC 0091-3715-01
Store, tightly closed, at controlled room temperature. Protect from excessive moisture.
If product package is subdivided, dispense in tight containers as described in USP-NF.
Manufactured for:
UCB, Inc.
Smyrna, GA 30080
Rev. 3E XX/20XX
Reference ID: 3004714
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:26.347979
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020312s033lbl.pdf', 'application_number': 20312, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
12,439
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
MIACALCIN nasal spray safely and effectively. See full prescribing
information for MIACALCIN nasal spray.
MIACALCIN® (calcitonin-salmon) nasal spray, for intranasal use
Initial U.S. Approval: 1975
-------------------------------RECENT MAJOR CHANGES-----------------------
Indications and Usage (1.2)
03/2014
Warnings and Precautions (5.4)
03/2014
----------------------------INDICATIONS AND USAGE---------------------------
Miacalcin nasal spray is a calcitonin, indicated for the treatment of
postmenopausal osteoporosis in women greater than 5 years postmenopause
when alternative treatments are not suitable. Fracture reduction efficacy has
not been demonstrated (1.1).
Limitations of Use:
Due to the possible association between malignancy and calcitonin
salmon use, the need for continued therapy should be re-evaluated on a
periodic basis (1.2, 5.4)
Miacalcin nasal spray has not been shown to increase bone mineral
density in early postmenopausal women (1.2)
----------------------DOSAGE AND ADMINISTRATION-----------------------
For intranasal use only: one spray (200 International Units) per day,
alternating nostrils daily (2.1)
Prior to first use, allow the bottle to reach room temperature and prime
the pump (2.2)
Ensure adequate calcium and vitamin D intake (2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Nasal Spray: 2200 International Units per mL of calcitonin-salmon in a 3.7
mL fill glass bottle with screw-on pump. Each actuation delivers 200
International Units of calcitonin-salmon (3)
-------------------------------CONTRAINDICATIONS------------------------------
Hypersensitivity to calcitonin-salmon or any of the excipients (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Serious hypersensitivity reactions including anaphylactic shock have
been reported. Consider skin testing prior to treatment in patients with
suspected hypersensitivity to calcitonin-salmon (5.1)
Hypocalcemia has been reported. Ensure adequate intake of calcium and
vitamin D (5.2)
Nasal adverse reactions, including severe ulceration can occur. Periodic
nasal examinations are recommended (5.3)
Malignancy: A meta-analysis of 21 clinical trials suggests an increased
risk of overall malignancies in calcitonin-salmon-treated patients (5.4,
6.1)
Circulating antibodies to calcitonin-salmon may develop, and may cause
loss of response to treatment (5.5)
------------------------------ADVERSE REACTIONS-------------------------------
Most common adverse reactions (3% or greater) are rhinitis, epistaxis and
other nasal symptoms, back pain, arthralgia, and headache (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA
1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Concomitant use of calcitonin-salmon and lithium may lead to a
reduction in plasma lithium concentrations due to increased urinary
clearance of lithium. The dose of lithium may require adjustment (7)
-----------------------USE IN SPECIFIC POPULATIONS----------------------
There are no data to support use in children (8.4)
Nasal reactions are more common in elderly patients (8.5)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 03/2014
Reference ID: 3467837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Postmenopausal Osteoporosis
1.2 Important Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1 Basic Dosing Information
2.2 Priming (Activation) of Pump
2.3 Recommendations for Calcium and Vitamin D Supplementation
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
5.2 Hypocalcemia
5.3 Nasal Adverse Reactions
5.4 Malignancy
5.5 Antibody Formation
5.6 Urine Sediment Abnormalities
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
6.3 Immunogenicity
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
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
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3467837
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 Postmenopausal Osteoporosis
Miacalcin nasal spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5
years postmenopause. Fracture reduction efficacy has not been demonstrated. Miacalcin nasal spray should be
reserved for patients for whom alternative treatments are not suitable (e.g., patients for whom other therapies
are contraindicated or for patients who are intolerant or unwilling to use other therapies).
1.2
Important Limitations of Use
Due to the possible association between malignancy and calcitonin-salmon use, the need for continued
therapy should be re-evaluated on a periodic basis [see Warnings and Precautions (5.4)].
Miacalcin nasal spray has not been shown to increase spinal bone mineral density in early postmenopausal
women.
2
DOSAGE AND ADMINISTRATION
2.1
Basic Dosing Information
The recommended dose of Miacalcin nasal spray is 1 spray (200 International Units) per day administered
intranasally, alternating nostrils daily.
2.2
Priming (Activation) of Pump
Unopened Miacalcin nasal spray should be stored in the refrigerator. Before using the first dose of Miacalcin
nasal spray, the patient should wait until it has reached room temperature. To prime the pump before it is used
for the first time, the bottle should be held upright and the two white side arms of the pump depressed toward
the bottle, repeat until a full spray is released. The pump is primed once the first full spray is emitted. To
administer, the nozzle should first be carefully placed into the nostril while the patient’s head is in the upright
position, then the pump should be firmly depressed toward the bottle. The pump should not be primed before
each daily dose.
2.3
Recommendations for Calcium and Vitamin D Supplementation
Patients who use Miacalcin nasal spray should receive adequate calcium (at least 1000 mg elemental calcium
per day) and vitamin D (at least 400 International Units per day).
3
DOSAGE FORMS AND STRENGTHS
Miacalcin nasal spray consists of one glass bottle and one screw-on pump. The bottle contains 3.7 mL of
calcitonin-salmon clear solution at a concentration of 2200 International Units per mL. A primed pump delivers
0.09 mL (200 International Units) calcitonin-salmon per actuation.
4
CONTRAINDICATIONS
Hypersensitivity to calcitonin-salmon or any of the excipients . Reactions have included anaphylactic shock,
anaphylaxis, bronchospasm, and swelling of the tongue or throat[see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
Serious hypersensitivity reactions have been reported in patients receiving Miacalcin nasal spray, e.g.,
bronchospasm, swelling of the tongue or throat, anaphylaxis and anaphylactic shock. Reports of serious
Reference ID: 3467837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hypersensitivity reactions with injectable calcitonin-salmon have also been reported, including reports of death
attributed to anaphylaxis. The usual provisions should be made for emergency treatment if such a reaction
occurs. Hypersensitivity reactions should be differentiated from generalized flushing and hypotension [see
Contraindications (4)].
For patients with suspected hypersensitivity to calcitonin-salmon, skin testing should be considered prior to
treatment utilizing a dilute, sterile solution of a calcitonin-salmon injectable product. Healthcare providers may
wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from
the Medical Services Department of Novartis Pharmaceuticals Corporation.
5.2
Hypocalcemia
Hypocalcemia associated with tetany (i.e. muscle cramps, twitching) and seizure activity has been reported with
calcitonin therapy. Hypocalcemia must be corrected before initiating therapy with Miacalcin nasal spray. Other
disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In
patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during
therapy with Miacalcin nasal spray. Use of Miacalcin nasal spray is recommended in conjunction with an
adequate intake of calcium and vitamin D [see Dosage and Administration (2.3)].
5.3
Nasal Adverse Reactions
Adverse reactions related to the nose including rhinitis and epistaxis have been reported. Development of
mucosal alterations may occur. Therefore, periodic nasal examinations with visualization of the nasal mucosa,
turbinates, septum and mucosal blood vessels are recommended prior to start of treatment with Miacalcin nasal
spray, periodically during the course of therapy, and at any time nasal symptoms occur.
Miacalcin nasal spray should be discontinued if severe ulceration of the nasal mucosa occurs, as indicated by
ulcers greater than 1.5 mm in diameter or penetrating below the mucosa, or those associated with heavy
bleeding. Although smaller ulcers often heal without withdrawal of Miacalcin nasal spray, medication should be
discontinued temporarily until healing occurs [see Adverse Reactions (6.1)].
5.4
Malignancy
In a meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray or
investigational oral formulations), the overall incidence of malignancies reported was higher among calcitonin
salmon-treated patients (4.1%) compared with placebo-treated patients (2.9%). This suggests an increased risk
of malignancies in calcitonin-salmon-treated patients compared to placebo-treated patients. The benefits for the
individual patient should be carefully considered against possible risks [see Adverse Reactions (6.1)].
5.5
Antibody Formation
Circulating antibodies to calcitonin-salmon have been reported with Miacalcin nasal spray. The possibility of
antibody formation should be considered in any patient with an initial response to Miacalcin nasal spray who
later stops responding to treatment [see Adverse Reactions (6.3)].
5.6
Urine Sediment Abnormalities
Coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers
at bed rest who were given injectable calcitonin-salmon to study the effect of immobilization on osteoporosis.
There was no other evidence of renal abnormality and the urine sediment normalized after calcitonin-salmon
was stopped. Periodic examinations of urine sediment should be considered. Urine sediment abnormalities have
not been reported in ambulatory volunteers treated with calcitonin-salmon nasal spray.
Reference ID: 3467837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Hypersensitivity Reactions, including anaphylaxis [see Warnings and Precautions (5.1)]
Hypocalcemia [see Warnings and Precautions (5.2)]
Nasal Adverse Reactions [see Warnings and Precautions (5.3)]
Malignancy [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.
The safety of Miacalcin (calcitonin-salmon) nasal spray in the treatment of postmenopausal osteoporosis was
assessed in 5 randomized, double-blind, placebo controlled trials that enrolled postmenopausal women, aged
45-75 years. The duration of the trials ranged from 1 to 2 years. The incidence of adverse reactions reported in
studies involving postmenopausal osteoporotic patients chronically exposed to Miacalcin nasal spray (N=341)
and to placebo nasal spray (N=131), and reported in greater than 3% of Miacalcin treated patients are presented
in the following table. Other than flushing, nausea, possible allergic reactions, and possible local irritative
effects in the respiratory tract, a relationship to Miacalcin nasal spray has not been established.
Table 1: Adverse Reactions Occurring in at Least 3% of
Postmenopausal Patients Treated with Miacalcin Nasal Spray
Miacalcin
Nasal Spray
Placebo
Nasal Spray
Adverse Reaction
N=341
% of Patients
N=131
% of Patients
Rhinitis
12
7
Symptom of Nose†
11
16
Back Pain
5
2
Arthralgia
4
5
Epistaxis
4
5
Headache
3
5
†Symptom of nose includes: nasal crusts, dryness, redness or erythema,
nasal sores, irritation, itching, thick feeling, soreness, pallor, infection,
stenosis, runny/blocked, small wound, bleeding wound, tenderness,
uncomfortable feeling and sore across bridge of nose.
Nasal Adverse Reactions: In all postmenopausal patients treated with Miacalcin nasal spray, the most
commonly reported nasal adverse reactions included rhinitis (12%), epistaxis (4%), and sinusitis (2%). Smoking
did not have a contributory effect on the occurrence of nasal adverse reactions.
Adverse reactions reported in 1-3% of patients treated with Miacalcin nasal spray include: influenza-like
symptoms, erythematous rash, arthrosis, myalgia, sinusitis, upper respiratory tract infection, bronchospasm,
abdominal pain, nausea, dizziness, paresthesia, abnormal lacrimation, conjunctivitis, lymphadenopathy,
infection, and depression.
Reference ID: 3467837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Malignancy
A meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray or
investigational oral formulations) was conducted to assess the risk of malignancies in calcitonin-salmon-treated
patients compared to placebo-treated patients. The trials in the meta-analysis ranged in duration from 6 months
to 5 years and included a total of 10883 patients (6151 treated with calcitonin-salmon and 4732 treated with
placebo). The overall incidence of malignancies reported in these 21 trials was higher among calcitonin-salmon
treated patients (254/6151 or 4.1%) compared with placebo-treated patients (137/4732 or 2.9%). Findings were
similar when analyses were restricted to the 18 nasal spray only trials [calcitonin-salmon 122/2712 (4.5%);
placebo 30/1309 (2.3%)].
The meta-analysis results suggest an increased risk of overall malignancies in calcitonin-salmon-treated patients
compared to placebo-treated patients when all 21 trials are included and when the analysis is restricted to the 18
nasal spray only trials (see Table 2). It is not possible to exclude an increased risk when calcitonin-salmon is
administered by the subcutaneous, intramuscular, or intravenous route because these routes of administration
were not investigated in the meta-analysis. The increased malignancy risk seen with the meta-analysis was
heavily influenced by a single large 5-year trial, which had an observed risk difference of 3.4% [95% CI (0.4%,
6.5%)]. Imbalances in risks were still observed when analyses excluded basal cell carcinoma (see Table 2); the
data were not sufficient for further analyses by type of malignancy. A mechanism for these observations has not
been identified. Although a definitive causal relationship between calcitonin-salmon use and malignancies
cannot be established from this meta-analysis, the benefits for the individual patient should be carefully
evaluated against all possible risks [see Warnings and Precautions (5.4)].
Table 2: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients
Compared with Placebo-Treated Patients
Patients
Malignancies
Risk Difference1
(%)
95%
Confidence
Interval2 (%)
All (nasal spray + oral)
All
1.0
(0.3, 1.6)
All (nasal spray + oral)
Excluding basal
cell carcinoma
0.5
(-0.1, 1.2)
All (nasal spray only)
All
1.4
(0.3, 2.6)
All (nasal spray only)
Excluding basal
cell carcinoma
0.8
(-0.2, 1.8)
1 The overall adjusted risk difference is the difference between the percentage of patients who had any malignancy
(or malignancy excluding basal cell carcinoma) in calcitonin-salmon and placebo treatment groups, using the
Mantel-Haenszel (MH) fixed-effect method. A risk difference of 0 is suggestive of no difference in malignancy
risks between the treatment groups.
2 The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect
method.
6.2
Postmarketing Experience
Because postmarketing 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.
The following adverse reactions have been reported during post-approval use of Miacalcin nasal spray.
Reference ID: 3467837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Allergic / Hypersensitivity Reactions: Serious allergic reactions have been reported in patients receiving
calcitonin-salmon nasal spray, including anaphylaxis and anaphylactic shock.
Hypocalcemia: Hypocalcemia with paresthesia has been reported.
Body as a whole: facial or peripheral edema
Cardiovascular: hypertension, vasodilatation, syncope, chest pain
Nervous system: dizziness, seizure, visual or hearing impairment, tinnitus
Respiratory/ Special Senses: cough, bronchospasm, dyspnea, loss of taste/smell
Skin: rash/dermatitis, pruritus, alopecia, increased sweating
Gastrointestinal: diarrhea
Nervous system disorders: tremor
6.3
Immunogenicity
Consistent with the potentially immunogenic properties of medicinal products containing peptides,
administration of Miacalcin may trigger the development of anti-calcitonin antibodies. In a two-year Miacalcin
nasal spray clinical study that evaluated immunogenicity, a measurable antibody titer was found in 69% of
patients treated with Miacalcin and 3% of placebo-treated patients. Antibody formation may be associated with
a loss of response to treatment [see Warnings and Precautions (5.5)].
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of a positive antibody test result may be influenced by several factors,
including assay methodology, sample handling, timing of sample collection, concomitant medications, and
underlying disease. For these reasons, comparison of antibodies to Miacalcin nasal spray with the incidence of
antibodies to other calcitonin-containing products may be misleading.
7
DRUG INTERACTIONS
No formal drug interaction studies have been performed with Miacalcin nasal spray.
Concomitant use of calcitonin-salmon and lithium may lead to a reduction in plasma lithium concentrations due
to increased urinary clearance of lithium. The dose of lithium may require adjustment.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C:
Risk Summary
There are no adequate and well-controlled studies in pregnant women. Miacalcin nasal spray should be used
during pregnancy only if the potential benefit justifies the use as compared with potential risks to the patient and
fetus. Based on animal data, Miacalcin is predicted to have low probability of increasing the risk of adverse
developmental outcomes above background risk.
Animal Data
Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by
subcutaneous injection in doses 4-18 times the parenteral dose (of 54 International Units/m2) and 70-278 times
the intranasal dose recommended for human use based on body surface area.
Reference ID: 3467837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
formula
No embryo/fetal toxicities related to Miacalcin were reported from maternal subcutaneous daily doses in rats up
to 80 International Units/kg/day from gestation day 6 to 15.
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. No studies have been conducted to assess the
impact of Miacalcin on milk production in humans, its presence in human breast milk, or its effects on the
breast-fed child. Because many drugs are excreted in human milk, caution should be exercised when Miacalcin
is administered to a nursing woman. Calcitonin has been shown to inhibit lactation in rats.
8.4
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5
Geriatric Use
In a multi-centered, double-blind, randomized clinical study of calcitonin-salmon nasal spray, 279 patients were
less than 65 years old, while 467 patients were 65 to 74 years old and 196 patients were 75 years old and older.
Compared to subjects less than 65 years old, the incidence of nasal adverse reactions (rhinitis, irritation,
erythema, and excoriation) was higher in patients over the age of 65, particularly among those over the age of
75. 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.
10
OVERDOSAGE
The pharmacologic actions of Miacalcin nasal spray suggest that hypocalcemic tetany could occur in overdose.
Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose.
Single doses of Miacalcin nasal spray up to 1600 International Units, doses up to 800 International Units per
day for 3 days and chronic administration of doses up to 600 International Units per day have been studied
without serious adverse effects.
11
DESCRIPTION
Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by
the ultimobranchial gland of birds and fish.
Miacalcin (calcitonin-salmon) nasal spray is a synthetic polypeptide of 32 amino acids in the same linear
sequence that is found in calcitonin of salmon origin. This is shown by the following graphic formula:
Reference ID: 3467837
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It is provided in a 3.7 mL fill glass bottle as a solution for nasal administration. This is sufficient medication for
30 doses.
Active Ingredient: calcitonin-salmon 2200 International Units per mL (corresponding to 200 International Units
per 0.09 mL actuation).
Inactive Ingredients: sodium chloride, benzalkonium chloride, hydrochloric acid (added as necessary to adjust
pH) and purified water.
The activity of Miacalcin nasal spray is stated in International Units based on bioassay in comparison with the
International Reference Preparation of calcitonin-salmon for Bioassay, distributed by the National Institute of
Biological Standards and Control, Holly Hill, London.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Calcitonin-salmon is a calcitonin receptor agonist. Calcitonin-salmon acts primarily on bone, but direct renal
effects and actions on the gastrointestinal tract are also recognized. Calcitonin-salmon appears to have actions
essentially identical to calcitonins of mammalian origin, but its potency per mg is greater and it has a longer
duration of action.
The actions of calcitonin on bone and its role in normal human bone physiology are still not completely
elucidated, although calcitonin receptors have been discovered in osteoclasts and osteoblasts.
12.2
Pharmacodynamics
The information below, describing the clinical pharmacology of calcitonin, has been derived from studies with
injectable calcitonin-salmon. The mean bioavailability of calcitonin-salmon nasal spray is approximately 3% of
the injectable calcitonin-salmon in healthy subjects and, therefore, the conclusions concerning the clinical
pharmacology of this preparation may be different.
Bone
Single injections of calcitonin-salmon caused a marked transient inhibition of the ongoing bone resorptive
process. With prolonged use, there is a persistent, smaller decrease in the rate of bone resorption.
Histologically, this is associated with a decreased number of osteoclasts and an apparent decrease in their
resorptive activity.
In healthy adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin
salmon results in decreases in serum calcium within the limits of the normal range. In healthy children and in
patients whose bone resorption is more rapid, decreases in serum calcium are more pronounced in response to
calcitonin-salmon.
Kidney
Studies with injectable calcitonin-salmon show increases in the excretion of filtered phosphate, calcium, and
sodium by decreasing their tubular reabsorption. Comparable studies have not been conducted with Miacalcin
nasal spray.
Gastrointestinal Tract
Some evidence from studies with injectable preparations suggests that calcitonin-salmon may have effects on
the gastrointestinal tract. Short-term administration of injectable calcitonin-salmon results in marked transient
decreases in the volume and acidity of gastric juice and in the volume and the trypsin and amylase content of
Reference ID: 3467837
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pancreatic juice. Whether these effects continue to be elicited after each injection of calcitonin-salmon during
chronic therapy has not been investigated. These studies have not been conducted with Miacalcin nasal spray.
Calcium Homeostasis
In two clinical studies designed to evaluate the pharmacodynamic response to calcitonin-salmon nasal spray,
administration of calcitonin-salmon 100-1600 International Units to healthy volunteers resulted in rapid and
sustained decreases within the normal range for both total serum calcium and serum ionized calcium. Single
doses of calcitonin-salmon greater than 400 International Units did not produce any further biological response
to the drug.
12.3
Pharmacokinetics
The bioavailability of Miacalcin nasal spray relative to intramuscular administration in healthy volunteers is
between 3 and 5%. Miacalcin nasal spray is absorbed rapidly by the nasal mucosa with a mean Tmax of about 13
minutes. The terminal half-life of calcitonin-salmon has been calculated to be around 18 minutes and no
evidence of accumulation was observed with multiple dosing.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
The incidence of pituitary adenomas was increased in rats after one and two years of subcutaneous exposure to
synthetic calcitonin-salmon. The significance of this finding to humans is unknown because pituitary adenomas
are very common in rats as they age, the pituitary adenomas did not transform into metastatic tumors, there
were no other clear treatment-related neoplasms, and synthetic calcitonin-salmon related neoplasms were not
observed in mice after two years of dosing.
Rat findings:
The only clear neoplastic finding in rats dosed subcutaneously with synthetic calcitonin-salmon was an increase
in the incidence of pituitary adenomas in male Fisher 344 rats and female Sprague Dawley rats after one year of
dosing and male Sprague Dawley rats dosed for one and two years. In female Sprague Dawley rats, the
incidence of pituitary adenomas after two years was high in all treatment groups (between 80% and 92%
including the control groups) such that a treatment-related effect could not be distinguished from natural
background incidence. The lowest dose in male Sprague Dawley rats that developed an increased incidence of
pituitary adenomas after two years of dosing (1.7 International Units/kg/day) is approximately 2 times the
maximum recommended intranasal dose in humans (200 International Units/day) based on body surface area
conversion between rats and humans and a 20-fold conversion factor to account for decreased clinical exposure
via the intranasal route. The findings suggest that calcitonin-salmon reduced the latency period for development
of non-functioning pituitary adenomas.
Mouse findings:
No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with
synthetic calcitonin-salmon at doses up to 800 International Units/kg/day. The 800 International Units/kg/day
dose is approximately 390 times the maximum recommended intranasal dose in humans (200 International
Units) based on scaling for body surface area and a 20-fold conversion factor to account for low clinical
exposure via the intranasal route.
Mutagenesis
Synthetic calcitonin-salmon tested negative for mutagenicity using Salmonella typhimurium (5 strains) and
Escherichia coli (2 strains), with and without rat liver metabolic activation, and was not clastogenic in a
Reference ID: 3467837
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chromosome aberration test in Chinese Hamster V79 cells. There was no evidence that calcitonin-salmon was
clastogenic in the in vivo mouse micronucleus test.
Fertility
Effects of calcitonin-salmon on fertility have not been assessed in animals.
14
CLINICAL STUDIES
Two randomized, placebo-controlled, two-year trials were conducted in 266 postmenopausal women who were
greater than 5 years postmenopause with spinal, forearm or femoral bone mineral density (BMD) at least one
standard deviation below the normal value for healthy premenopausal women (T-score < -1). In both studies, a
total of 144 patients received Miacalcin nasal spray 200 International Units or placebo daily. The intent-to-treat
population comprised 139 patients who had at least one follow-up BMD measurement. In study 1, patients also
received 500 mg daily calcium supplements, while in study 2, patients received no calcium supplementation.
The primary endpoint for both studies was percent change in lumbar spine BMD at 2 years. Miacalcin nasal
spray increased lumbar vertebral BMD relative to placebo in women with low bone mass who were greater than
5 years post menopause (see Table 3 below).
Table 3:
Miacalcin nasal spray: Lumbar Spine Bone Mineral Density In Women Greater
Than 5 years Postmenopause With Low Bone Mass
Lumbar Spine Bone Mineral Density,
Mean Change From Baseline (in %) at Month 24
Study 1
(with calcium
supplement)
n (ITT) = 100
Study 2
(no calcium supplement)
n (ITT) = 39
Miacalcin 200 IU NS daily
+1.56
+1.02
Placebo
+0.20
-1.85
Treatment Difference
+1.36
+2.87
p-value†
< 0.05
< 0.005
ITT: Intent To Treat
IU: International Units
NS: nasal spray
†p-values by parametric testing (2-tailed 2-sample t-test)
No effects of calcitonin-salmon nasal spray on cortical bone of the forearm or hip were demonstrated.
In clinical studies of postmenopausal osteoporosis, bone biopsy and radial bone mass assessments at baseline
and after 26 months of daily injectable calcitonin-salmon indicate that calcitonin therapy results in the
formation of normal bone.
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Miacalcin Nasal Spray is available as a metered dose clear solution in a 3.7 mL fill clear glass bottle that
contains 2200 International Units calcitonin-salmon per mL. A screw-on pump is provided. After priming, the
Reference ID: 3467837
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pump will deliver 200 International Units per activation (0.09 mL per
spray)................................................................. NDC 0078-0311-54
Storage and Handling
Store unopened bottle in refrigerator between 2°C-8°C (36°F-46°F). Protect from freezing.
Store bottle in use at room temperature between 15°C-30°C (59°F-86°F) in an upright position, for up to 35
days. Each bottle contains at least 30 doses.
Discard bottle after 30 doses.
17
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Instruct patients on pump assembly, priming of the pump, and nasal introduction of Miacalcin nasal spray.
Although instructions for patients are supplied with the individual bottle, procedures for use should be
demonstrated to each patient [see Dosage and Administration (2.2)]. Patients should notify their healthcare
provider if they develop significant nasal irritation [see Warnings and Precautions (5.3)].
Inform patients of the potential increase in risk of malignancy [see Warnings and Precautions (5.4)].
Advise patients to maintain an adequate calcium (at least 1000 mg elemental calcium per day) and vitamin
D (at least 400 International Units per day) intake [see Dosage and Administration (2.3)].
Instruct patients to seek emergency medical help or go to the nearest hospital emergency room right away if
they develop any signs or symptoms of a serious allergic reaction.
Advise patients how to correctly store unopened and opened product [see How Supplied/Storage and
Handling (16)]. Advise patients that the bottle should be discarded after 30 doses, because after 30 doses,
each spray may not deliver the correct amount of medication even if the bottle is not completely empty.
T201X-XX
March 2014
Reference ID: 3467837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
Miacalcin® (MEE-uh-KAL-sin)
(calcitonin-salmon)
nasal spray
Read this Patient Information before you start using Miacalcin and each time you get a refill.
There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or your treatment.
What is Miacalcin?
Miacalcin is a prescription medicine used to treat osteoporosis in women more than 5 years after
menopause. Miacalcin should be used for women who cannot use other treatments or who choose
not to use other treatments for osteoporosis.
It is not known if Miacalcin lowers the chance of having bone fractures.
Miacalcin has not been shown to be effective in women less than 5 years after menopause.
It is not known if Miacalcin is safe and effective in children under 18 years of age.
Who should not use Miacalcin?
Do not use Miacalcin if you:
are allergic to calcitonin-salmon or any of the ingredients in Miacalcin. See the end of this
leaflet for a complete list of ingredients in Miacalcin.
What should I tell my healthcare provider before using Miacalcin?
Before you use Miacalcin, tell your healthcare provider if you:
have any other medical conditions
have low calcium levels in your blood
are pregnant or plan to become pregnant. It is not known if Miacalcin can harm your
unborn baby.
are breastfeeding or plan to breastfeed. It is not known if Miacalcin passes into your
breast milk. You and your healthcare provider should decide if you will use Miacalcin or
breastfeed.
Tell your healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
Especially tell your healthcare provider if you take:
lithium. Your healthcare provider may need to change your dose of lithium while you use
Miacalcin.
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 use Miacalcin?
For detailed instructions, see the Instructions for Use at the end of this Patient
Information leaflet.
Reference ID: 3467837
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Use Miacalcin exactly as your healthcare provider tells you to use it.
Do not use Miacalcin until your healthcare provider shows you and you understand how
to use it correctly.
Use 1 spray of Miacalcin, 1 time each day, in 1 nostril (inside your nose).
o Start with 1 spray in your left nostril on your first day, followed by 1 spray in your
right nostril on the second day.
o Continue to switch nostrils for your dose each day.
Your healthcare provider should check your nose before you start using Miacalcin and often
while you are using it.
Tell your healthcare provider if you start to have discomfort (irritation) in your nose that
bothers you while you use Miacalcin.
Your health care provider should prescribe calcium and vitamin D to help prevent low
calcium levels in your blood while you use Miacalcin.
Take your calcium and vitamin D as your healthcare provider tells you to.
There are 30 doses (sprays) of Miacalcin in each bottle. After 30 doses, each spray may not
give you the right amount of medicine, even if the bottle is not completely empty. Keep
track of the number of doses of medicine used from your bottle.
If you use too much Miacalcin, call your healthcare provider or go to the nearest hospital
emergency room right away.
What are the possible side effects of Miacalcin?
Miacalcin may cause serious side effects, including:
allergic reactions
Some people have had an allergic reaction when using Miacalcin. Some reactions may be
serious and can be life threatening. Call your healthcare provider or go to the nearest
hospital emergency room right away if you have any of these symptoms of an allergic
reaction.
o trouble breathing
o swelling of your face, throat or tongue
o fast heartbeat
o chest pain
o feel dizzy or faint
If you might be allergic to calcitonin-salmon, your healthcare provider should do a skin test
before you use Miacalcin.
low calcium levels in your blood (hypocalcemia)
Miacalcin may lower the calcium levels in your blood. If you have low blood calcium before
you start using Miacalcin, it may get worse during treatment. Your low blood calcium must
be treated before you use Miacalcin. Most people with low blood calcium levels do not have
symptoms, but some people may have symptoms. Call your healthcare provider right away
if you have any of these symptoms of low blood calcium:
o numbness or tingling in your fingers, toes, or around your mouth
Your healthcare provider should:
Reference ID: 3467837
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o do blood tests while you use Miacalcin
o prescribe calcium and vitamin D to help prevent low calcium levels in your blood
while you use Miacalcin.
Take your calcium and vitamin D as your healthcare provider tells you to.
nose irritation
Irritation of your nose can happen while you are using Miacalcin, especially if you are over
65 years of age. Call your healthcare provider right way if you have any of these symptoms
of nose irritation:
o crusting
o dryness
o redness or swelling
o nose sores (ulcers)
o nose bleeds
Your healthcare provider may stop your treatment with Miacalcin until your nose irritation
symptoms go away.
risk of cancer
People who use calcitonin-salmon, the medicine in Miacalcin, may have an increased risk of
cancer.
increase of certain cells (sediment) in your urine
Your healthcare provider should test your urine often while you are using Miacalcin.
The most common side effects of Miacalcin include:
back pain
muscle aches
headache
runny nose
These are not all the possible side effects of Miacalcin. For more information, ask your healthcare
provider or pharmacist.
Tell your healthcare provider right away if you have any side effect that bothers you or does not
go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1
800-FDA-1088.
How do I store Miacalcin?
Store open bottles of Miacalcin at room temperature between 59°F to 86°F (15°C to 30°C)
for 35 days.
Store unopened bottles of Miacalcin in the refrigerator between 36°F to 46F (2C to 8°C).
Do not freeze.
Store Miacalcin bottles in an upright position.
Safely throw away Miacalcin in the trash after you have used 30 doses (sprays).
Keep Miacalcin and all other medicines out of the reach of children.
Reference ID: 3467837
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General information about the safe and effective use of Miacalcin.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use Miacalcin for a condition for which it was not prescribed. Do not give Miacalcin
to other people, even if they have the same symptoms you have. It may harm them.
This Patient Information summarizes the most important information about Miacalcin. If you
would like more information, talk with your healthcare provider. You can ask your pharmacist or
healthcare provider for information about Miacalcin that is written for health professionals.
For more information, call 1-888-669-6682.
What are the ingredients in Miacalcin?
Active Ingredients: calcitonin-salmon
Inactive Ingredients: sodium chloride, benzalkonium chloride, hydrochloric acid and purified
water.
Reference ID: 3467837
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Instructions for Use
Miacalcin® (MEE-uh-KAL-sin)
(calcitonin-salmon)
nasal spray
For Nasal Use Only.
Important information about your Miacalcin:
A single spray of MIACALCIN (calcitonin-salmon) nasal spray contains 1 daily dose of
medicine.
Each Miacalcin bottle contains the right amount of medicine. The bottle may not be
completely filled to the top. This is normal.
This package contains 1 bottle of Miacalcin and 1 screw-on pump. See Figure A.
Store unopened bottles of Miacalcin in the refrigerator between 36°F to 46F (2C to
8°C). Do not freeze.
After you open your bottle of Miacalcin, store it at room temperature between 59°F to
86°F (15°C to 30°C) in an upright position. Do not shake the bottle.
Figure A usage illustration
Preparing your Miacalcin:
Step 1. Remove the bottle from your refrigerator and let it
reach room temperature. Check the medicine in the bottle to
make sure it is clear and colorless without particles.
Important: If your Miacalcin bottle and pump has
already been put together by your pharmacist or
healthcare provider, go to Step 7.
Reference ID: 3467837
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Step 2. Lift up the blue plastic tab and carefully pull the metal
safety seal off the bottle. See Figure B. usage illustration
Figure B
Step 3. Keep the bottle upright and remove the rubber stopper
from the bottle. See Figure C. usage illustration
Figure C
Step 4. Hold the nose spray pump and gently remove the
plastic protective cap from the bottom of the nose spray pump.
See Figure D.
Do not push down on the pump when it is not attached to the
bottle. usage illustration
Figure D
Reference ID: 3467837
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usage illustration
Figure E usage illustration
Step 5. Hold the bottle upright and insert the nose spray
pump into the bottle. Turn the pump clockwise to tighten it
until it is securely attached to the bottle. See Figure E.
Step 6. Gently pull the clear protective cap to remove it from
the top of the nose spray pump. See Figure F.
Figure F
Step 7. Check to see if your Miacalcin has been primed.
To make sure you get the right dose of Miacalcin
medicine you must prime each new bottle and pump
before you use it for the first time.
If your pharmacist or healthcare provider puts the
bottle and pump together for you, check to see if it
has already been primed by pressing on the pump 1
time. See Figure G.
If you see a full spray from the pump, the bottle and
pump has already been primed for you.
If you do not see a full spray, you must prime the
bottle and pump.
Step 8. Priming your Miacalcin:
Hold the bottle upright with your pointer finger and
middle finger on the 2 side arms of the pump, and
your thumb on the bottom of the bottle. Firmly press
down on the arms of the pump and press down again
if needed until you see a full spray of medicine. See
Reference ID: 3467837 usage illustration
Figure G
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usage illustration
Figure H
Figure G.
Now your Miacalcin is ready for you to use.
Do not prime the pump before you use it each day
because this will waste your medicine.
Giving your Miacalcin dose:
Step 9. Insert the nasal spray pump in 1 side of your
nose. See Figure H.
Keep your head upright. Carefully tilt the bottle and
place the nose spray pump into 1 side of your nose. usage illustration
Figure I usage illustration
Step 10. Firmly press down on the nose spray pump to
release the medicine. See Figure I.
Give 1 spray of Miacalcin, 1 time daily, in 1 side of
your nose (nostril). Spray your medicine in a different
side of your nose each day.
You do not need to breathe in or inhale while you are
giving your dose.
You may not feel the spray inside your nose.
Some of the medicine may drip out of your nose. This
is normal, and you are still getting all of the medicine
you need.
Cleaning your Miacalcin pump:
Step 11. Wipe the nose spray pump with a clean, damp cloth 1
to 2 times a week. See Figure J.
Dry the nose spray pump with a clean cloth.
Reference ID: 3467837
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Figure J usage illustration
Storing your Miacalcin:
Step 12 . Gently put the protective cap back on the nasal spray
pump.
Hold the bottle with 2 fingers u nder the 2 side arms
of the pump. See Figure K.
Be careful not push down on the pump while you are
putting the cap back on it.
Do not refrigerate Miacalcin b etween doses.
Store Miacalcin upright.
Do not shake the bottle.
Figure K
When should I throw away Miacalcin?
•
Unopened, refrigerat ed bottles can be used until the expiration date stamped on
the bottle and box.
•
Throw away Miacalcin after you use 30 doses (sprays).
•
Throw away Miacalcin bottle s left at room temperature (opened or unopened) for
more than 35 days.
For more information on MIACALCIN nasal spray a nd how to put it together, call Novartis
Pharmaceuticals Corporation at 1-888-669-6682.
This Patient Info rmation and Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T201X-XX/T201X-XX
March 2014
Reference ID: 3467837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:26.605921
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020313s034lbl.pdf', 'application_number': 20313, 'submission_type': 'SUPPL ', 'submission_number': 34}
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12,441
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T2000-08
89008101
Vivelle®
estradiol transdermal system
Continuous delivery for twice-weekly application
Rx only
Prescribing Information
ESTROGENS
HAVE
BEEN
REPORTED
TO
INCREASE
THE
RISK
OF
ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN.
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that
"natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.
DESCRIPTION
The Vivelle estradiol transdermal system contains estradiol in a multipolymeric adhesive. The system
is designed to release estradiol continuously upon application to intact skin.
Five systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.075,
or 0.1 mg of estradiol per day via skin of average permeability. Each corresponding system having an
active surface area of 7.25, 11.0, 14.5, 22.0 or 29.0 cm
2 contains 2.17, 3.28, 4.33, 6.57, or
8.66 mg of estradiol USP, respectively. The composition of the systems per unit area is
identical.
Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5
(10)-triene-3,17ß-diol.
The structural formula is
HO
H
H
H
H
CH3
OH
The molecular formula of estradiol is C18H24O2. The molecular weight is 272.39.
The Vivelle system comprises three layers. Proceeding from the visible surface toward the
surface attached to the skin, these layers are (1) a translucent flexible film consisting of an ethylene
This label may not be the latest approved by FDA.
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Page 2
vinyl alcohol copolymer film, a polyurethane film, urethane polymer and epoxy resin, (2) an adhesive
formulation containing estradiol, acrylic adhesive, polyisobutylene, ethylene vinyl acetate copolymer,
1,3 butylene glycol, styrene-butadiene rubber, oleic acid, lecithin, propylene glycol, bentonite,
mineral oil, and dipropylene glycol, and (3) a polyester release liner that is attached to the adhesive
surface and must be removed before the system can be used.
The active component of the system is estradiol. The remaining components of the
system are pharmacologically inactive.
CLINICAL PHARMACOLOGY
Vivelle system provides systemic estrogen replacement therapy by releasing estradiol, the major
estrogenic hormone secreted by the human ovary. Estrogens are largely responsible for the
development and maintenance of the female reproductive system and secondary sexual
characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic
interconversions, estradiol is the principal intracellular human estrogen and is substantially more
potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen
in
normally
cycling
adult
women
is
the
ovarian
follicle,
which
secretes
70 to 500 µg of estradiol daily, depending on the phase of the menstrual cycle. After menopause,
most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal
cortex,
to
estrone
by
peripheral
tissues.
Thus,
estrone
and
the
sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in
postmenopausal women.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing
hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism and
estrogen
replacement
therapy
acts
to
reduce
the
elevated
levels
of
these
hormones seen in postmenopausal women.
Pharmacokinetics
Absorption
In a multiple-dose study consisting of three consecutive patch applications of the Vivelle
system, which was conducted in 17 healthy, postmenopausal women, blood levels of
estradiol and estrone were compared following application of these units to sites on the abdomen and
buttocks in a crossover fashion. Patches that deliver nominal estradiol doses of approximately
0.0375 mg/day and 0.1 mg/day were applied to abdominal application sites while the 0.1 mg/day
doses were also applied to sites on the buttocks. These systems increased estradiol levels above
baseline within 4 hours and maintained respective mean levels of 25 and 79 pg/mL above baseline
following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were
observed following application to the buttocks. At the same time, increases in estrone plasma
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Page 3
concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen
and 61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained
slightly above baseline at 12 hours following removal of the patches in this study, results from another
study show these levels to return to baseline values within 24 hours following removal of the patches.
The figure (see Figure 1) illustrates the mean plasma concentrations of estradiol at steady-
state during application of these patches at four different dosages.
Figure 1. Steady-State Estradiol Plasma Concentrations
for Systems Applied to the Abdomen
Nonbaseline-corrected levels
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Page 4
The corresponding pharmacokinetic parameters are summarized in the table below.
Steady-State Estradiol Pharmacokinetic Parameters
for Systems Applied to the Abdomen (mean ± standard deviation)
Nonbaseline-corrected data*
Dosage
(mg/day)
Cmax
†
(pg/mL)
Cavg
‡
(pg/mL)
Cmin (84 hr)§
(pg/mL)
0.0375
046 ± 16
34 ± 10
30 ± 10
0.05
083 ± 41
#57 ± 23#
41 ± 11#
0.075
099 ± 35
072 ± 24
60 ± 24
0.1
133 ± 51
089 ± 38
90 ± 44
0.1¶
145 ± 71
104 ± 52
85 ± 47
*Mean baseline estradiol concentration = 11.7 pg/mL
†Peak plasma concentration
‡Average plasma concentration
§Minimum plasma concentration at 84 hr
#Measured over 80 hr
¶Applied to the buttocks
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentrations in the sex hormone
target organs. Estradiol and other naturally occurring estrogens are bound mainly to sex hormone
binding globulin (SHBG), and to a lesser degree to albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take
place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to
estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via
sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and
hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the
circulating estrogens exist as sulfate conjugated, especially estrone sulfate, which serves as a
circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Studies conducted with the Vivelle system show the drug has an apparent mean half-life of 4.4 ± 2.3
This label may not be the latest approved by FDA.
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Page 5
hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone
returned to baseline levels within 24 hours.
Special Populations
The Vivelle system has been studied only in healthy postmenopausal women (approximately 90%
Caucasian). The Vivelle system has not been studied in patients with renal or hepatic impairment.
Drug Interactions
No drug interaction studies were conducted with the Vivelle system.
Adhesion
Data showing the number of systems in controlled studies that required replacement due to
inadequate adhesion is not available.
Clinical Studies
In two controlled clinical trials of 356 subjects, the 0.075 and 0.1 mg doses were superior to
placebo in relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and
12 of treatment. The 0.0375 and 0.05 mg doses, however, did not differ from placebo until
approximately Week 6.
Therefore, an additional 12-week placebo-controlled study in 255 patients was performed to
establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot
flushes in these 255 patients was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in the
figure below (see Figure 2).
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Page 6
Figure 2.
The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of
vasomotor symptoms at Week 4 and maintained efficacy through Weeks 8 and 12 of treatment. All
doses of Vivelle (0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of
vasomotor symptoms.
Efficacy and safety of the Vivelle system in the prevention of postmenopausal osteoporosis have
been studied in a 2-year double-blind, randomized, placebo-controlled, parallel group study. A total
of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal
women (within 5 years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral
density within 2 standard deviation of average peak bone mass, i.e., ≥ 0.827 g/cm2) were enrolled in
this study; 194 patients were randomized to one of the four doses of Vivelle (0.1, 0.05, 0.0375 or
0.025 mg/day) and 67 patients to placebo. Over 2 years, study systems were applied to the buttock
or the abdomen twice a week. Nonhysterectomized women received oral medroxy progesterone
acetate (2.5 mg/day) throughout the study.
The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized
(61%) or nonhysterectomized (39%) women with a mean age of 52.0 years (range 27 to 62 years;
the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty two
(89%) of randomized subjects (173 on active drug, 59 on placebo) contributed data to the analysis
of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary
efficacy variable. Patients were given supplemental dietary calcium (1000 mg elemental calcium/day)
but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle
This label may not be the latest approved by FDA.
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Page 7
dose groups; in contrast to this a decrease in AP lumbar spine BMD was observed in placebo
patients. All Vivelle doses were significantly superior to placebo (p<0.05) at all time points with the
exception of Vivelle 0.05 mg/day at 6 months. The highest dose of Vivelle was superior to the three
lower doses. There were no statistically significant differences in pairwise comparisons among the
three lower doses. (See Figure 3.)
Figure 3. Bone mineral density - AP Lumbar spine
Least squares means of percentage change from baseline
All randomized patients with at least one post-baseline assessment available
with last post-baseline observation carried forward
-4
-3
-2
-1
0
1
2
3
4
5
6
7
Week26
Week52
Week78
Week104
Treatment duration
% change from baseline
Vivelle 0.1mg/day
Vivelle 0.05mg/day
Vivelle 0.0375mg/day
Vivelle 0.025mg/day
Placebo
Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome
variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to
placebo (p<0.05) at 24 months. The highest Vivelle dose was superior to placebo at all timepoints.
A mixture of significant and non significant results were obtained for the lower dose groups at earlier
time points. Again, the highest Vivelle dose was superior to the three lower doses, and there were
no significant differences among the three lower doses at this skeletal site. (See Figure 4).
Figure 4. Bone mineral density - Femoral neck
Least squares means of percentage change from baseline
All randomized patients with at least one post-baseline assessment available
with last post-baseline observation carried forward
-4
-3
-2
-1
0
1
2
3
4
5
6
7
Week26
Week52
Week78
Week104
Treatment duration
% change from baseline
Vivelle 0.1mg/day (A)
Vivelle 0.05mg/day (B)
Vivelle 0.0375mg/day (C)
Vivelle 0.025mg/day (D)
Placebo (P)
A vs P: p<0.05
A,B,C vs P: p<0.05
A,B,C,D vs P: p<0.05
A,B,C,D vs P: p<0.05
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Page 8
The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-
telopeptides of type 1 collagen (a marker of bone resorption) decreased numerically in most of the
active treatment groups relative to baseline. However, the decreases in both markers were
inconsistent across treatment groups and the differences between active treatment groups and
placebo were not statistically significant.
INDICATIONS AND USAGE
Vivelle
® (estradiol transdermal system) is indicated in the following:
1. Treatment of moderate-to-severe vasomotor symptoms associated with the menopause.
2. Treatment of vulvar and vaginal atrophy.
3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian
failure.
4. Prevention of postmenopausal osteoporosis (in at risk patients). Estrogen replacement therapy
reduces bone resorption and retards postmenopausal bone loss. When estrogen therapy is
discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal
period.
White and Asian women are at higher risk for osteoporosis than black women, and thin women
are at a higher risk than heavier women, who generally have higher endogenous estrogen levels.
Early menopause is one of the strongest predictors for the develpoment of osteoporosis. Other
factors associated with osteoporosis include genetic factors (small build, family history), lifestyle
(cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body
weight and dietary calcium intake).
Essential to the prevention and management of osteoporosis are weight bearing exercise,
adequate calcium intake. Postmenopausal women absorb dietary calcium less efficiently than
premenopausal women and require an average of 1500 mg/day of elemental calcium to remain in
neutral calcium balance. The average calcium intake in the USA in 400-600 mg/day. Therefore,
when not contraindicated, calcium supplementation may be helpful for women with suboptimal
dietary intake.
CONTRAINDICATIONS
Patients with known hypersensitivity to any of the components of the therapeutic system should not
use Vivelle.
Estrogens should not be used in individuals with any of the following conditions:
1.
Known or suspected pregnancy (see PRECAUTIONS). Estrogen may cause fetal harm
when administered to a pregnant woman.
2.
Undiagnosed abnormal genital bleeding.
3.
Known or suspected cancer of the breast.
4.
Known or suspected estrogen-dependent neoplasia.
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Page 9
5.
Active thrombophlebitis or thromboembolic disorders, or a documented history of these
conditions.
WARNINGS
1.
Induction of Malignant Neoplasms.
a.
Breast cancer. Some studies have suggested a possible increased incidence of breast cancer
in women taking estrogen therapy at higher doses for prolonged periods of time, especially in excess
of 10 years. The majority of studies, however, have not shown an association with the usual doses
used for estrogen replacement therapy. Women on this therapy should have regular breast
examinations and should be instructed in breast self-examination.
b.
Endometrial cancer. The reported endometrial cancer risk among unopposed estrogen
users is about 2- to 12-fold greater than in nonusers and appears dependent on duration of treatment
and on estrogen dose. Most studies show no significant increased risk associated with the use of
estrogens
for
less
than
1
year.
The
greatest
risk
appears
associated
with
prolonged use with increased risks of 15- to 24-fold for five to 10 years or more. In three studies,
persistence of risk was demonstrated for 8 to over 15 years after cessation of
estrogen treatment. In one study, a significant decrease in the incidence of endometrial
cancer occurred six months after estrogen withdrawal. Concurrent progestin therapy may
offset this risk, but the overall health impact in postmenopausal women is not known
(see PRECAUTIONS).
c.
Congenital reproductive tract disorders. Estrogen therapy during pregnancy is associated
with an increased risk of fetal congenital reproductive tract disorders. In female offspring, there is an
increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and clear cell vaginal cancer
later in life; in males, urogenital and possibly testicular abnormalities. Although some of these changes
are benign, it is not known whether they are precursors of malignancy.
2.
Gallbladder Disease. Two studies have reported a 2- to 4-fold increase in the risk of
surgically confirmed gallbladder disease in postmenopausal women receiving oral estrogen
replacement therapy, similar to the 2-fold increase previously noted in users of oral
contraceptives.
3.
Cardiovascular Disease. Large doses of estrogen (5 mg conjugated estrogens per day),
comparable to those used to treat cancer of the prostate and breast, have been shown in a large
prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary
embolism, and thrombophlebitis. These risks cannot necessarily be extrapolated from men to
women. However, to avoid the theoretical cardiovascular risk to women caused by high estrogen
doses, the dose for estrogen replacement therapy should not exceed the lowest effective dose.
4.
Elevated Blood Pressure. Occasional blood pressure increases during estrogen
replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often, blood
pressure has remained the same or has dropped. Postmenopausal estrogen use does not increase the
risk of stroke. Nonetheless, blood pressure should be monitored at regular intervals with estrogen
use, especially if high doses are used. Ethinyl estradiol and conjugated estrogens have been shown to
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Page 10
increase renin substrate. In contrast to these oral estrogens, transdermally administered estradiol
does not affect renin substrate.
5.
Hypercalcemia. Administration of estrogen may lead to severe hypercalcemia in patients
with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
PRECAUTIONS
General
1.
Addition of a Progestin. Studies of the addition of a progestin for 10 or more days of a
cycle of estrogen administration or daily in an estrogen/progestin continuous regimen have reported a
lower incidence of endometrial hyperplasia than would be induced by estrogen treatment alone.
Morphologic and biochemical studies of endometria suggest that 10 to 14 days of progestin are
needed to provide maximal maturation of the endometrium and to reduce the likelihood of
hyperplastic changes.
There are, however, possible risks that may be associated with the use of progestins in
estrogen replacement regimens. These include:
(1)
adverse effects on lipoprotein metabolism (lowering HDL and raising LDL), which could
diminish the purported cardioprotective effect of estrogen therapy (see PRECAUTIONS,
below);
(2)
impairment of glucose tolerance; and
(3)
possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiologic
data are available to address this point (see PRECAUTIONS, below).
The choice of progestin, its dose, and its regimen may be important in minimizing these
adverse effects, but these issues will require further study before they are clarified.
2.
Cardiovascular Risk. A causal relationship between estrogen replacement therapy and
reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore,
the effect of added progestins on this putative benefit is not yet known.
In recent years, many published studies have suggested that there may be a cause-effect
relationship between postmenopausal oral estrogen replacement therapy without added progestins
and a decrease in cardiovascular disease in women. Although most of the observational studies
which assessed this statistical association have reported a 20% to 50% reduction in coronary heart
disease
risk
and
associated
mortality
in
estrogen
takers,
the
following should be considered when interpreting these reports:
(1)
Because only one of these studies was randomized and it was too small to yield statistically
significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced
risk of coronary artery disease cannot be attributed with certainty to estrogen replacement therapy. It
may instead have been caused by life-style and medical characteristics of the women studied with the
result that healthier women were selected for estrogen therapy. In general, treated women were of
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Page 11
higher socioeconomic and educational status, more slender, more physically active, more likely to
have undergone surgical menopause, and less likely to have diabetes than the untreated women.
Although some studies attempted to control for these selection factors, it is common for properly
designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus,
ongoing and future large-scale randomized trials may fail to confirm this apparent benefit.
(2)
Current medical practice often includes the use of concomitant progestin therapy in women
with intact uteri (see PRECAUTIONS and WARNINGS). While the effects of added progestins
on the risk of ischemic heart disease are not known, all available progestins reverse at least some of
the favorable effects of estrogens on HDL and LDL levels.
(3)
While the effects of added progestins on the risk of breast cancer are also unknown,
available epidemiologic evidence suggests that progestins do not reduce, and may enhance, the
moderately increased breast cancer incidence that has been reported with prolonged estrogen
replacement therapy (see WARNINGS, above).
Because relatively long-term use of estrogens by a woman with a uterus has been shown to
induce endometrial cancer, physicians often recommend that women who are deemed candidates for
hormone replacement should take progestins as well as estrogens. When considering prescribing
concomitant
estrogens
and
progestins
for
hormone
replacement
therapy, physicians and patients are advised to carefully weigh the potential benefits and risks of the
added progestin. Large-scale randomized, placebo-controlled, prospective clinical trials are required
to clarify these issues.
3.
Physical Examination. A complete medical and family history should be taken prior to the
initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include
special reference to blood pressure, breasts, abdomen, and pelvic organs and should include a
Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one year
without reexamining the patient.
4.
Hypercoagulability. Some studies have shown that women taking estrogen replacement
therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect
appears dose- and duration-dependent and is less pronounced than that associated with oral
contraceptive use. Also, postmenopausal women tend to have increased coagulation parameters at
baseline compared to premenopausal women. Epidemiological studies, which employed primary
orally
administered
estrogen
products,
have
suggested
that
hormone replacement therapy (HRT) is associated with an increased relative risk of
developing venous thromboembolism (VTE), e.g., deep venous thrombosis or pulmonary embolism.
Risk/benefit should therefore be carefully weighed in consultation with the patient when prescribing
any form of HRT to women with a risk factor for VTE.
5.
Familial Hyperlipoproteinemia. Estrogen therapy may be associated with massive
elevations of plasma triglycerides leading to pancreatitis and other complications in patients with
familial defects of lipoprotein metabolism.
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Page 12
6.
Fluid Retention. Because estrogens may cause some degree of fluid retention, conditions
that might be exacerbated by this factor, such as asthma, epilepsy, migraine, and cardiac or renal
dysfunction, require careful observation.
7.
Uterine Bleeding and Mastodynia. Certain patients may develop undesirable manifestations
of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.
8.
Impaired Liver Function. Estrogens may be poorly metabolized in patients with impaired
liver function and should be administered with caution.
Information for the Patient
See text of Patient Package Insert, which appears after the HOW SUPPLIED section.
Laboratory Tests
Estrogen administration should generally be guided by clinical response at the smallest dose, rather
than laboratory monitoring, for relief of symptoms for those indications in which
symptoms are observable.
Drug/Laboratory Test Interactions
Some of these drug/laboratory test interactions have been observed only with estrogen
progestin combinations (oral contraceptives):
1.
Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX,
X, XII, VII-X complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-
factor Xa and antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and
fibrinogen activity; increased plasminogen antigen and activity.
2.
Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the
elevated TBG. Free T4 and free T3 concentrations are unaltered.
3.
Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG),
sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex
steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other
plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
ceruloplasmin).
4.
Increased plasma HDL and HDL2 subfraction concentrations, reduced LDL cholesterol
concentration, increased triglyceride levels.
5.
Impaired glucose tolerance.
6.
Reduced response to metyrapone test.
7.
Reduced serum folate concentration.
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Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term, continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, cervix, vagina, testis, and liver (see
CONTRAINDICATIONS and WARNINGS).
Pregnancy Category X
Estrogens should not be used during pregnancy. There is no indication for estrogen therapy during
pregnancy or during the immediate postpartum period. Estrogens are ineffective for the prevention or
treatment of threatened or habitual abortion. Estrogens are not indicated for the prevention of
postpartum breast engorgement.
Estrogen therapy during pregnancy is associated with an increased risk of congenital defects
in the reproductive organs of the fetus, and possibly other birth defects. Studies of women who
received
diethylstilbestrol
(DES)
during
pregnancy
have
shown
that
female
offspring have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix,
and clear cell vaginal cancer later in life; male offspring have an increased risk of
urogenital abnormalities and possibly testicular cancer later in life. The 1985 DES Task Force
concluded that use of DES during pregnancy is associated with a subsequent increased risk of breast
cancer in the mothers, although a causal relationship remains unproven and the observed level of
excess risk is similar to that for a number of other breast cancer risk factors.
Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of
the milk.
Pediatric Use
The safety and effectiveness in pediatric patients have not been established.
Geriatric Use
The safety and effectiveness in geriatric patients (over age 65) have not been established.
ADVERSE REACTIONS
See WARNINGS and Boxed Warning regarding the potential adverse effects on the fetus, the
induction of malignant neoplasms, gallbladder disease, cardiovascular disease, elevated blood
pressure, and hypercalcemia.
The most commonly reported systemic adverse event to the Vivelle system in two 12 week
controlled clinical trials was headache. This occurred in approximately 36% of patients treated with
active systems and in 30% of patients treated with placebo. The most common topical adverse
events in these trials were erythema and pruritus at the application site. Most cases were considered
mild. Fewer than 5% of patients on active drug at the final visit of the study had reactions of greater
than mild intensity. Rash was reported in approximately 5% of patients treated with active systems
and in approximately 4% of patients treated with placebo in these trials. Two patients out of 356
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Page 14
were discontinued from the trials due to skin
irritation/erythema.
In a 2-year controlled trial, back pain was reported in 13% of patients treated with the Vivelle
system and 4.5% of patients treated with placebo. Local application site reactions (patch site
erythema, itching, rash, burning, irritation) were reported in approximately 9% of patients treated
with active systems and 10% of patients treated with placebo. In most cases the local application
site reactions were considered mild; none was considered severe. Two patients out of 259 were
discontinued from the trial due to local application site reactions. Vaginal bleeding and breast
tenderness were more common in the highest dose group (0.1 mg/day) than in the three other active
treatment groups or in placebo-treated patients.
The following additional adverse reactions have been reported with estrogen therapy:
1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding
or flow; breakthrough bleeding, spotting; increase in size of uterine leiomyomata; vaginal
candidiasis; change in amount of cervical secretion.
2. Breasts. Tenderness, enlargement.
3. Gastrointestinal. Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice;
gallbladder disease.
4. Skin. Chloasma or melasma that may persist when drug is discontinued; erythema
multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism.
5. Eyes. Steepening of corneal curvature; intolerance to contact lenses.
6. Central Nervous System. Headache, migraine, dizziness; mental depression; chorea.
7. Miscellaneous. Increase or decrease in weight; reduced carbohydrate tolerance;
aggravation of porphyria; edema; changes in libido.
Post-Marketing Adverse Events
Although a causal relationship with Vivelle has not been established, adverse events
reported from marketing experience include: isolated reports of anaphylaxis, rare elevated liver
function tests, and reports of leg pain.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause
nausea and vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
The adhesive side of the Vivelle system should be placed on a clean, dry area of the trunk of the
body (including the abdomen or buttocks). The Vivelle system should not be applied to the
breasts. The Vivelle system should be replaced twice weekly. The sites of application must be
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Page 15
rotated, with an interval of at least 1 week allowed between applications to a particular site. The area
selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight
clothing may rub the system off. The system should be applied immediately after opening the pouch
and removing the protective liner. The system should be pressed firmly in place with the palm of the
hand for about 10 seconds, making sure there is good contact, especially around the edges. In the
event that a system should fall off, the same system may be reapplied. If necessary, a new system
may be applied. In either case, the original treatment schedule should be continued.
Initiation of Therapy
For treatment of moderate-to-severe vasomotor symptoms and vulvar and vaginal atrophy
associated with the menopause, start therapy with Vivelle estradiol transdermal system
0.0375 mg/day applied to the skin twice weekly. In order to use the lowest dosage necessary for the
control of symptoms, decisions to increase dosage should not be made until after the first month of
therapy.
Attempts
to
discontinue
or
taper
medication
should
be
made
at
3-month to 6-month intervals.
In women not currently taking oral estrogens or in women switching from another
estradiol transdermal therapy, treatment with the Vivelle estradiol transdermal system may be initiated
at once. In women who are currently taking oral estrogens, treatment with the Vivelle estradiol
transdermal system should be initiated 1 week after withdrawal of oral hormone replacement
therapy, or sooner if menopausal symptoms reappear in less than 1 week.
For the prevention of postmenopausal osteoporosis, the minimum dose that has been shown to be
effective is the 0.025 mg/day system. The dosage may be adjusted as necessary. Reproductive
system-associated adverse events were encountered more frequently in the highest dose group (0.1
mg/day) than in other active treatment dose groups or in placebo-treated patients.
Therapeutic Regimen
Vivelle may be given continuously in patients who do not have an intact uterus. In those patients with
an intact uterus, Vivelle may be given continuously or on a cyclic schedule (e.g., three weeks on drug
followed by one week off drug) with a progestin.
HOW SUPPLIED
Vivelle estradiol transdermal system 0.025 mg/day – each 7.25 cm2 system contains 2.17 mg of
estradiol USP for nominal* delivery of 0.025 mg of estradiol per day
Patient Calendar Pack of 8 systems………………………………………..NDC 0078-0348-42
Carton of 6 patient Calendar Packs of 8 systems…………………………..NDC 0078-0348-44
Vivelle estradiol transdermal system 0.0375 mg/day - each 11.0 cm2 system contains 3.28 mg
of estradiol USP for nominal* delivery of 0.0375 mg of estradiol per day.
Patient Calendar Pack of 8 systems............................................................... NDC 0083-2325-08
Carton of 6 Patient Calendar Packs of 8 systems........................................... NDC 0083-2325-62
Carton of 24 systems ................................................................................... NDC 0083-2325-25
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Page 16
Vivelle estradiol transdermal system 0.05 mg/day - each 14.5 cm2 system contains 4.33 mg of
estradiol USP for nominal* delivery of 0.05 mg of estradiol per day.
Patient Calendar Pack of 8 systems............................................................... NDC 0083-2326-08
Carton of 6 Patient Calendar Packs of 8 systems........................................... NDC 0083-2326-62
Carton of 24 systems .................................................................................... NDC 0083-2326-25
Vivelle estradiol transdermal system 0.075 mg/day - each 22.0 cm2 system contains 6.57 mg of
estradiol USP for nominal* delivery of 0.075 mg of estradiol per day.
Patient Calendar Pack of 8 systems............................................................... NDC 0083-2327-08
Carton of 6 Patient Calendar Packs of 8 systems........................................... NDC 0083-2327-62
Carton of 24 systems ................................................................................... NDC 0083-2327-25
Vivelle estradiol transdermal system 0.1 mg/day - each 29.0 cm2 system contains 8.66 mg of
estradiol USP for nominal* delivery of 0.1 mg of estradiol per day.
Patient Calendar Pack of 8 systems............................................................... NDC 0083-2328-08
Carton of 6 Patient Calendar Packs of 8 systems........................................... NDC 0083-2328-62
Carton of 24 systems ................................................................................... NDC 0083-2328-25
*See DESCRIPTION
Do not store above 86°F (30°C). Do not store unpouched. Apply immediately upon removal from
the protective pouch.
REV: Aug 2000 T2000-08
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Page 17
Information for the Patient
T2000-09
Vivelle®
estradiol transdermal system
Rx only
ESTROGENS INCREASE THE RISK OF CANCER OF THE UTERUS IN WOMEN
WHO HAVE HAD THEIR MENOPAUSE ("CHANGE OF LIFE").
If you use any estrogen-containing drug, it is important to visit your doctor regularly and report any
unusual vaginal bleeding right away. Vaginal bleeding after menopause may be a warning sign of
uterine cancer. Your doctor should evaluate any unusual vaginal bleeding to find out the cause.
INTRODUCTION
Your doctor has prescribed the Vivelle system for the treatment of your menopausal symptoms and
to help prevent osteoporosis. During menopause, production of estrogen hormones by your body
decreases well below the amounts normally produced during your fertile years. In many women this
decrease in estrogen production causes uncomfortable symptoms, most noticeably hot flushes and
sleep disturbance. Estrogens can be given to reduce or eliminate these symptoms and help prevent
osteoporosis.
The Vivelle system that your doctor has prescribed for you releases small amounts of
estradiol through the skin in a continuous way. Estradiol is the same hormone that your ovaries
produce abundantly before menopause. The dose of estradiol you require will depend upon your
individual
response.
The
dose
is
adjusted
by
the
size
of
the
Vivelle
system used; the systems are available in five sizes.
INFORMATION ABOUT VIVELLE
How Vivelle works
Vivelle contains estradiol. When applied to the skin as directed below, the Vivelle system releases
estradiol, which flows through the skin into the bloodstream.
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How and Where to Apply Vivelle
Each system is individually sealed in a protective pouch. Tear open this pouch at the indentation (do
not use scissors) and remove the system.
A stiff protective liner covers the adhesive side of the system-the side that will be placed against your
skin. This liner must be removed before applying the system. Hold the unit with the protective liner
facing you.
Peel off one side of the protective liner and discard it. Try to avoid touching the sticky side of the
system with your fingers.
Using the other half of the liner as a handle, apply the sticky side of the system to a dry area of the
skin on the trunk of the body (including the abdomen or buttocks). Press the sticky side on the skin
and smooth down.
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Page 19
Fold back the remaining side of the system. Grasp the straight edge of the protective liner and pull it
off the system.
Press the system firmly in place.
OR
Some women may find that it is more comfortable to wear Vivelle on the buttocks. Do not apply
Vivelle to your breasts. The sites of application must be rotated, with an interval of at least 1 week
allowed between applications to a particular site. The area selected should not be oily, damaged, or
irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system
immediately after opening the pouch and removing the protective liner. Press the system firmly in
place with the palm of your hand for about 10 seconds, making sure there is good contact, especially
around the edges.
The Vivelle system should be worn continuously until it is time to replace it with a new
system. You may wish to experiment with different locations when applying a new system, to find
ones that are most comfortable for you and where clothing will not rub on the system.
When to Apply Vivelle
The Vivelle system should be replaced twice weekly. Your Vivelle package contains a
calendar checklist to help you remember a schedule. Mark the 2-day schedule you plan to follow.
Always change the system on the 2 days of the week you have marked.
When changing the system, remove the used Vivelle system and discard it. Any
adhesive that might remain on your skin can be easily rubbed off. Then place the new Vivelle system
on a different skin site. (The same skin site should not be used again for at least 1 week after
removal of the system.)
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Please note: Contact with water when you are bathing, swimming, or showering will not
affect the system. In the event that a system should fall off, put this same system back on and
continue to follow your original treatment schedule. If necessary, you may apply a new system but
continue to follow your original schedule.
Benefits of treatment with Vivelle
Regular use of the Vivelle twice weekly offers relief of moderate-to-severe symptoms of menopause
and helps to prevent osteoporosis.
Small quantities of the naturally occurring hormone estradiol
are absorbed through the skin from the Vivelle system, ensuring a continuous supply of circulating
hormone in the body.
USES OF ESTROGEN
To reduce moderate or severe menopausal symptoms. Estrogens are hormones produced by the
ovaries. The decrease in the amount of estrogen that occurs in all women, usually between ages 45
and 55, causes the menopause. Sometimes the ovaries are removed by an operation, causing
"surgical menopause." When the amount of estrogen begins to decrease, some women develop very
uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden intense
episodes of heat and sweating ("hot flashes"). The use of drugs containing estrogens can help the
body adjust to lower estrogen levels.
Some women have only mild menopausal symptoms, or none at all, and do not need
estrogen therapy for these particular symptoms. Other women may need estrogens for a few months
while their bodies adjust to lower estrogen levels. For the treatment of menopausal symptoms only,
most
women
need
estrogen
replacement
therapy
for
no
longer
than
6 months.
To treat vulvar and vaginal atrophy (itching, burning, dryness in or around the vagina,
difficulty or burning on urination) associated with menopause.
To treat certain conditions in which a young woman's ovaries do not produce enough
estrogen naturally.
To help prevent osteoporosis (thinning of bones). Osteoporosis is a thinning of the bones that
makes them weaker and allows them to break more easily. The bones of the spine, wrists and hips
break most often in osteoporosis. Both men and women start to lose bone mass after about age 40,
but women lose bone mass faster after the menopause. Women who are likely to develop
osteoporosis often have one or more of the following characteristics: white or Asian race, slim,
cigarette smokers, and a family history of osteoporosis in a mother, sister, or aunt. Women who
have relatively early menopause, often because their ovaries were removed during an operation
(surgical menopause), also are more likely to develop osteoporosis than women whose menopause
happens at the average age.
Using estrogens after the menopause slows down bone thinning and may prevent bones from
breaking. Lifelong adequate calcium intake, either in the diet (such as dairy products) or by calcium
supplements (to reach a total daily intake of 1000 milligrams per day before menopause or 1500
milligrams per day after menopause), may help to prevent osteoporosis. Regular weight-bearing
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 21
exercise may also help to prevent osteoporosis. Before you change your calcium intake or exercise
habits, it is important to discuss these lifestyle changes with your doctor to find out if they are safe for
you.
WHEN ESTROGENS SHOULD NOT BE USED
During pregnancy. If you think you may be pregnant, do not use any form of estrogen-
containing drug. Using estrogens while you are pregnant may cause your unborn child to have birth
defects. Estrogens do not prevent miscarriage (spontaneous abortion) and are not needed in the days
following childbirth. If you take estrogens during pregnancy, your unborn child has a greater than
usual chance of having birth defects. The risk of developing these defects is small, but clearly larger
than
the
risk
in
children
whose
mothers
did
not
take
estrogens during pregnancy. These birth defects may affect the baby's urinary system and sex organs.
Daughters born to mothers who took DES (an estrogen drug) have a higher
than usual chance of developing cancer of the vagina or cervix when they become teenagers or young
adults. Sons may have a higher than usual chance of developing cancer of the
testicles when they become teenagers or young adults.
If you have unusual vaginal bleeding which has not been evaluated by your doctor (see
Boxed Warning). Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially
if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she
can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you
serious harm if your vaginal bleeding is caused by cancer of the uterus.
If you have had cancer. Since estrogens increase the risk of certain types of cancer, you should not
use estrogens if you have or have ever had cancer of the breast or uterus.
If you have any circulation problems. Estrogen therapy should be used only after consultation
with your doctor and only in recommended doses. Patients with current or past abnormal blood
clotting should not use estrogens (see DANGERS OF ESTROGENS, below).
When they are ineffective. During menopause, some women develop nervous symptoms or
depression. Estrogens do not relieve these symptoms. You may have heard that taking estrogens for
years
after
menopause
will
keep
your
skin
soft
and
supple
and
keep
you
feeling young. There is no evidence for these claims and such long-term estrogen use may have
serious risks.
After childbirth or when breastfeeding a baby. Estrogens should not be used to try to stop the
breasts from filling with milk after a baby is born. Such treatment may increase the risk of developing
blood clots (see DANGERS OF ESTROGENS, below).
If you are breastfeeding, you should avoid using any drugs because many drugs pass through
to the baby in the milk. While nursing a baby, you should take drugs only on the advice of your
healthcare provider.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 22
DANGERS OF ESTROGENS
Cancer of the uterus. The risk of developing cancer of the uterus gets higher the longer estrogens
are
used
and
when
larger
doses
are
taken.
One
study
showed
that
when
estrogens are discontinued, this increased risk of cancer seems to fall off quickly. Three other studies
showed that the risk for uterine cancer stayed high for 8 to more than 15 years after stopping
estrogen treatment. Because of this risk, it is important to take the lowest dose that works and to
take it only as long as you need it. Using progestin therapy together with
estrogen therapy may reduce the higher risk of uterine cancer related to estrogen use
(see OTHER INFORMATION, below).
If you have had your uterus removed (total hysterectomy), there is no danger of developing
cancer of the uterus.
Cancer of the breast. The majority of studies have shown no association between the usual doses
used
for
estrogen
replacement
therapy
and
breast
cancer.
Some
studies
have
suggested a possible increased incidence of breast cancer in women taking estrogens for prolonged
periods of time, especially in excess of 10 years if higher doses are used.
Regular breast examinations by a health professional, and monthly self-examinations,
are recommended for women receiving estrogen therapy, as they are for all women.
Gallbladder disease. Women who use estrogens after menopause are more likely to
develop gallbladder disease needing surgery than women who do not use estrogens.
Abnormal blood clotting. Taking estrogens may increase the risk of blood clots. These clots can
cause a stroke, heart attack, or pulmonary embolus, any of which may cause death or long term
serious disability.
SIDE EFFECTS
In addition to the risks listed above, the following side effects have been reported with
estrogen use:
• Headache.
• Nausea and vomiting.
• Breast tenderness or enlargement.
• Enlargement of benign tumors ("fibroids") of the uterus.
• Retention of excess fluid. This may make some conditions worsen, such as asthma, epilepsy,
migraine, heart disease, or kidney disease.
• A spotty darkening of the skin, particularly on the face. Skin irritation, redness, or rash may
occur at the site of application.
• Back pain.
• Vaginal spotting or bleeding.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 23
In Postmarketing experience, although a causal relationship with Vivelle has not been
established, isolated reports of anaphylaxis as well as rare reports of elevated liver function tests have
been received.
REDUCING RISK OF ESTROGEN USE
If you use estrogens, you can reduce your risks by doing these things:
See your doctor regularly. While you are using estrogens, it is important to visit your doctor at
least once a year for a check-up. If you develop vaginal bleeding while taking estrogens, you may
need further evaluation. If members of your family have had breast cancer or if you have ever had
breast lumps or an abnormal mammogram (breast x-ray), you may need to have more frequent
breast examinations.
Reassess your need for estrogens. You and your doctor should reevaluate whether or not you still
need estrogens at least every six months.
Be alert for signs of trouble. Report these or any other unusual side effects to your doctor
immediately:
• Abnormal bleeding from the vagina.
• Pains in the calves or chest, sudden shortness of breath, or coughing blood (indicating possible
clots in the legs, heart, or lungs).
• Severe headache, dizziness, faintness, or changes in vision (indicating possible clots in the brain
or eye).
• Breast lumps.
• Yellowing of the skin or eyes.
• Pain, swelling, or tenderness in the abdomen.
• Skin irritation, redness, or rash.
OTHER INFORMATION
If your uterus has not been removed, your doctor may choose to prescribe a progestin, a
different hormonal drug to be used in association with estrogen treatment. Progestins lower the risk
of
developing
endometrial
hyperplasia,
a
possible
precancerous
condition
of
the
uterine lining, which may occur while using estrogen. There are possible additional risks that may be
associated with the inclusion of a progestin in estrogen treatment. The possible risks include
unfavorable effects on blood fats and sugars, as well as a possible further increase in breast cancer
risk that may be associated with long-term estrogen use.
Some research has suggested that estrogen taken without progestins may protect women
against developing heart disease. However, this effect of estrogen is not certain.
You are cautioned to discuss very carefully with your doctor or healthcare provider all the
possible risks and benefits of long-term estrogen and progestin treatment, as they affect you
personally.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 24
Your doctor has prescribed this drug for you and you alone. Do not give the drug to
anyone else.
Keep this and all drugs out of the reach of children. In case of overdose, remove the
system and call your doctor, hospital, or poison control center immediately.
This leaflet provides a summary of the most important information about estrogens. If you
want more information, ask your doctor or pharmacist to show you the professional labeling.
T2000-09
T2000-08/T2000-09
REV: Aug 2000
Printed in U.S.A.
89008101
Distributed by
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
©2000 Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:26.704546
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20323S23lbl.pdf', 'application_number': 20323, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
12,440
|
NOT FOR INTRATHECAL USE
OXILAN® (Ioxilan Injection) 300 mgI/mL
OXILAN® (Ioxilan Injection) 350 mgI/mL
OXILAN® (Ioxilan Injection) 300 mgI/mL Pharmacy Bulk Package
OXILAN® (Ioxilan Injection) 350 mgI/mL Pharmacy Bulk Package
PHARMACY BULK PACKAGE IS NOT FOR DIRECT INFUSION
Nonionic Contrast Agents
DESCRIPTION
OXILAN® (Ioxilan Injection) formulations are stable, aqueous, sterile, and non- pyrogenic solutions for intravascular
administration as diagnostic radiopaque media. Ioxilan is designated chemically as N-(2,3-dihydroxypropyl)-N’-(2-
hydroxyethyl)-5-[N-(2,3-dihydroxypropyl) acetamido]-2,4,6-triiodoisophthal-amide and has the following structural
formula:
The molecular weight of ioxilan is 791.12 and the organically bound iodine content is 48.1%. Ioxilan is nonionic and
does not dissociate in solution. OXILAN® (Ioxilan Injection) Pharmacy Bulk Package is available in two strengths:
OXILAN® (Ioxilan Injection) 300 mgI/mL and OXILAN® (Ioxilan Injection) 350 mgI/mL.
Each mL of OXILAN® (Ioxilan Injection) 300 mgI/mL provides 623 mg ioxilan. Each mL of OXILAN® (Ioxilan Injection)
350 mgI/mL provides 727 mg ioxilan. Each mL of OXILAN® (Ioxilan Injection) 300 mgI/mL Pharmacy Bulk Package
provides 623 mg ioxilan.
Each mL of OXILAN® (Ioxilan Injection) 350 mgI/mL Pharmacy Bulk Package provides 727 mg ioxilan.
Each mL of OXILAN® solution contains 0.1 mg edetate calcium disodium (anhydrous basis), 1.0 mg tromethamine,
0.5 mg sodium chloride and a minimum of 0.2 mg (0.01 mEq) sodium. The pH is adjusted to 6.8 (5.5 to 7.5) with
hydrochloric acid and sodium hydroxide. The solutions contain no preservative.
Pertinent physicochemical data are below. OXILAN® (Ioxilan Injection) is hypertonic compared to plasma
(approximately 285 mOsm/kg water).
Concentration (mgI/mL)
Concentration W/V
300
350
Measured Osmolality
(mOsm/kg water) @ 37°C
610
721
Viscosity (cPs)
@ 37°C
@ 20°C
5.1
9.4
8.1
16.3
Specific Gravity
@ 37°C
@ 20°C
1.319
1.327
1.373
1.382
The OXILAN® formulations are clear, colorless to pale yellow solutions containing no undissolved solids.
Crystallization does not occur at room temperature. OXILAN® solutions have osmolalities of 2.1 and 2.5 times that of
plasma (285 mOsm/kg water) and are hypertonic under conditions of use.
Page 1 of 11
Reference ID: 3788321
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each bottle of OXILAN® Pharmacy Bulk Package is to be used for dispensing multiple single dose preparations
utilizing a suitable transfer device.
CLINICAL PHARMACOLOGY
General
Ioxilan is a nonionic, water soluble, triiodinated x-ray contrast agent for intravascular injection. Intravascular injection
of a radiopaque diagnostic agent opacifies those vessels in the path of flow of the contrast medium, permitting
radiographic visualization of the internal structures of the human body until significant hemodilution occurs.
Pharmacokinetics
In healthy young (21-27 years) male (n = 4) and female volunteers (n = 4) who each received OXILAN® Injection,
72.8 g ioxilan (35.0 g iodine), the drug showed biphasic and first order pharmacokinetics. Ioxilan is distributed mainly
in the blood as suggested by the apparent volume of distribution (central compartment), 7.2 ± 1.0 L in women and
10.0 ± 2.4 L in men (mean ± sd). The total clearance values were 95.4 ± 11.1 mL·min-1 and 101.0 ± 14.7 mL·min-1
and the renal clearance values were 89.4 ± 13.3 mL·min-1 and 94.9 ± 16.6 mL·min-1 for women and men,
respectively. An initial fast distribution phase with a half-life of 13.1 ± 4.2 minutes (women) or 23.5 ± 15.3 minutes
(men) was followed by an elimination phase with a half-life of 102.0 ± 16.9 minutes (women) and 137 ± 35.4 minutes
(men). Binding of ioxilan to plasma protein is negligible.
The average amount of ioxilan excreted unchanged in urine at 24 hours represents 93.7% of the dose in young
healthy subjects (21-27 years) after intravenous administration of OXILAN® Injection. This finding suggests that,
compared to the renal excretion, biliary and/or gastrointestinal excretion are not important for OXILAN®.
The pharmacokinetics profile and total clearance of ioxilan in patients with significantly impaired renal function have
not been studied. In pooled data from 80 subjects with abnormal baseline BUNS or creatinines, who received either
ioxilan (n = 44) or iohexol (n = 36), there was a higher occurrence of post-procedure increased creatinine levels (p =
0.008); also, the systolic pressure was lower at 2-6 hours (p = 0.043). Dose adjustment in patients with renal failure
and blood brain barrier interaction has not been studied. OXILAN® Injection binds negligibly to plasma or serum
protein and can be dialyzed.
Metabolism
There is no evidence for metabolism of OXILAN® Injection.
Pharmacodynamics
As with other iodinated contrast agents, following OXILAN® Injection, the degree of contrast enhancement is directly
related to the iodine content in the administered dose; peak iodine plasma levels occur immediately following rapid
intravenous injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution
in the vascular and extravascular fluid compartments.
Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds
to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to- three second
scans performed within 30 to 90 seconds after injection (i.e., dynamic computed tomographic imaging).
OXILAN® Injection may be visualized in the renal parenchyma within 30-60 seconds following rapid intravenous
injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within
1-3 minutes, with optimum contrast occurring within 5-15 minutes.
Contrast Enhanced Computerized Tomography (CECT): AS WITH OTHER IODINATED CONTRAST AGENTS, THE
USE OF OXILAN® INJECTION CONTRAST ENHANCEMENT MAY OBSCURE SOME LESIONS WHICH WERE
SEEN ON PREVIOUSLY UNENHANCED CT SCANS.
In CECT some performance characteristics are different in the brain and body. In CECT of the body, iodinated
contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of
iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the
contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus
due to any relative differences in extravascular diffusion between adjacent tissues.
In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast
agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous
malformations and aneurysms, depends on the iodine content of the circulating blood pool.
In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time
to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after
intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part
dependent on the accumulation of iodine containing medium within the lesion and outside the blood pool. The
mechanism by which this occurs is not clear.
Page 2 of 11
Reference ID: 3788321
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
IN PATIENTS WITH NORMAL BLOOD BRAIN BARRIERS and RENAL FAILURE, iodinated contrast agents have
been associated with blood brain barrier DISRUPTION and ACCUMULATION OF CONTRAST IN THE BRAIN. (See
PRECAUTIONS.)
The usefulness of contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative
glioma has not been demonstrated. Calcified lesions are less likely to enhance. The enhancement of tumors after
therapy may decrease. The opacification of the inferior vermis following contrast agent administration has resulted in
false-positive diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement.
Older infarctions are obscured by the contrast agent.
For information on coagulation parameters, fibrinolysis and complement system, please refer to the Laboratory Test
Findings section.
CLINICAL TRIALS
OXILAN® Injection was administered to 834 patients in controlled and uncontrolled studies. Of these 679 patients
were between 18 and 69 years of age, and 155 patients were 70 years of age or older; the mean age was 56.4 years
(range 18-88). Of the 834 patients, 579 (69%) were male and 255 (31%) were female. The racial distribution was:
Caucasian 668 (80%), Black 84 (10%), Hispanic 58 (7%), Asian 14 (2%), and other or unknown 10 (1%). The
demographic information for patients who received the comparator (iohexol) was similar.
In the controlled studies, 530 patients given OXILAN® Injection and 540 patients given the comparator (iohexol) were
evaluated for efficacy. Efficacy assessment was based on the global evaluation of the quality of the radiographs by
rating visualization as either excellent, good, poor, or no image, and on the ability to make a diagnosis. Results were
compared to those with the active control (iohexol injection) at concentrations which were identical to those of
OXILAN® Injection.
Four (4) intraarterial and three (3) intravenous procedures were studied with 1 of 2 concentrations (350 mgI/mL and
300 mgI/mL). These procedures were: aortography/visceral angiography, coronary arteriography and left
ventriculography, cerebral arteriography, peripheral arteriography, contrast- enhanced computed tomography (CECT)
of head and body, and excretory urography.
Cerebral arteriography was evaluated in 3 randomized, double-blind clinical trials of OXILAN® Injection 300 mgI/mL
in patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central nervous
system diseases due to various CNS disorders. Results were assessed in 78 patients with OXILAN® (Ioxilan
Injection) and 83 with iohexol injection 300 mgI/mL. Visualization ratings were good or excellent in 95% of the patients
with OXILAN® Injection; a radiologic diagnosis was made in the majority of the patients. The results were similar to
those with iohexol injection. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Coronary arteriography/left ventriculography was evaluated in 4 randomized, double-blind clinical trials of OXILAN®
Injection 350 mgI/mL in patients with conditions such as altered coronary artery perfusion due to metabolic causes
and in patients with conditions such as altered ventricular function. Results were assessed in 139 patients with
OXILAN® Injection and 142 with iohexol injection 350 mgI/mL. Visualization ratings were good or excellent in 99% or
more of the patients with OXILAN® Injection; a radiologic diagnosis was made in the majority of the patients. The
results were similar to those with iohexol injection. Confirmation of the radiologic findings by other diagnostic methods
was not obtained.
Aortography/visceral angiography was evaluated in 3 randomized, double- blind clinical trials of OXILAN® Injection
350 mgI/mL in patients with conditions such as altered aortic blood flow and/or visceral vascular disorders. The
results were assessed in 51 patients with OXILAN® Injection 350 mgI/mL and 47 with iohexol injection 350 mgI/mL.
Visualization ratings were good or excellent in the majority of the patients; a radiologic diagnosis was made in
90% of the patients with OXILAN® Injection. The results were similar to those with iohexol injection. Confirmation of
radiologic findings by other diagnostic methods was not obtained.
Intravenous excretory urography was evaluated in 2 randomized, double- blind clinical trials of OXILAN® Injection
350 mgI/mL. The results were assessed in 61 patients with OXILAN® Injection 350 mgI/mL and 62 with iohexol
injection 350 mgI/mL. Visualization ratings were good or excellent in all of the patients; a radiologic diagnosis was
made in 100% of the patients with OXILAN® Injection. The results were similar to those with iohexol injection.
Confirmation of radiologic findings by other diagnostic methods was not obtained.
CECT of head and body was evaluated in 5 randomized, double-blind clinical trials in patients with vascular disorders.
A total of 146 patients received OXILAN® Injection 300 mgI/mL and 149 received iohexol injection 300 mgI/mL.
Visualization ratings were good or excellent in 98% of the patients with OXILAN® Injection; a radiologic diagnosis was
made in the majority of the patients. The results were similar to those with iohexol injection.
Page 3 of 11
Reference ID: 3788321
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
INTRAARTERIAL:
OXILAN® Injection (300 mgI/mL) is indicated for cerebral arteriography. OXILAN® Injection (350 mgI/mL) is indicated
for coronary arteriography and left ventriculography, visceral angiography, aortography, and peripheral arteriography.
INTRAVENOUS:
OXILAN® Injection (300 mgI/mL) and OXILAN® Injection (350 mgI/mL) are indicated for excretory urography and
contrast enhanced computed tomographic (CECT) imaging of the head and body.
CONTRAINDICATIONS
OXILAN® Injection is not indicated for intrathecal use.
WARNINGS
SEVERE ADVERSE EVENTS-INADVERTENT INTRATHECAL ADMINISTRATION: Serious adverse reactions have
been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for
intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis,
arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special
attention must be given to insure that this drug product is not administered intrathecally.
Nonionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media. Clotting has been
reported when blood remains in contact with syringes containing nonionic contrast media. The use of plastic syringes
in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during
angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular
administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic
events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and
concomitant medications may contribute to the development of thromboembolic events. For these reasons,
meticulous angiographic techniques are recommended including close attention to guidewire and catheter
manipulation, use of manifold systems and/or three way stopcocks, frequent catheter flushing with heparinized saline
solutions, and minimizing the length of the procedure.
Serious or fatal reactions have been associated with the administration of iodine-containing radiopaque media. It is of
utmost importance to be completely prepared to treat any contrast agent reaction.
Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease,
combined renal and cardiac disease, severe thyrotoxicosis, myelomatosis, or anuria, particularly when large doses
are administered. (See PRECAUTIONS.)
Intravascularly administered iodine-containing radiopaque media are potentially hazardous in patients with multiple
myeloma or other paraproteinacious diseases, who are prone to disease-induced renal insufficiency and/or failure.
Although neither the contrast agent nor dehydration has been proven to be the cause of renal insufficiency (or
worsening renal insufficiency) in myelomatous patients, it has been speculated that the combination of both may be
causative. Special precautions, including maintenance of normal hydration and close monitoring, are required. Partial
dehydration in the preparation of these patients prior to injection is not recommended since this may predispose the
patient to precipitation of the myeloma protein.
Reports of thyroid storm following the intravascular use of iodinated radiopaque agents in patients with
hyperthyroidism, or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in
such patients before use of any contrast agent.
Administration of radiopaque materials to patients with known or suspected pheochromocytoma should be performed
with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the
considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be
kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for
treatment of a hypertensive crisis should be available. These patients should be monitored very closely during
contrast enhanced procedures.
Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when administered
intravascularly.
PRECAUTIONS
Page 4 of 11
Reference ID: 3788321
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General: THE DECISION TO USE CONTRAST ENHANCEMENT IS ASSOCIATED WITH RISK AND INCREASED
RADIATION EXPOSURE, AND SHOULD BE BASED UPON A CAREFUL EVALUATION OF CLINICAL, OTHER
RADIOLOGIC DATA, AND THE RESULTS OF UNENHANCED CT FINDINGS.
Patients receiving contrast agents, and especially those who are medically unstable, must be closely supervised.
Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under
the direction of personnel skilled and experienced in the particular procedure to be performed. A fully equipped
emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse
reactions of all types should always be available. Since severe delayed reactions have been known to occur,
emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration.
Dehydration, Renal Insufficiency, Congestive Heart Failure: Preparatory dehydration is dangerous and may contribute
to acute renal failure in patients with advanced vascular disease, congestive heart disease, diabetic patients, and
other patients such as those on medications which alter renal function and the elderly with age related renal
impairment. Patients should be adequately hydrated prior to and following the intravascular administration of
iodinated contrast agents. Dose adjustments in renal impairment have not been studied.
Iodinated contrast agents may cross the blood-brain barrier. In patients where the blood-brain barrier is known or
suspected to be disrupted, or in patients with normal blood-brain barriers and associated renal impairment, CAUTION
MUST BE EXERCISED IN CONSIDERING THE USE OF AN IODINATED CONTRAST AGENT. (See
Pharmacodynamics.)
Patients with congestive heart failure receiving concurrent diuretic therapy may have relative intravascular volume
depletion, which may affect the renal response to the contrast agent osmotic load. Such patients should be observed
for several hours following the procedure to detect delayed hemodynamic renal function disturbances.
Immunologic Reactions: The possibility of a reaction, including serious, life- threatening, fatal, anaphylactoid or
cardiovascular reactions, should always be considered. Increased risk is associated with a history of previous
reaction to a contrast agent, a known sensitivity to iodine and known allergies (i.e., bronchial asthma, hay fever and
food allergies) other hypersensitivities, and underlying immune disorders, autoimmunity or immunodeficiencies that
predispose to specific or non-specific mediator release.
Skin testing cannot be relied upon to predict severe reactions and may itself be hazardous to the patient. A thorough
medical history with emphasis on allergy and hypersensitivity, immune, autoimmune and immunodeficiency disorders,
and prior receipt of and response to the injection of any contrast agent, may be more accurate than pretesting in
predicting potential adverse reactions.
Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions does not prevent
serious life-threatening reactions, but may reduce both their incidence and severity. Extreme caution should be
exercised in considering the use of iodinated contrast agents in patients with these histories or disorders.
Anesthesia: General anesthesia may be indicated in the performance of some procedures in selected patients;
however, a higher incidence of adverse reactions has been reported in these patients. It is not clear if this is due to
the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia, which can
prolong the circulation time and increase the duration of exposure to the contrast agent.
Angiography: In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel
wall with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery etc., should be
considered during catheter manipulations and contrast agent injection. Angiography may be associated with local and
distal organ damage, ischemia, thrombosis and organ failure (e.g., brachial plexus palsy, chest pain, myocardial
infarction, sinus arrest, hepato-renal function abnormalities, etc.). Test injections to insure proper catheter placement
are suggested. Increased thrombosis and activation of the complement system have also occurred. (See
WARNINGS.)
Angiography also should be avoided whenever possible in patients with homocystinuria because of the risk of
inducing thrombosis and embolism. (See Pharmacodynamics.)
Selective coronary arteriography should be performed only in selected patients and those in whom the expected
benefits outweigh the procedural risk. Also, the inherent risks of angiocardiography in patients with chronic pulmonary
emphysema must be weighed against the necessity for performing this procedure.
Venography: The safety of ioxilan in venographic procedures has not been studied.
Extreme caution during injection of a contrast agent is necessary to avoid extravasation. This is especially important
in patients with severe arterial or venous disease.
GENERAL ADVERSE REACTIONS TO CONTRAST AGENTS
The following adverse reactions are possible with any parenterally administered iodinated contrast agent. Severe life-
Page 5 of 11
Reference ID: 3788321
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threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Most deaths occur during injection
or 5 to 10 minutes later; the main feature being cardiac arrest with cardiovascular disease as the main aggravating
factor. Isolated reports of hypotensive collapse and shock are found in the literature. Based upon clinical literature,
reported deaths from the administration of other iodinated contrast agents range from 6.6 per 1 million (0.00066
percent) to 1 in 10,000 patients (0.01 percent).
The reported incidence of adverse reactions to contrast agents in patients with a history of allergy is twice that of the
general population. Patients with a history of previous reactions to a contrast agent are three times more susceptible
than other patients. However, sensitivity to contrast agents does not appear to increase with repeated examinations.
Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported
following iodinated contrast media administration to adult and pediatric patients, including infants. Some patients were
treated for hypothyroidism.
Adverse reactions to injectable contrast agents fall into two categories: chemotoxic reactions and idiosyncratic
reactions. Chemotoxic reactions result from the physicochemical properties of the contrast agent, the dose and the
speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast agent are
included in this category.
Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old.
Idiosyncratic reactions may or may not be dependent on the dose injected, the speed of injection, the mode of
injection and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate and severe.
The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is
urgent and mandatory.
Information for Patients:
Patients receiving iodinated intravascular contrast agents should be instructed to:
1. Inform your physician if you are pregnant. (See PRECAUTIONS - PREGNANCY.)
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle
cell disease, or known thyroid disorder. (See WARNINGS.)
3. Inform your physician if you are allergic to any drugs, or food, or if you have immune, autoimmune or immune
deficiency disorders. Also inform your physician if you had any reactions to previous injections of dyes used for x-
ray procedures. (See PRECAUTIONS, General.)
4. Inform your physician about all medications you are currently taking, including non-prescription drugs (over-the-
counter) drugs, before you have this procedure.
DRUG INTERACTIONS
Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic
agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore
be postponed in any patient with a known or suspected hepatic or biliary disorder who has recently received a
cholecystographic contrast agent.
Other drugs should not be admixed with OXILAN® (Ioxilan Injection).
DRUG/LABORATORY TEST INTERACTIONS
The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimations, will
not accurately reflect thyroid function for at least 16 days following administration of iodinated contrast media.
However, thyroid function tests which do not depend on iodine estimations, e.g., T3 resin uptake and total or free
thyroxine (T4) assays are not affected.
LABORATORY TEST FINDINGS:
In vitro assays were performed with human blood to assess the effects of ioxilan, iohexol and iopamidol on red blood
cell morphology and platelet aggregation. Ioxilan, at a concentration of 35 mgI/mL, did not affect red blood cell
morphology. Ioxilan, iohexol and iopamidol all inhibited ADP-induced platelet aggregation in a concentration-
dependent manner.
In vitro assays with human blood and serum were performed to determine the effects of ioxilan, iohexol, and
iopamidol at a dose of 35 mgI/mL on the following coagulation factors; thrombin time, prothrombin time and partial
thromboplastin time. Data on reversibility are not available. The thrombin time increased from an average baseline
value of 8.0 seconds to average values of 36.9 seconds for ioxilan, (comparable to iohexol and iopamidol.)
Page 6 of 11
Reference ID: 3788321
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Prothrombin time increased from an average baseline value of 12.3 seconds to an average value of 17.6 seconds for
ioxilan, 18.8 seconds for iopamidol, and 27.8 seconds for iohexol. Partial thromboplastin time increased from an
average baseline value of 55.8 seconds to an average value of 77.4 seconds for ioxilan, 89.4 seconds for iohexol,
and 70.9 seconds for iopamidol. The duration of these effects was not studied and the clinical impact is unknown.
In vitro assays with human serum were performed to determine the effects of ioxilan and iohexol on complement
levels. Total complement consumption (CH50) was not significantly affected by either ioxilan or iohexol. However, the
C3 and C4 components of complement decreased by 14% and 19%, respectively, with ioxilan and by 18% and 23%
with iohexol. C3c was not detected for either agent.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term animal studies have not been performed with ioxilan to evaluate carcinogenic potential or effects on
fertility. Ioxilan was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes
analysis of chromosomal aberrations, an in vivo mouse micronucleus assay, and in an in vivo mouse dominant lethal
assay.
PREGNANCY
Teratogenic Effects: Pregnancy Category B
Reproduction studies performed with ioxilan injection in rats at doses up to 6.5 gI/kg (3.7 times the recommended
dose for a 50 kg human, or approximately
0.7 times the human dose following normalization of the data to body surface area estimates) and rabbits at doses up
to 3.5 gI/kg (2 times the recommended dose for a 50 kg human, or approximately the same as the human dose
following normalization of the data to body surface area estimates) did not reveal evidence of direct harm to the fetus.
Embryolethality was not detected. Adequate and well-controlled studies in pregnant women have not been
conducted. 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 ioxilan is excreted in human milk. However, many injectable contrast agents are excreted
unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing
infants, caution should be exercised when intravascular contrast media are administered to nursing women because
of potential adverse reactions, and consideration should be given to temporarily discontinuing nursing.
PEDIATRIC USE
Safety and effectiveness in children have not been established.
ADVERSE REACTIONS
For demographics, see CLINICAL TRIALS section.
The following table of incidence of reactions is based upon controlled clinical studies in which OXILAN® was
compared with a nonionic contrast agent (iohexol) in 531 patients. It includes all reported adverse events, regardless
of attribution.
Adverse reactions are listed by body system and in decreasing order of occurrence greater than 0.5% in the
OXILAN® group.
Body System
Adverse Event
Ioxilan (n=531)
Comparator (n=542)
Body as a Whole
Headache
19 (3.6%)
15 (2.8%)
Fever
9 (1.7%)
11 (2.0%)
Hematoma at Injection Site
4 (0.8%)
0 (0%)
Chills
3 (0.6%)
0 (0%)
Cardiovascular
Angina Pectoris
7 (1.3%)
11 (2.0%)
Hypertension
6 (1.1%)
3 (0.6%)
Bradycardia
4 (0.8%)
0 (0%)
Hypotension
5 (0.9%)
3 (0.6%)
Page 7 of 11
Reference ID: 3788321
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Digestive
Nausea
8 (1.5%)
7 (1.3%)
Diarrhea
5 (0.9%)
4 (0.7%)
Nausea with Vomiting
5 (0.9%)
5 (0.9%)
Vomiting
3 (0.6%)
4 (0.7%)
Nervous
Dizziness
4 (0.8%)
1 (0.2%)
Skin
Urticaria
4 (0.8%)
4 (0.7%)
Rash
3 (0.6%)
4 (0.7%)
One or more adverse reactions were reported in 76 of 531 (14.3%) of patients in the clinical trials, coincidental with
the administration of OXILAN® or within the study follow-up period of 24 to 72 hours. The incidence and type of
adverse reactions were similar to those associated with the nonionic comparator (iohexol) used in the clinical trials.
OXILAN®, as do other iodinated contrast agents, often causes warmth and/or pain on injection. The rates are similar
to that of the iohexol comparator.
Serious, life threatening and fatal reactions have been associated with the administration of iodine-containing contrast
media. In all clinical trials 3/835 (0.3%) patients given OXILAN® and 3/542 (0.6%) given iohexol died 4 days or later
after drug administration. In the controlled trials 8/531 (1.5%) patients given OXILAN® and 6/542 (1.1%) given iohexol
had serious adverse events.
The following adverse reactions were observed ≤ 0.5% of patients receiving
OXILAN® Injection:
BODY: allergic reaction, asthenia, chest and back pain, edema of the neck, facial edema, pain, peripheral edema;
CARDIOVASCULAR: atrial fibrillation, syncope, tachycardia, vasodilation, ventricular extrasystole; DIGESTIVE:
anorexia, constipation, dyspepsia, dysphagia, GI hemorrhage, ileus, liver failure; NERVOUS: hypotonia, nystagmus,
paresthesia, somnolence, vertigo; RESPIRATORY: dyspnea, pharyngitis, rhinitis; SKIN: pruritus, sweating; SPECIAL
SENSES: amblyopia, conjunctivitis, taste perversion, vision abnormality; UROGENITAL: anuria, dysuria, hematuria,
infection of urinary tract, impairment of urination, kidney failure.
Additional adverse events reported in postmarketing surveillance with the use of OXILAN® Injection include:
bronchospasm.
OVERDOSAGE
The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems.
Treatment of overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic
therapy.
OXILAN® Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.
ADULT DOSAGE AND ADMINISTRATION - General
The combination of volume and OXILAN® concentration to be used should be carefully individualized accounting for
factors such as age, body weight, size of the vessel and the rate of blood flow within the vessel. Specific dose
adjustments for age, gender, weight, and renal function have not been studied for OXILAN®. As with all iodinated
contrast agents, lower doses of OXILAN® Injection may have less risk. The efficacy of OXILAN® Injection below
doses recommended has not been studied. Other factors such as anticipated pathology, degree and extent of
opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment
and technique to be employed should also be considered.
The maximum recommended total dose of iodine is 86 grams.
If during administration a reaction occurs, the injection should be immediately stopped.
Patients should be adequately hydrated prior to and following intravascular administration of OXILAN®
Injection. (See WARNINGS and PRECAUTIONS.)
INTRAARTERIAL PROCEDURES
Coronary Arteriography and Left Ventriculography
OXILAN® Injection (350 mgI/mL) is indicated for intraarterial injection in the radiographic contrast evaluation of
coronary arteries and the left ventricle. Injection rates should be approximately equal to flow rate in the vessel being
injected.
The usual individual injection volumes for visualization of the coronary arteries and the left ventricle are as follows:
Page 8 of 11
Reference ID: 3788321
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Left and Right Coronary:
2 mL to 10 mL (0.7 to 3.5 gI) of OXILAN® Injection - 350 (350 mgI/mL)
Left Ventricle:
25 mL to 50 mL (8.75 to 17.5 gI) of OXILAN® Injection - 350 (350 mgI/mL)
Total dose for the procedure should not usually exceed 250 mL.
When large individual volumes are administered, as in ventriculography and aortography, it is recommended that
sufficient time be permitted to elapse between each injection to allow for subsidence of possible hemodynamic
disturbances.
Mandatory prerequisites to the procedure are specialized personnel, ECG monitoring apparatus and adequate
facilities for immediate resuscitation and cardioversion. Electrocardiograms and vital signs should be routinely
monitored throughout the procedure.
Aortography and Selective Visceral Arteriography
OXILAN® Injection (350 mgI/mL) is indicated for intraarterial injection in the radiographic contrast evaluation of the
aorta and major visceral arterial branches. The volume and rate of contrast injection should be proportional to the
blood flow through the vessels of interest, and related to the vascular and pathological characteristics of the specific
vessels being studied.
Total dose for the procedure should not usually exceed 250 mL.
Peripheral Arteriography
OXILAN® Injection (350 mgI/mL) is indicated for intraarterial injection in the radiographic contrast evaluation of
peripheral arteries. Injection rates should be approximately equal to flow rate in the vessel being injected. The usual
individual injection volumes for visualization of various peripheral arteries are as follows:
Aortic bifurcation for distal runoff:
45 mL to 100 mL (26 to 70 gI) of OXILAN® Injection - 350 (350 mgI/mL)
Subclavian or femoral artery:
10 mL to 40 mL (4 to 14 gI) of OXILAN® Injection - 350 (350 mgI/mL)
Total dose for the procedure should not usually exceed 250 mL. Pulsation should be present in the artery to be
injected.
Cerebral Arteriography
OXILAN® Injection (300 mgI/mL) is indicated for intraarterial injection in the radiographic contrast evaluation of
arterial lesions of the brain. The usual individual volumes per injection are 8 mL to 12 mL (2.4 to 3.6 gI) of OXILAN®
Injection - 300 (300 mgI/mL).
Total dose for the procedure should not usually exceed 150 mL.
INTRAVENOUS PROCEDURES
Intravenous Excretory Urography
OXILAN® Injection (300 mgI/mL or 350 mgI/mL) is indicated for intravenous injection for routine excretory urography.
A volume of contrast which gives a dose of approximately 250 to 390 mgI/kg of body weight is recommended as
suitable for adults with normal renal function.
Total dose for the procedure should not usually exceed 100 mL.
Contrast Enhanced Computed Tomography
OXILAN® Injection (300 mgI/mL or 350 mgI/mL) is indicated for intravenous injection for contrast-enhancement in the
evaluation of neoplastic and non- neoplastic lesions of the head and body (intrathoracic, intraabdominal, and
retroperitoneal regions).
CECT of the Head:
The usual dose is 100 mL to 200 mL (30 to 60 gI) of OXILAN® Injection (300 mgI/mL) or 86 mL to 172 mL of
OXILAN® Injection (350 mgI/mL). Scanning may be performed immediately after completion of the intravenous
administration.
Total dose for the procedure should not usually exceed 200 mL. CECT of the Body:
OXILAN® Injection (300 mgI/mL or 350 mgI/mL) may be administered intravenously by bolus, by rapid infusion, or by
a combination of both. The usual dose is 50 mL to 200 mL (15 to 60 gI) of OXILAN® (300 mgI/mL) or 43 mL to 172
mL of OXILAN® (350 mgI/mL).
Page 9 of 11
Reference ID: 3788321
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Total dose for the procedure should not usually exceed 200 mL.
DRUG HANDLING:
As with all contrast media, because of the potential for chemical incompatibility, OXILAN® Injection should not be
mixed with, or injected in, intravenous administration lines containing other drugs, solutions, or total nutritional
admixtures.
Sterile technique must be used in all vascular injections involving contrast media.
It is desirable that intravascularly administered iodinated contrast agents be at or close to body temperature when
injected.
If non-disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces
of cleaning agents.
Withdrawal of contrast agents from their containers should be accomplished under aseptic conditions using only
sterile syringes and transfer devices. Contrast agents which have been transferred into other delivery systems should
be used immediately.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. Ioxilan solutions should be used only if clear and within the normal colorless
to pale yellow range.
OXILAN® formulations are supplied in single dose containers. Discard unused portion.
Direction for proper use of OXILAN®, Pharmacy Bulk Package
a. The transfer of OXILAN® (ioxilan Injection) from the Pharmacy Bulk Package is restricted to a suitable work
area, such as a laminar flow hood.
b. The container closure may be penetrated only one time, utilizing a suitable transfer device and aseptic
technique.
c. The withdrawal of container contents should be accomplished without delay. However, should this not be
possible, a maximum time of [4] hours from initial closure entry is permitted to complete fluid transfer
operations. The container should not be removed from the aseptic area during the entire 4 hour period.
d. The temperature of the container should not exceed 30°C, after the closure has been entered.
HOW SUPPLIED
OXILAN® (Ioxilan Injection) 300 mgI/mL -
Ten 50 mL single dose bottles, NDC 67684-1000-1
Ten 100 mL single dose bottles, NDC 67684-1000-2
Ten 150 mL single dose bottles, NDC 67684-1000-3
OXILAN® (Ioxilan Injection) 350 mgI/mL -
Ten 50 mL single dose bottles, NDC 67684-1001-1
Ten 100 mL single dose bottles, NDC 67684-1001-2
Ten 150 mL single dose bottles, NDC 67684-1001-3
Ten 200 mL single dose bottles, NDC 67684-1001-4
OXILAN® (Ioxilan Injection) 300 mgI/mL Pharmacy Bulk Package - Six 500 mL
bottles, NDC 67684-1000-5
OXILAN® (Ioxilan Injection) 350 mgI/mL Pharmacy Bulk Package - Six 500 mL
bottles, NDC 67684-1001-5
STORAGE
Store at room temperature between 15° and 30°C (59° and 86°F) and protect from light. Do not freeze.
RX only.
Page 10 of 11
Reference ID: 3788321
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
U.S. patent numbers 4,954,348; 5,035,877
Guerbet LLC - Bloomington, IN 47404
Distributed by Guerbet LLC - 120 W. 7th Street,
Suite 108, Bloomington, IN 47404
For further information or ordering, call
1-877-729-6679
Revised 03/2015
M087711/02
Page 11 of 11
Reference ID: 3788321
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/
----------------------------------------------------
IRA P KREFTING
07/06/2015
Reference ID: 3788321
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:26.818868
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020316Orig1s028lbl.pdf', 'application_number': 20316, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
12,442
|
Directions
• adults and children 12 years and over:
• to relieve symptoms, swallow 1 tablet with a glass
of water
• to prevent symptoms, swallow 1 tablet with a glass
of water at any time from 15 to 60 minutes before
eating food or drinking beverages that cause heartburn
• do not use more than 2 tablets in 24 hours
• children under 12 years: ask a doctor
Warnings
Allergy alert: Do not use if you are allergic to famotidine or
other acid reducers
Do not use
• if you have trouble swallowing
• with other acid reducers
• if you have kidney disease, except under the advice and
supervision of a doctor
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.
Stop use and ask a doctor if • stomach pain continues
• you need to take this product for more than 14 days
Active ingredient (in each tablet) Purpose
Famotidine 20 mg...........................................................Acid reducer
Questions or comments?
1-800-755-4008
Drug Facts
Uses
• relieves heartburn associated with acid indigestion and sour
stomach
• prevents heartburn associated with acid indigestion and sour
stomach brought on by eating or drinking certain
food and beverages
Inactive ingredients carnauba wax, hydroxypropyl
cellulose, hypromellose, magnesium stearate, microcrystalline
cellulose, pregelatinized starch, talc, titanium dioxide
Drug Facts (continued)
Other information
• read the directions and warnings before use
• keep the carton and package insert. They contain
important information.
• store at 20° - 30°C (68° - 86°F)
• protect from moisture
Do not use if the individual blister unit
is open or torn.
Read Package Insert before use.
®
TABLETS
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
Prevents & Relieves Heartburn
Due to Acid Indigestion
Famotidine Tablets 20mg Acid Reducer
5 TABLETS
Just One Tablet
Just One Tablet
5 TABLETS
NDC 16837-855-05
NEW!
NEW!
TABLETS
®
Distributed by:
CONSUMER PHARMACEUTICALS CO
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON
FORT WASHINGTON, PA 19034 USA
PA 19034 USA
®Registered trademark of Merck & Co., Inc.
Registered trademark of Merck & Co., Inc.
Please visit our web site at:
Please visit our web site at:
www.pepcidac.com
www.pepcidac.com
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MAXIMUM STRENGTH
®
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Drug Facts (continued): 8 pt
Leading: 6.5 pt
Bullets:
5 pt
Barlines:
2.5 pt
Hairlines: 0.5 pt
Horizontal Scale: 90% Average Kerning: 0
7
16837 85505
7
00000000
00000000
0000000
BLISTER CARTON PEPCID MAX STRENGTH FCT 5 (VERSION E)
3004095 A-21
JULY 17, 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inactive ingredients
carnauba wax, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose,
pregelatinized starch, talc, titanium dioxide
Other information
• read the directions and warnings before use
• keep the carton and package insert. They contain important information.
• store at 20˚ - 30˚C (68˚ - 86˚F)
• protect from moisture
Drug Facts (continued)
Questions or comments? 1-800-755-4008
• 1 tablet relieves heartburn due to acid indigestion
(Read Package Insert before use).
• PEPCID AC prevents heartburn due to acid indigestion brought on by
eating and drinking certain foods and beverages.
The makers of Pepcid AC do not manufacture store brands.
The makers of Pepcid AC do not manufacture store brands.
Do not use if the individual blister unit is open or torn.
TABLETS
®
MAXIMUM STRENGTH
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.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg......................................................................................................................................................Acid reducer
Warnings
Allergy alert: Do not use if you are allergic to famotidine or other acid reducers
Do not use
• if you have trouble swallowing
• with other acid reducers
• if you have kidney disease, except under the advice and supervision of a doctor
Stop use and ask a doctor if
• stomach pain continues • you need to take this product for more than 14 days
Drug Facts
Uses
• relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach brought on by eating or drinking certain
food and beverages
Directions
• adults and children 12 years and over:
• to relieve symptoms, swallow 1 tablet with a glass of water
• to prevent symptoms, swallow 1 tablet with a glass of water at any time from 15 to 60 minutes before
eating food or drinking beverages that cause heartburn
• do not use more than 2 tablets in 24 hours
• children under 12 years: ask a doctor
7
16837 85525
5
MAXIMUN STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
Famotidine Tablets 20mg Acid Reducer
NEW!
NEW!
Prevents & Relieves Heartburn
Due to Acid Indigestion
Just One Tablet
Just One Tablet
25 TABLETS
25 TABLETS
The Pepcid AC Brand name is a guarantee
of our commitment to you. W
of our commitment to you. We have
e have
worked hard to earn your trust and we'll
work even harder to maintain it.
work even harder to maintain it.
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Distributed by:
CONSUMER PHARMACEUTICALS CO
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
®Registered trademark of Merck & Co., Inc.
Registered trademark of Merck & Co., Inc.
Please visit our web site at:
Please visit our web site at:
www.pepcidac.com
www.pepcidac.com
The makers
The makers
of Pepcid AC
do not
manufacture
manufacture
store brands
®
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
NDC 16837-855-25
0000000
®
®
00000000
BLISTER CARTON PEPCID MAX STRENGTH FCT 25 (VERSION E) 3004104 D-13
JULY 17, 2003
Labeling Format Information:
Fonts: Univers Condensed regular, bold and bold oblique.
Drug Facts:
Header:
Subheader:
Body Text:
Drug Facts (continued):
Leading:
Bullets:
Barlines:
Hairlines:
Average Kerning: 0
10 pt
8 pt
6 pt
6 pt
8 pt
6.5 pt
5 pt
2.5 pt
0.5 pt
Horizontal Scale: 95%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LOT
EXP.
0000000
Labeling Format Information:
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Drug Facts:
NA
Header:
NA
Subheader:
4.5 pt
Body Text:
4.5 pt
Drug Facts (continued): NA
Leading: 4.5 pt
Bullets:
4.5 pt
Barlines:
NA
Hairlines: NA
Horizontal Scale: 77% Average Kerning: -15
150% OF SIZE
Do not use if printed foil seal under bottle cap is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg..........................................................................Acid reducer
Uses • relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach
brought on by eating or drinking certain food and beverages
Warnings Allergy alert: Do not use if you are allergic to famotidine or
other acid reducers.
Do not use
• if you have trouble
swallowing • with other
acid reducers • if you
have kidney disease,
except under the
advice and supervision
of a doctor
Stop use and ask a
doctor if • stomach
pain continues
• you need to take this product for more than 14 days
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 • adults and children 12 years and over: • to
relieve symptoms, swallow 1 tablet with a glass of water
• to prevent symptoms, swallow 1 tablet with a glass of
water at any time from 15 to 60 minutes before eating food
or drinking beverages that cause heartburn • do not use
more than 2 tablets in 24 hours • children under 12 years:
ask a doctor. Other information • read the directions,
warnings and accompanying product information before
use • keep the carton and package insert. They contain
important information. • store at 20˚ - 30˚C (68˚ - 86˚F)
• protect from moisture
LOT
EXP.
0000000
Do not use if printed foil seal under bottle cap is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg..........................................................................Acid reducer
Uses • relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach
brought on by eating or drinking certain food and beverages
Warnings Allergy alert: Do not use if you are allergic to famotidine or
other acid reducers.
Do not use
• if you have trouble
swallowing • with other
acid reducers • if you
have kidney disease,
except under the
advice and supervision
of a doctor
Stop use and ask a
doctor if • stomach
pain continues
• you need to take this product for more than 14 days
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 • adults and children 12 years and over: • to
relieve symptoms, swallow 1 tablet with a glass of water
• to prevent symptoms, swallow 1 tablet with a glass of
water at any time from 15 to 60 minutes before eating food
or drinking beverages that cause heartburn • do not use
more than 2 tablets in 24 hours • children under 12 years:
ask a doctor. Other information • read the directions,
warnings and accompanying product information before
use • keep the carton and package insert. They contain
important information. • store at 20˚ - 30˚C (68˚ - 86˚F)
• protect from moisture
MAXIMUM STRENGTH
MAXIMUM STRENGTH
Prevents & Relieves Heartburn
Due to Acid Indigestion
Famotidine Tablets 20mg Acid Reducer
Just One Tablet
Just One Tablet
NDC 16837-855-50
50 TABLETS
®
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
Dist. by:
®Registered trademark
of Merck & Co., Inc.
LABEL PEPCID MAX STRENGTH FCT 50 (VERSION E)
3004095 E-14
JULY 18, 2003
MAXIMUM STRENGTH
Prevents & Relieves Heartburn
Prevents & Relieves Heartburn
Due to Acid Indigestion
Due to Acid Indigestion
Famotidine Tablets 20mg Acid Reducer
Just One Tablet
Just One Tablet
NDC 16837-855-50
50 TABLETS
®
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
Dist. by:
®Registered trademark
of Merck & Co., Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Prevents & Relieves Heartburn
Prevents & Relieves Heartburn
Due to Acid Indigestion
Due to Acid Indigestion
Just One Tablet
Famotidine Tablets 20mg Acid Reducer
®
MAXIMUM STRENGTH
MAXIMUM STRENGTH
1 TABLET
Labeling Format Information:
Fonts: Universe Cond regular, bold and bold italic.
Drug Facts:
NA
Header:
4.5 pt
Subheader:
4.5 pt
Body Text:
4.5 pt
Drug Facts (continued): NA
Leading: 4.5 pt
Bullets:
4.5 pt
Barlines:
NA
Hairlines: NA
Horizontal Scale: 76% Average Kerning: -4
Do not use if pouch is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg.............................................................................................................................Acid reducer
Uses • relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach brought on by eating or
drinking certain food and beverages
Warnings: Allergy alert: Do not use if you are allergic to famotidine or other acid reducers
Do not use • if you have trouble swallowing • with other acid reducers • if you have kidney disease,
except under the advice and supervision of a doctor. Stop use and ask a doctor if • stomach pain
continues • you need to take this product for more than 14 days. 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 • adults and children 12 years and over:
• to relieve symptoms, swallow 1 tablet with a glass of water • to prevent symptoms, swallow 1 tablet
with a glass of water at any time from 15 to 60 minutes before eating food or drinking beverages that
cause heartburn • do not use more than 2 tablets in 24 hours • children under 12 years: ask a doctor
Other information • read the directions and warnings before use • store at 20 - 30C (68 - 86F)
• protect from moisture. Inactive ingredients carnauba wax, hydroxypropyl cellulose, hypromellose,
magnesium stearate, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide
Questions or comments? 1-800-755-4008
CONSUMER PHARMACEUTICALS CO., FORT WASHINGTON, PA 19034 USA
Dist. by:
®Registered trademark of Merck & Co., Inc. www.pepcidac.com
0000000
X
130% OF SIZE
To Open: While Folded on Line, Tear At Slit
Prevents & Relieves Heartburn
Prevents & Relieves Heartburn
Due to Acid Indigestion
Due to Acid Indigestion
Just One T
st One Tablet
Famotidine Tablets 20mg Acid Reducer
®
MAXIMUM STRENGTH
1 TABLET
Do not use if pouch is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg.............................................................................................................................Acid reducer
Uses • relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach brought on by eating or
drinking certain food and beverages
Warnings: Allergy alert: Do not use if you are allergic to famotidine or other acid reducers
Do not use • if you have trouble swallowing • with other acid reducers • if you have kidney disease,
except under the advice and supervision of a doctor. Stop use and ask a doctor if • stomach pain
continues • you need to take this product for more than 14 days. 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 • adults and children 12 years and over:
• to relieve symptoms, swallow 1 tablet with a glass of water • to prevent symptoms, swallow 1 tablet
with a glass of water at any time from 15 to 60 minutes before eating food or drinking beverages that
cause heartburn • do not use more than 2 tablets in 24 hours • children under 12 years: ask a doctor
Other information • read the directions and warnings before use • store at 20 - 30C (68 - 86F)
• protect from moisture. Inactive ingredients carnauba wax, hydroxypropyl cellulose, hypromellose,
magnesium stearate, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide
Questions or comments? 1-800-755-4008
CONSUMER PHARMACEUTICALS CO., FORT WASHINGTON, PA 19034 USA
Dist. by:
®Registered trademark of Merck & Co., Inc. www.pepcidac.com
0000000
X
To Open: While Folded on Line, Tear At Slit
POUCH PEPCID MAX STRENGTH FCT CR 1 (VERSION E)
3004095 G-5
JULY 17, 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dist. by
J&J•MERCK CPC
Ft. Wash., PA 19034 USA
EXP XX/XX
LOT XXXXXX
XXXXXXX
Famotidine 20mg
M
FRONT
BACK
1 Tablet
®
AC
MAXIMUM STRENGTH
Labeling Format Information:
Helvetica Neue condensed and bold condensed
Zapf Humanist 601BT bold and bold italic
Humanist 777BT bold condensed
Fonts:
Drug Facts:
Header:
Subheader:
Body Text:
Drug Facts (continued):
Avg Horizontal Scale:
FILE SCALE: 100%
Leading:
Bullets:
Barlines:
Hairlines:
Avg Kerning:
PEPCID AC MAX STRENGTH TRADE POUCH
2/3/03
TRADE POUCH
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PUSH TABLET
THROUGH FROM
OTHER SIDE
Dist. by J&J•MERCK CPC
Ft. Wash., PA 19034 USA
EXP XX/XX
LOT XXXXXX
EXP XX/XX
LOT XXXXXX
EXP XX/XX
LOT XXXXXX
EXP XX/XX
LOT XXXXXX
XXXXXXX
XXXXXXX
Famotidine Tablets 20mg
PUSH TABLET
THROUGH FROM
OTHER SIDE
Dist. by J&J•MERCK CPC
Ft. Wash., PA 19034 USA
EXP XX/XX
LOT XXXXXX
Famotidine Tablets 20mg
PUSH TABLET
THROUGH FROM
OTHER SIDE
Dist. by J&J•MERCK CPC
Ft. Wash., PA 19034 USA
XXXXXXX
Famotidine Tablets 20mg
PUSH TABLET
THROUGH FROM
OTHER SIDE
Dist. by J&J•MERCK CPC
Ft. Wash., PA 19034 USA
XXXXXXX
Famotidine Tablets 20mg
PUSH TABLET
THROUGH FROM
OTHER SIDE
Dist. by J&J•MERCK CPC
Ft. Wash., PA 19034 USA
XXXXXXX
Famotidine Tablets 20mg
MAXIMUM STRENGTH
®
AC
®
AC
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
®
AC
®
AC
®
AC
Labeling Format Information:
Century Bold, Helvetica narrow, compressed,
condensed bold, Zapf Humanist 601BT bold
Humanist 777BT black italic
Fonts:
Drug Facts:
Header:
Subheader:
Body Text:
Drug Facts (continued):
Avg Horizontal Scale:
FILE SCALE: 100%
6.5 pt
100%
Leading:
Bullets:
Barlines:
Hairlines:
Avg Kerning:
7 pt
0
PEPCID AC MAX STRENGTH BLISTER PKG
2/3/03
BLISTER INSIDE TRADE BOX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
Prevents & Relieves Heartburn
Prevents & Relieves Heartburn
Due to Acid Indigestion
Due to Acid Indigestion
Famotidine Tablets 20mg Acid Reducer
75
75 TABLET
LETS
Just One Tablet
Just One T
st One Tablet
blet
NDC 16837-855-75
NEW!
NEW!
®
Distributed by:
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
®Registered trademark of Merck & Co., Inc.
Registered trademark of Merck & Co., Inc.
Please visit our web site at:
Please visit our web site at:
www.pepcidac.com
www.pepcidac.com
®
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
The makers
The makers
of Pepcid AC
of Pepcid AC
do not
do not
manufacture
manufacture
store brands
store brands
75
75 TABLET
LETS
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
MAXIMUM STRENGTH
®
8726570
Labeling Format Information:
Fonts: Universe Cond regular, bold and bold italic.
Drug Facts:
8.5 pt
Header:
8 pt
Subheader:
6 pt
Body Text:
6 pt
Drug Facts (continued): 8 pt
Leading: 6.5 pt
Bullets:
5 pt
Barlines:
2.5 pt
Hairlines: 0.5 pt
Horizontal Scale: 100%
Average Kerning: 0
CTN PEPCID MAX STR 75ct CLUB CODE
3004404 A-1 JULY 30, 2003
08726570
08726570
7
16837 85575
0
The Pepcid AC Brand name is a guarantee
epcid AC Brand name is a guarantee
of our commitment to you. W
of our commitment to you. We have
e have
worked hard to ear
worked hard to earn your tr
n your trust and we'll
ust and we'll
work even harder to maintain it.
work even harder to maintain it.
J
o
h
n
s
o
n
&
J
o
h
n
s
o
n
•
M
E
R
C
K
C
o
m
m
i
t
t
e
d
T
o
Q
u
a
l
i
t
y
Other information
• read the directions and warnings before use
• keep the carton and package insert. They contain important information.
• store at 20˚ - 30˚C (68˚ - 86˚F)
• protect from moisture
Inactive ingredients carnauba wax, hydroxypropyl cellulose, hypromellose, magnesium stearate,
microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide
Drug Facts (continued)
Questions or comments? 1-800-755-4008
• 1 tablet relieves heartburn due to acid indigestion (Read Package Insert before use).
• PEPCID AC prevents heartburn due to acid indigestion brought on by eating and drinking certain foods
and beverages.
Do not use if carton is open or printed foil seal under bottle cap is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg............................................................................................................................................. Acid reducer
Warnings
Allergy alert: Do not use if you are allergic to famotidine or other acid reducers
Do not use
• if you have trouble swallowing
• with other acid reducers
• if you have kidney disease, except under the advice and supervision of a doctor
Stop use and ask a doctor if
• stomach pain continues • you need to take this product for more than 14 days
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.
Uses
• relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach brought on by eating or
drinking certain food and beverages
Drug Facts
The makers of Pepcid AC do not manufacture store brands.
The makers of Pepcid AC do not manufacture store brands.
Directions
• adults and children 12 years and over:
• to relieve symptoms, swallow 1 tablet with a glass of water
• to prevent symptoms, swallow 1 tablet with a glass of water at any time from 15 to 60 minutes before
eating food or drinking beverages that cause heartburn
• do not use more than 2 tablets in 24 hours
• children under 12 years: ask a doctor
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MAXIMUM STRENGTH
MAXIMUM STRENGTH
Prevents & Relieves Heartburn
Due to Acid Indigestion
Famotidine Tablets 20mg Acid Reducer
50 TABLETS
Just One Tablet
Just One Tablet
NDC 16837-855-50
NEW!
NEW!
®
Distributed by:
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
®Registered trademark of Merck & Co., Inc.
Registered trademark of Merck & Co., Inc.
Please visit our web site at:
Please visit our web site at:
www.pepcidac.com
www.pepcidac.com
®
MAXIMUM STRENGTH
MAXIMUM STRENGTH
The makers
The makers
of Pepcid AC
do not
manufacture
manufacture
store brands
50 TABLETS
MAXIMUM STRENGTH
MAXIMUM STRENGTH
®
0000000
00000000
00000000
00000000
7
16837 85550
7
Other information
• read the directions and warnings before use
• keep the carton and package insert. They contain important information.
• store at 20˚ - 30˚C (68˚ - 86˚F)
• protect from moisture
Inactive ingredients carnauba wax, hydroxypropyl cellulose, hypromellose, magnesium stearate,
microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide
Drug Facts (continued)
Questions or comments? 1-800-755-4008
• 1 tablet relieves heartburn due to acid indigestion (Read Package Insert before use).
• PEPCID AC prevents heartburn due to acid indigestion brought on by eating and drinking certain foods
and beverages.
Do not use if carton is open or printed foil seal under bottle cap is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg............................................................................................................................................. Acid reducer
Warnings
Allergy alert: Do not use if you are allergic to famotidine or other acid reducers
Do not use
• if you have trouble swallowing
• with other acid reducers
• if you have kidney disease, except under the advice and supervision of a doctor
Stop use and ask a doctor if
• stomach pain continues • you need to take this product for more than 14 days
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.
Uses
• relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach brought on by eating or
drinking certain food and beverages
Drug Facts
The makers of Pepcid AC do not manufacture store brands.
Directions
• adults and children 12 years and over:
• to relieve symptoms, swallow 1 tablet with a glass of water
• to prevent symptoms, swallow 1 tablet with a glass of water at any time from 15 to 60 minutes before
eating food or drinking beverages that cause heartburn
• do not use more than 2 tablets in 24 hours
• children under 12 years: ask a doctor
Labeling Format Information:
Fonts: Universe Cond regular, bold and bold italic.
Drug Facts:
8.5 pt
Header:
8 pt
Subheader:
6 pt
Body Text:
6 pt
Drug Facts (continued): 8 pt
Leading: 6.5 pt
Bullets:
5 pt
Barlines:
2.5 pt
Hairlines: 0.5 pt
Horizontal Scale: 100%
Average Kerning: 0
BOTTLE CARTON PEPCID MAX STRENGTH FCT 50 (VERSION E)
3004095 C-15
JULY 18, 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LOT
EXP.
Labeling Format Information:
Fonts: Universe Cond regular, bold and bold italic.
Drug Facts:
NA
Header:
NA
Subheader:
4.5 pt
Body Text:
4.5 pt
Drug Facts (continued): NA
Leading: 4.5 pt
Bullets:
4.5 pt
Barlines:
NA
Hairlines: NA
Horizontal Scale: 77% Average Kerning: -15
150% OF SIZE
Do not use if printed foil seal under bottle cap is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg..........................................................................Acid reducer
Uses • relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach
brought on by eating or drinking certain food and beverages
Warnings Allergy alert: Do not use if you are allergic to famotidine or
other acid reducers.
Do not use
• if you have trouble
swallowing • with other
acid reducers • if you
have kidney disease,
except under the
advice and supervision
of a doctor
Stop use and ask a
doctor if • stomach
pain continues
• you need to take this product for more than 14 days
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 • adults and children 12 years and over: • to
relieve symptoms, swallow 1 tablet with a glass of water
• to prevent symptoms, swallow 1 tablet with a glass of
water at any time from 15 to 60 minutes before eating food
or drinking beverages that cause heartburn • do not use
more than 2 tablets in 24 hours • children under 12 years:
ask a doctor. Other information • read the directions,
warnings and accompanying product information before
use • keep the carton and package insert. They contain
important information. • store at 20˚ - 30˚C (68˚ - 86˚F)
• protect from moisture
LOT
EXP.
Do not use if printed foil seal under bottle cap is open or torn.
Active ingredient (in each tablet) Purpose
Famotidine 20 mg..........................................................................Acid reducer
Uses • relieves heartburn associated with acid indigestion and sour stomach
• prevents heartburn associated with acid indigestion and sour stomach
brought on by eating or drinking certain food and beverages
Warnings Allergy alert: Do not use if you are allergic to famotidine or
other acid reducers.
Do not use
• if you have trouble
swallowing • with other
acid reducers • if you
have kidney disease,
except under the
advice and supervision
of a doctor
Stop use and ask a
doctor if • stomach
pain continues
• you need to take this product for more than 14 days
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 • adults and children 12 years and over: • to
relieve symptoms, swallow 1 tablet with a glass of water
• to prevent symptoms, swallow 1 tablet with a glass of
water at any time from 15 to 60 minutes before eating food
or drinking beverages that cause heartburn • do not use
more than 2 tablets in 24 hours • children under 12 years:
ask a doctor. Other information • read the directions,
warnings and accompanying product information before
use • keep the carton and package insert. They contain
important information. • store at 20˚ - 30˚C (68˚ - 86˚F)
• protect from moisture
LBL PEPCID MAX STR 75ct CLUB CODE
3004404 B-1 JULY 30, 2003
MAXIMUM STRENGTH
MAXIMUM STRENGTH
Prevents & Relieves Heartburn
Prevents & Relieves Heartburn
Due to Acid Indigestion
Due to Acid Indigestion
Famotidine Tablets 20mg Acid Reducer
Just One Tablet
Ju
Just One T
st One Tablet
blet
NDC 16837-855-75
75 TABLETS
®
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
Dist. by:
®Registered trademark
of Merck & Co., Inc.
MAXIMUM STRENGTH
MAXIMUM STRENGTH
Prevents & Relieves Heartburn
Due to Acid Indigestion
Famotidine Tablets 20mg Acid Reducer
Just One Tablet
Ju
Just One T
st One Tablet
blet
NDC 16837-855-75
75
75 TABLET
LETS
®
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
Dist. by:
®Registered trademark
of Merck & Co., Inc.
7836340
7836340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MANUFACTURER COUPON NO EXPIRATION DATE
on your next purchase of
Pepcid ®AC or Pepcid ® Complete
25 count or larger
Save
$2.00
any
strength
Questions or comments?
Please call 1-800-755-4008 for more information
and a guide of how to help your heartburn.
www.pepcidac.com
Distributed by:
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
® Registered trademark of Merck & Co., Inc.
0000000
0000000
Excellent safety record
The ingredient in MAXIMUM STRENGTH PEPCID® AC, famotidine, has been prescribed by doctors for
years to treat millions of patients safely and effectively. The active ingredient in MAXIMUM STRENGTH
PEPCID® AC has been taken safely with many frequently prescribed medications.
Know when to see your doctor
Proven effective in clinical studies
Percent of heartburn episodes
completely relieved within 3 hours
Percent of patients with prevention
or reduction of heartburn symptoms
In clinical studies, MAXIMUM STRENGTH PEPCID
® AC film-coated tablets were
significantly better than placebo tablets (tablets without the medicine) in relieving and
preventing heartburn.
0
20
40
60
80
72
50
61
70
Study C
Study D
MAXIMUM
STRENGTH
PEPCID® AC
Placebo
0
20
40
60
80
67
41
53
69
Study A
Study B
MAXIMUM
STRENGTH
PEPCID® AC
Placebo
A non-prescription stomach medicine
MAXIMUM STRENGTH PEPCID® AC contains a medicine, different from antacids, that doctors have
prescribed for years to treat acid-related problems in millions of people.
• 1 tablet relieves heartburn due to acid indigestion.
• MAXIMUM STRENGTH PEPCID® AC prevents heartburn associated with acid
indigestion and sour stomach brought on by eating or drinking certain foods
or beverages.
• It contains famotidine, a prescription-proven medicine.
Tablets
How to use MAXIMUM STRENGTH PEPCID® AC
WHAT
YOU
SHOULD
KNOW
ABOUT:
PACKAGE INSERT
Product Benefits:
It is normal for the stomach to produce acid, especially after consuming food and beverages. However,
acid in the wrong place (the esophagus), or too much acid, can cause burning pain and discomfort that
interfere with everyday activities.
Heartburn—
Caused by acid in the esophagus
A valve-like
muscle called
the lower
esophageal
sphincter
(LES) is
relaxed in an
open position
Excess acid
moves
up into
esophagus
Burning
pain/
discomfort
Tips for Managing Heartburn
• Do not lie flat or bend over soon after eating.
• Do not eat late at night, or just before bedtime.
• Certain foods or drinks are more likely to cause
heartburn, such as rich, spicy, fatty, and fried
foods, chocolate, caffeine, alcohol, and even some
fruits and vegetables.
• Eat slowly and do not eat big meals.
• If you are overweight, lose weight.
• If you smoke, quit smoking.
• Raise the head of your bed.
• Wear loose fitting clothing around your stomach.
Excess acid: a burning problem
®
Famotidine Tablets 20mg/
Acid Reducer
Use MAXIMUM STRENGTH
PEPCID® AC to relieve or
prevent these symptoms:
• Do not take more than 1 tablet at a time.
• Do not take more than 2 tablets in 24 hours.
MAXIMUM STRENGTH
PEPCID® AC can be used up to
twice daily (up to 2 tablets in
24 hours).
• Heartburn
• Acid indigestion
• Sour stomach
TO RELIEVE SYMPTOMS
Swallow 1 tablet with a glass
of water (do not chew).
TO PREVENT SYMPTOMS
Swallow 1 tablet with a glass of water
at any time from 15 to 60 minutes
before eating food or drinking
beverages that cause heartburn.
MAXIMUM STRENGTH
Do not use if the individual blister unit is open or torn.
Heartburn and acid indigestion are common, but you should stop taking MAXIMUM STRENGTH
PEPCID
® AC and see your doctor promptly if:
• You have trouble swallowing or stomach pain continues. You may have a serious condition that
may need different treatment.
• You need to take this product for more than 14 days.
Allergy alert: Do not use if you are allergic to famotidine or other acid reducers. Do not use with
other acid reducers. Do not use if you have kidney disease, except under the advice and supervision of
a doctor. This product should not be given to children under 12 years old, unless directed by a doctor.
As with any drug, if you are pregnant or nursing a baby, seek the advice of a health professional before
using this product. Keep this and all drugs out of the reach of children. In case of accidental overdose,
seek professional assistance or contact a Poison Control Center immediately.
Shown
actual
size
INSERT PEPCID MAX STRENGTH FCT 5 (VERSION 3) 3004316 B-5
JULY 18, 2003
This coupon good only on purchase of product indicated. Any other use constitutes fraud. COUPON
CANNOT BE BOUGHT, TRANSFERRED OR SOLD. LIMIT — ONE COUPON PER PURCHASE. VOID IF TAXED,
RESTRICTED OR PROHIBITED BY LAW. To the retailer: Johnson & Johnson • Merck Consumer
Pharmaceuticals Co. will reimburse you for the face value of this coupon plus 8¢ if submitted in compliance
with Johnson & Johnson • Merck Consumer Pharmaceuticals Company Coupon Redemption Policy. Cash
value 1/20th of one cent. Send coupons to Johnson & Johnson • Merck Consumer Pharmaceuticals Co.,
CMS Department 00045, 1 Fawcett Drive, Del Rio, TX 78840. ©JJMCP 2003.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Questions or comments?
Please call 1-800-755-4008 for more information
and a guide of how to help your heartburn.
www.pepcidac.com
Distributed by:
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
® Registered trademark of Merck & Co., Inc.
0000000
0000000
Excellent safety record
The ingredient in MAXIMUM STRENGTH PEPCID® AC, famotidine, has been prescribed by doctors for
years to treat millions of patients safely and effectively. The active ingredient in MAXIMUM STRENGTH
PEPCID® AC has been taken safely with many frequently prescribed medications.
Know when to see your doctor
Proven effective in clinical studies
Percent of heartburn episodes
completely relieved within 3 hours
Percent of patients with prevention
or reduction of heartburn symptoms
In clinical studies, MAXIMUM STRENGTH PEPCID
® AC film-coated tablets were
significantly better than placebo tablets (tablets without the medicine) in relieving and
preventing heartburn.
0
20
40
60
80
72
50
61
70
Study C
Study D
MAXIMUM
STRENGTH
PEPCID® AC
Placebo
0
20
40
60
80
67
41
53
69
Study A
Study B
MAXIMUM
STRENGTH
PEPCID® AC
Placebo
A non-prescription stomach medicine
MAXIMUM STRENGTH PEPCID® AC contains a medicine, different from antacids, that doctors have
prescribed for years to treat acid-related problems in millions of people.
• 1 tablet relieves heartburn due to acid indigestion.
• MAXIMUM STRENGTH PEPCID® AC prevents heartburn associated with acid
indigestion and sour stomach brought on by eating or drinking certain foods
or beverages.
• It contains famotidine, a prescription-proven medicine.
How to use MAXIMUM STRENGTH PEPCID® AC
Tablets
PACKAGE INSERT
®
Famotidine Tablets 20mg/
Acid Reducer
MAXIMUM STRENGTH
WHAT
YOU
SHOULD
KNOW
ABOUT:
Product Benefits:
It is normal for the stomach to produce acid, especially after consuming food and beverages. However,
acid in the wrong place (the esophagus), or too much acid, can cause burning pain and discomfort that
interfere with everyday activities.
Heartburn—
Caused by acid in the esophagus
A valve-like
muscle called
the lower
esophageal
sphincter
(LES) is
relaxed in an
open position
Excess acid
moves
up into
esophagus
Burning
pain/
discomfort
Tips for Managing Heartburn
• Do not lie flat or bend over soon after eating.
• Do not eat late at night, or just before bedtime.
• Certain foods or drinks are more likely to cause
heartburn, such as rich, spicy, fatty, and fried foods,
chocolate, caffeine, alcohol, and even some fruits
and vegetables.
• Eat slowly and do not eat big meals.
• If you are overweight, lose weight.
• If you smoke, quit smoking.
• Raise the head of your bed.
• Wear loose fitting clothing around your stomach.
Excess acid: a burning problem
Use MAXIMUM STRENGTH
PEPCID® AC to relieve or
prevent these symptoms:
• Do not take more than 1 tablet at a time.
• Do not take more than 2 tablets in 24 hours.
MAXIMUM STRENGTH
PEPCID® AC can be used up to
twice daily (up to 2 tablets in
24 hours).
• Heartburn
• Acid indigestion
• Sour stomach
TO RELIEVE SYMPTOMS
Swallow 1 tablet with a glass
of water (do not chew).
TO PREVENT SYMPTOMS
Swallow 1 tablet with a glass of water
at any time from 15 to 60 minutes
before eating food or drinking
beverages that cause heartburn.
Do not use if the individual pouch is open or torn.
Heartburn and acid indigestion are common, but you should stop taking MAXIMUM STRENGTH
PEPCID
® AC and see your doctor promptly if:
• You have trouble swallowing or stomach pain continues. You may have a serious condition that
may need different treatment.
• You need to take this product for more than 14 days.
Allergy alert: Do not use if you are allergic to famotidine or other acid reducers. Do not use with
other acid reducers. Do not use if you have kidney disease, except under the advice and supervision
of a doctor. This product should not be given to children under 12 years old, unless directed by a doctor.
As with any drug, if you are pregnant or nursing a baby, seek the advice of a health professional before
using this product. Keep this and all drugs out of the reach of children. In case of accidental overdose,
seek professional assistance or contact a Poison Control Center immediately.
Shown
actual
size
INSERT PEPCID MAX STRENGTH FCT 25 (VERSION 3) 3004316 D-5
JULY 30, 2003
VALUABLE MAIL-IN OFFER
Please circle one: Dr. Mr. Mrs. Miss.
Name (please print)
Address Apt.
City State Zip
E-mail Age: under 35 35-49 50-54 55-64 65 yrs+
product with purchase of 25 count or larger
Here's how you can get $3.00 off your next purchase:
BUY: Pepcid AC (any strength) or Pepcid Complete Package 25 count or Larger.
SEND: This completed certificate, UPC from the Pepcid AC or Pepcid Complete package, plus dated
cash register receipt with purchase price circled.
RECEIVE: $3.00 Coupon by mail.
SEND TO: Pepcid AC / Pepcid Complete $3 Offer 780
P.O. Box 6607
Douglas, AZ 85655-6607
© Johnson & Johnson • Merck 2003
NOTE: Offer good only in U.S.A. and APO/FPO addresses. This request
form may not be mechanically reproduced. LIMIT TWO OFFERS PER
FAMILY AND/OR ADDRESS, PER YEAR. No group or organization requests
will be honored. Your offer rights may not be transferred or assigned. Offer
void where prohibited or taxed. You should expect to receive your coupon
in 6-8 weeks. Cannot be combined with any other offers.
Yes, I'd like to receive future communications from McNeil-PPC, Inc., Splenda, Inc. and
Johnson & Johnson • Merck Consumer Pharmaceuticals Co.
Pepcid
®
AC Pepcid
®
Complete
Save $3.00
on
or
any
any
strength
strength
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Please call 1-800-755-4008 for more information
and a guide of how to help your heartburn.
www.pepcidac.com
Distributed by:
CONSUMER PHARMACEUTICALS CO.
FORT WASHINGTON, PA 19034 USA
0000000
A non-prescription stomach medicine
MAXIMUM STRENGTH PEPCID® AC contains a medicine, different from antacids, that doctors have
prescribed for years to treat acid-related problems in millions of people.
• 1 tablet relieves heartburn due to acid indigestion.
• MAXIMUM STRENGTH PEPCID® AC prevents heartburn associated with acid
indigestion and sour stomach brought on by eating or drinking certain foods
or beverages.
• It contains famotidine, a prescription-proven medicine.
How to use MAXIMUM STRENGTH PEPCID® AC
Tablets
PACKAGE INSERT
®
Famotidine Tablets 20mg/
Acid Reducer
MAXIMUM STRENGTH
WHAT
YOU
SHOULD
KNOW
ABOUT:
Product Benefits:
It is normal for the stomach to produce acid, especially after consuming food and beverages. However,
acid in the wrong place (the esophagus), or too much acid, can cause burning pain and discomfort that
interfere with everyday activities.
Heartburn—
Caused by acid in the esophagus
A valve-like
muscle called
the lower
esophageal
sphincter
(LES) is
relaxed in an
open position
Excess acid
moves
up into
esophagus
Burning
pain/
discomfort
Tips for Managing Heartburn
• Do not lie flat or bend over soon after eating.
• Do not eat late at night, or just before bedtime.
• Certain foods or drinks are more likely to cause
heartburn, such as rich, spicy, fatty, and fried foods,
chocolate, caffeine, alcohol, and even some fruits
and vegetables.
• Eat slowly and do not eat big meals.
• If you are overweight, lose weight.
• If you smoke, quit smoking.
• Raise the head of your bed.
• Wear loose fitting clothing around your stomach.
Excess acid: a burning problem
VALUABLE MAIL-IN OFFER
Please circle one: Dr. Mr. Mrs. Miss.
Name (please print)
Address Apt.
City State Zip
E-mail Age: under 35 35-49 50-54 55-64 65 yrs+
product with purchase of 25 count or larger
Here's how you can get $3.00 off your next purchase:
BUY: Pepcid AC (any strength) or Pepcid Complete Package 25 count or Larger.
SEND: This completed certificate, UPC from the Pepcid AC or Pepcid Complete package, plus dated
cash register receipt with purchase price circled.
RECEIVE: $3.00 Coupon by mail.
SEND TO: Pepcid AC / Pepcid Complete $3 Offer 780
P.O. Box 6607
Douglas, AZ 85655-6607
© Johnson & Johnson • Merck 2003
NOTE: Offer good only in U.S.A. and APO/FPO addresses. This request
form may not be mechanically reproduced. LIMIT TWO OFFERS PER
FAMILY AND/OR ADDRESS, PER YEAR. No group or organization requests
will be honored. Your offer rights may not be transferred or assigned. Offer
void where prohibited or taxed. You should expect to receive your coupon
in 6-8 weeks. Cannot be combined with any other offers.
Yes, I'd like to receive future communications from McNeil-PPC, Inc., Splenda, Inc. and
Johnson & Johnson • Merck Consumer Pharmaceuticals Co.
Pepcid
®AC Pepcid
®Complete
Save $3.00
on
or
any
any
strength
strength
Do not use if printed foil seal under bottle cap is open or torn.
Excellent safety record
The ingredient in MAXIMUM STRENGTH PEPCID® AC, famotidine, has been prescribed by doctors for
years to treat millions of patients safely and effectively. The active ingredient in MAXIMUM STRENGTH
PEPCID® AC has been taken safely with many frequently prescribed medications.
Proven effective in clinical studies
Percent of heartburn episodes
completely relieved within 3 hours
Percent of patients with prevention
or reduction of heartburn symptoms
In clinical studies, MAXIMUM STRENGTH PEPCID
® AC film-coated tablets were
significantly better than placebo tablets (tablets without the medicine) in relieving and
preventing heartburn.
0
20
40
60
80
72
50
61
70
Study C
Study D
MAXIMUM
STRENGTH
PEPCID® AC
Placebo
0
20
40
60
80
67
41
53
69
Study A
Study B
MAXIMUM
STRENGTH
PEPCID® AC
Placebo
Questions or comments?
® Registered trademark of Merck & Co., Inc.
0000000
Use MAXIMUM STRENGTH
PEPCID® AC to relieve or
prevent these symptoms:
• Do not take more than 1 tablet at a time.
• Do not take more than 2 tablets in 24 hours.
MAXIMUM STRENGTH
PEPCID® AC can be used up to
twice daily (up to 2 tablets in
24 hours).
• Heartburn
• Acid indigestion
• Sour stomach
TO RELIEVE SYMPTOMS
Swallow 1 tablet with a glass
of water (do not chew).
TO PREVENT SYMPTOMS
Swallow 1 tablet with a glass of water
at any time from 15 to 60 minutes
before eating food or drinking
beverages that cause heartburn.
Know when to see your doctor
Heartburn and acid indigestion are common, but you should stop taking MAXIMUM STRENGTH
PEPCID
® AC and see your doctor promptly if:
• You have trouble swallowing or stomach pain continues. You may have a serious condition that
may need different treatment.
• You need to take this product for more than 14 days.
Allergy alert: Do not use if you are allergic to famotidine or other acid reducers. Do not use with
other acid reducers. Do not use if you have kidney disease, except under the advice and supervision of
a doctor. This product should not be given to children under 12 years old, unless directed by a doctor.
As with any drug, if you are pregnant or nursing a baby, seek the advice of a health professional before
using this product. Keep this and all drugs out of the reach of children. In case of accidental overdose,
seek professional assistance or contact a Poison Control Center immediately.
Shown
actual
size
INSERT PEPCID MAX STRENGTH FCT 50 (VERSION 3) 3004316 F-4
JULY 18, 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:27.120659
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20325se2-015_pepcid_lbl.pdf', 'application_number': 20325, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
12,445
|
1
NEUTREXIN® (trimetrexate glucuronate for injection)
Black Box
WARNINGS
NEUTREXIN (TRIMETREXATE GLUCURONATE FOR INJECTION) MUST BE USED
WITH CONCURRENT LEUCOVORIN (LEUCOVORIN PROTECTION) TO AVOID
POTENTIALLY SERIOUS OR LIFE-THREATENING TOXICITIES (SEE PRECAUTIONS
AND DOSAGE AND ADMINISTRATION).
DESCRIPTION
Neutrexin is the brand name for trimetrexate glucuronate. Trimetrexate, a 2,4-diaminoquinazoline, non-
classical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase (DHFR). Neutrexin
is available as a sterile lyophilized powder, containing trimetrexate glucuronate equivalent to either 200mg
or 25mg of trimetrexate without any preservatives or excipients. The powder is reconstituted prior to
intravenous infusion (see DOSAGE AND ADMINISTRATION, RECONSTITUTION AND
DILUTION).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Trimetrexate glucuronate is chemically known as 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]
quinazoline mono-D-glucuronate, and has the following structure:
OCH3
CH3O
CH3O
N
N
N
CH3
NH2
NH2
H
CHO
OH
H
H
HO
OH
H
OH
H
COOH
The empirical formula for trimetrexate glucuronate is C19H23N5O3 • C6H10O7 with a molecular weight of
563.56. The active ingredient, trimetrexate free base, has an empirical formula of C19H23N5O3 with a
molecular weight of 369.42. Trimetrexate glucuronate for injection is a pale greenish-yellow powder or
cake. Trimetrexate glucuronate is soluble in water (>50 mg/mL), whereas trimetrexate free base is
practically insoluble in water (<0.1 mg/mL). The pKa of trimetrexate free base in 50% methanol/water is
8.0. The logarithm10 of the partition coefficient of trimetrexate free base between octanol and water is 1.63.
CLINICAL PHARMACOLOGY
Mechanism of Action
In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR)
from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular
dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this
coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The end result is disruption
of DNA, RNA, and protein synthesis, with consequent cell death. Leucovorin (folinic acid) is readily
transported into mammalian cells by an active, carrier-mediated process and can be assimilated into cellular
folate pools following its metabolism. In vitro studies have shown that leucovorin provides a source of
reduced folates necessary for normal cellular biosynthetic processes. Because the Pneumocystis carinii
organism lacks the reduced folate carrier-mediated transport system, leucovorin is prevented from entering
the organism. Therefore, at concentrations achieved with therapeutic doses of trimetrexate plus leucovorin,
the selective transport of trimetrexate, but not leucovorin, into the Pneumocystis carinii organism allows
the concurrent administration of leucovorin to protect normal host cells from the cytotoxicity of trimetrexate
without inhibiting the antifolate's inhibition of Pneumocystis carinii. It is not known if considerably higher
doses of leucovorin would affect trimetrexate's effect on Pneumocystis carinii.
Microbiology
Trimetrexate inhibits, in a dose-related manner, in vitro growth of the trophozoite stage of rat
Pneumocystis carinii cultured on human embryonic lung fibroblast cells. Trimetrexate concentrations
between 3 and 54.1 ìM were shown to inhibit the growth of trophozoites. Leucovorin alone at a
concentration of 10 ìM did not alter either the growth of the trophozoites or the anti-pneumocystis activity
of trimetrexate. Resistance to trimetrexate's antimicrobial activity against Pneumocystis carinii 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
4
Pharmacokinetics
Trimetrexate pharmacokinetics were assessed in six patients with acquired immunodeficiency syndrome
(AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate
was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20
mg/m2 every 6 hours for 21 days. Trimetrexate clearance (mean ± SD) was 38 ± 15 mL/min/m2 and
volume of distribution at steady state (Vdss) was 20 ± 8 L/m2. The plasma concentration time profile
declined in a biphasic manner over 24 hours with a terminal half-life of 11 ± 4 hours.
The pharmacokinetics of trimetrexate without the concomitant administration of leucovorin have been
evaluated in cancer patients with advanced solid tumors using various dosage regimens. The decline in
plasma concentrations over time has been described by either biexponential or triexponential equations.
Following the single-dose administration of 10 to 130 mg/m2 to 37 patients, plasma concentrations were
obtained for 72 hours. Nine plasma concentration time profiles were described as biexponential. The alpha
phase half-life was 57 ± 28 minutes, followed by a terminal phase with a half-life of 16 ± 3 hours. The
plasma concentrations in the remaining patients exhibited a triphasic decline with half-lives of 8.6 ± 6.5
minutes, 2.4 ± 1.3 hours, and 17.8 ± 8.2 hours.
Trimetrexate clearance in cancer patients has been reported as 53 ± 41 mL/min (14 patients) and 32 ± 18
mL/min/m2 (23 patients) following single-dose administration. After a five-day infusion of trimetrexate to
16 patients, plasma clearance was 30 ± 8 mL/min/m2.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Renal clearance of trimetrexate in cancer patients has varied from about 4 ± 2 mL/min/m2 to 10 ± 6
mL/min/m2. Ten to 30% of the administered dose is excreted unchanged in the urine. Considering the free
fraction of trimetrexate, active tubular secretion may possibly contribute to the renal clearance of
trimetrexate. Renal clearance has been associated with urine flow, suggesting the possibility of tubular
reabsorption as well.
The Vdss of trimetrexate in cancer patients after single-dose administration and for whom plasma
concentrations were obtained for 72 hours was 36.9 ± 17.6 L/m2 (n=23) and 0.62 ± 0.24 L/kg (n=14).
Following a constant infusion of trimetrexate for five days, Vdss was 32.8 ± 16.6 L/m2. The volume of
the central compartment has been estimated as 0.17 ± 0.08 L/kg and 4.0 ± 2.9 L/m2.
There have been inconsistencies in the reporting of trimetrexate protein binding. The in vitro plasma protein
binding of trimetrexate using ultrafiltration is approximately 95% over the concentration range of 18.75 to
1000 ng/mL. There is a suggestion of capacity limited binding (saturable binding) at concentrations greater
than about 1000 ng/mL, with free fraction progressively increasing to about 9.3% as concentration is
increased to 15 ìg/mL. Other reports have declared trimetrexate to be greater than 98% bound at
concentrations of 0.1 to 10 ìg/mL; however, specific free fractions were not stated. The free fraction of
trimetrexate also has been reported to be about 15 to 16% at a concentration of 60 ng/mL, increasing to
about 20% at a trimetrexate concentration of 6 ìg/mL.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Trimetrexate metabolism in man has not been characterized. Preclinical data strongly suggest that the major
metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the
sulfate. N-demethylation and oxidation is a related minor pathway. Preliminary findings in humans indicate
the presence of a glucuronide conjugate with DHFR inhibition and a demethylated metabolite in urine.
The presence of metabolite(s) in human plasma following the administration of trimetrexate is suggested by
the differences seen in trimetrexate plasma concentrations when measured by HPLC and a nonspecific
DHFR inhibition assay. The profiles are similar initially, but diverge with time; concentrations determined
by DHFR being higher than those determined by HPLC. This suggests the presence of one or more
metabolites with DHFR inhibition activity. After intravenous administration of trimetrexate to humans,
urinary recovery averaged about 40%, using a DHFR assay, in comparison to 10% urinary recovery as
determined by HPLC, suggesting the presence of one or more metabolites that retain inhibitory activity
against DHFR. Fecal recovery of trimetrexate over 48 hours after intravenous administration ranged from
0.09 to 7.6% of the dose as determined by DHFR inhibition and 0.02 to 5.2% of the dose as determined
by HPLC.
The pharmacokinetics of trimetrexate have not been determined in patients with renal insufficiency or hepatic
dysfunction.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
INDICATIONS AND USAGE
Neutrexin (trimetrexate glucuronate for injection) with concurrent leucovorin administration (leucovorin
protection) is indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis
carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired
immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-
sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated.
This indication is based on the results of a randomized, controlled double-blind trial comparing Neutrexin
with concurrent leucovorin protection (TMTX/LV) to trimethoprim-sulfamethoxazole (TMP/SMX) in
patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results of a Treatment IND.
These studies are summarized below:
Neutrexin Comparative Study with TMP/SMX: This double-blind, randomized trial initiated by the
AIDS Clinical Trials Group (ACTG) in 1988 was designed to compare the safety and efficacy of
TMTX/LV to that of TMP/SMX for the treatment of histologically confirmed, moderate-to-severe PCP,
defined as (A-a) baseline gradient >30 mmHg, in patients with AIDS.
Of the 220 patients with histologically confirmed PCP, 109 were randomized to receive TMTX/LV and
111 to TMP/SMX. Study patients randomized to TMTX/LV treatment were to receive 45 mg/m2 of
TMTX daily for 21 days plus 20 mg/m2 of LV every 6 hours for 24 days. Those randomized to
TMP/SMX were to receive 5 mg/kg TMP plus 25 mg/kg SMX four times daily for 21 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Response to therapy, defined as alive and off ventilatory support at completion of therapy, with no change
in anti-pneumocystis therapy, or addition of supraphysiologic doses of steroids, occurred in fifty percent
of patients in each treatment group.
The observed mortality in the TMTX/LV treatment group was approximately twice that in the TMP/SMX
treatment group (95% CI: 0.99 - 4.11). Thirty of 109 (27%) patients treated with TMTX/LV and 18 of
111 (16%) patients receiving TMP/SMX died during the 21-day treatment course or 4-week follow-up
period. Twenty-seven of 30 deaths in the TMTX/LV arm were attributed to PCP; all 18 deaths in the
TMP/SMX arm were attributed to PCP.
A significantly smaller proportion of patients who received TMTX/LV compared to TMP/SMX failed
therapy due to toxicity (10% vs. 25%), and a significantly greater proportion of patients failed due to lack
of efficacy (40% vs. 24%). Six patients (12%) who responded to TMTX/LV relapsed during the one-
month follow-up period; no patient responding to TMP/SMX relapsed during this period. Information is
not available as to whether these patients received prophylaxis therapy for PCP.
Treatment IND: The FDA granted a Treatment IND for Neutrexin with leucovorin protection in
February 1988 to make Neutrexin therapy available to HIV-infected patients with histologically confirmed
PCP who had disease refractory to or who were intolerant of TMP/SMX and/or intravenous pentamidine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Over 500 physicians in the United States participated in the Treatment IND. Of the first 753 patients
enrolled, 577 were evaluable for efficacy. Of these, 227 patients were intolerant of both TMP/SMX and
pentamidine (IST - patients intolerant of both standard therapies), 146 were intolerant of one therapy and
refractory to the other (RIST - patients refractory to one therapy and intolerant of the other) and 204 were
refractory to both therapies (RST - refractory to both standard therapies). This was a very ill patient
population; 38% required ventilatory support at entry (Table 1). These studies did not have concurrent
control groups.
TABLE 1
TREATMENT IND
Baseline Characteristics
IST
(n = 227)
RIST
(n = 146)
RST
(n = 204)
TOTAL
(n = 577)
Ventilatory Support Required
n (%)
39
(17)
50
(34)
129
(63)
218
(38)
Median Days on Standard Therapy
10
12
16
14
First Episode of PCP
n (%)
104
(46)
103
(71)
190
(93)
397
(69)
The overall survival rate one month after completion of TMTX/LV as salvage therapy was 48%. Patients
who had not responded to treatment with both TMP/SMX and pentamidine, of whom 63% required
mechanical ventilation at entry, achieved a survival rate of 25% following treatment with TMTX/LV.
Survival was 67% in patients who were intolerant to both TMP/SMX and pentamidine (Table 2).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
TABLE 2
TREATMENT IND
Survival Rate One Month After Completion of Neutrexin
Therapy
IST
RIST
RST
All Patients
153/227
(67%)
73/146
(50%)
50/204
(25%)
Baseline Ventilatory
Support
No Baseline Ventilatory
Support
9/39
144/188
(23%)
(77%)
15/50
58/96
(30%)
(60%)
18/129
32/75
(14%)
(43%)
In the Treatment IND, 12% of the patients discontinued Neutrexin therapy (with leucovorin protection) for
toxicity.
CONTRAINDICATIONS
Neutrexin (trimetrexate glucuronate for injection) is contraindicated in patients with clinically significant
sensitivity to trimetrexate, leucovorin, or methotrexate.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
WARNINGS
Neutrexin (trimetrexate glucuronate for injection) must be used with concurrent leucovorin to avoid
potentially serious or life-threatening complications including bone marrow suppression, oral and
gastrointestinal mucosal ulceration, and renal and hepatic dysfunction. Leucovorin therapy must extend for
72 hours past the last dose of Neutrexin. Patients should be informed that failure to take the recommended
dose and duration of leucovorin can lead to fatal toxicity. Patients should be closely monitored for the
development of serious hematologic adverse reactions (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION).
Neutrexin can cause fetal harm when administered to a pregnant woman. Trimetrexate has been shown to
be fetotoxic and teratogenic in rats and rabbits. Rats administered 1.5 and 2.5 mg/kg/day intravenously on
gestational days 6-15 showed substantial postimplantation loss and severe inhibition of maternal weight gain.
Trimetrexate administered intravenously to rats at 0.5 and 1.0 mg/kg/day on gestational days 6-15 retarded
normal fetal development and was teratogenic. Rabbits administered trimetrexate intravenously at daily
doses of 2.5 and 5.0 mg/kg/day on gestational days 6-18 resulted in significant maternal and fetal toxicity.
In rabbits, trimetrexate at 0.1 mg/kg/day was teratogenic in the absence of significant maternal toxicity.
These effects were observed using doses 1/20 to 1/2 the equivalent human therapeutic dose based on a
mg/m2 basis. Teratogenic effects included skeletal, visceral, ocular, and cardiovascular abnormalities. If
Neutrexin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient
should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised
to avoid becoming pregnant.
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12
PRECAUTIONS
General
Patients receiving Neutrexin (trimetrexate glucuronate for injection) may experience severe hematologic,
hepatic, renal, and gastrointestinal toxicities. Caution should be used in treating patients with impaired
hematologic, renal, or hepatic function. Patients who require concomitant therapy with nephrotoxic,
myelosuppressive, or hepatotoxic drugs should be treated with Neutrexin at the discretion of the physician
and monitored carefully. To allow for full therapeutic doses of Neutrexin, treatment with zidovudine should
be discontinued during Neutrexin therapy.
Neutrexin-associated myelosuppression, stomatitis, and gastrointestinal toxicities generally can be
ameliorated by adjusting the dose of leucovorin. Mild elevations in transaminases and alkaline phosphatase
have been observed with Neutrexin administration and are usually not cause for modification of Neutrexin
therapy (see DOSAGE AND ADMINISTRATION). Seizures have been reported rarely (< 1%) in
AIDS patients receiving Neutrexin; however, a causal relationship has not been established. Trimetrexate
is a known inhibitor of histamine metabolism. Hypersensitivity/allergic type reactions including but not
limited to rash, chills/rigors, fever, diaphoresis and dypsnea have occurred with trimetrexate primarily when
it is administered as a bolus infusion or at doses higher than those recommended for PCP, and most
frequently in combination with 5FU and leucovorin. In rare cases, anaphylactoid reactions, including acute
hypotension and loss of consciousness have occurred.
Neutrexin has not been evaluated clinically for the treatment of concurrent pulmonary conditions such as
bacterial, viral, or fungal pneumonia or mycobacterial diseases. In vitro activity has been observed against
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13
Toxoplasma gondii, Mycobacterium avium complex, gram positive cocci, and gram negative rods. If
clinical deterioration is observed in patients, they should be carefully evaluated for other possible causes of
pulmonary disease and treated with additional agents as appropriate.
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14
Laboratory Tests
Patients receiving Neutrexin with leucovorin protection should be seen frequently by a physician. Blood
tests to assess the following parameters should be performed at least twice a week during therapy:
hematology (absolute neutrophil counts [ANC], platelets), renal function (serum creatinine, BUN), and
hepatic function (AST, ALT, alkaline phosphatase).
Drug Interactions
Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug
metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma
concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications
that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In
vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate
metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly
by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole
drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate
metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Long term studies in animals to evaluate the carcinogenic potential of trimetrexate have not
been performed.
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15
Mutagenesis: Trimetrexate was not mutagenic when tested using the standard Ames Salmonella
mutagenicity assay with and without metabolic activation. Trimetrexate did not induce mutations in Chinese
hamster lung cells or sister-chromatid exchange in Chinese hamster ovary cells. Trimetrexate did induce
an increase in the chromosomal aberration frequency of cultured Chinese hamster lung cells; however,
trimetrexate showed no clastogenic activity in a mouse micronucleus assay.
Impairment of fertility: No studies have been conducted to evaluate the potential of trimetrexate to impair
fertility. However, during standard toxicity studies conducted in mice and rats, degeneration of the testes
and spermatocytes including the arrest of spermatogenesis was observed.
Pregnancy, Teratogenic Effects
See WARNINGS.
Pregnancy Category D
Nursing Mothers
It is not known if trimetrexate is excreted in human milk. Because many drugs are excreted in human milk
and because of the potential for serious adverse reactions in nursing infants from trimetrexate, it is
recommended that breast feeding be discontinued if the mother is treated with Neutrexin.
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16
Pediatric Use
The safety and effectiveness of Neutrexin for the treatment of histologically confirmed PCP has not been
established for patients under 18 years of age. Two children, ages 15 months and 9 months, were treated
with trimetrexate and leucovorin using a dose of 45 mg/m2 of trimetrexate per day for 21 days and 20
mg/m2 of leucovorin every 6 hours for 24 days. There were no serious or unexpected adverse effects.
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17
ADVERSE REACTIONS
Because many patients who participated in clinical trials of Neutrexin (trimetrexate glucuronate for injection)
had complications of advanced HIV disease, it is difficult to distinguish adverse events caused by Neutrexin
from those resulting from underlying medical conditions.
Table 3 lists the adverse events that occurred in ≥ 1% of the patients who participated in the Comparative
Study of Neutrexin plus leucovorin versus TMP/SMX.
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18
TABLE 3
NEUTREXIN COMPARATIVE TRIAL
Comparison of Adverse Events Reported for ≥≥ 1% of Patients
Number and Percent (%) of Patients
with Adverse Events
Adverse Events
TMTX/LV
(n = 109)
TMP/SMX
(n = 111)
Non-Laboratory Adverse Events:
Fever
Rash/Pruritus
Nausea/Vomiting
Confusion
Fatigue
9
6
5
3
2
(8.3)
(5.5)
(4.6)a
(2.8)
(1.8)
14
14
15
3
0
(12.6)
(12.6)
(13.5)a
(2.7)
(0.0)
Hematologic Toxicity:
Neutropenia (<1000/mm3)
Thrombocytopenia (<75,000/mm3)
Anemia (Hgb <8 g/dL)
33
11
8
(30.3)
(10.1)
(7.3)
37
17
10
(33.3)
(15.3)
(9.0)
Hepatotoxicity:
Increased AST (>5 x ULNb)
Increased ALT (>5 x ULN)
Increased Alkaline Phosphatase (>5 x ULN)
Increased Bilirubin (2.5 x ULN)
15
12
5
2
(13.8)
(11.0)
(4.6)
(1.8)
10
13
3
1
(9.0)
(11.7)
(2.7)
(0.9)
Renal:
Increased Serum Creatinine (>3 x ULN)
1
(0.9)
2
(1.8)
Electrolyte Imbalance:
Hyponatremia
Hypocalcemia
5
2
(4.6)
(1.8)
10
0
(9.0)
(0.0)
No. of Patients With at Least one Adverse Eventc
58
(53.2)
60
(54.1)
a
Statistically significant difference between treatment groups (Chi-square: p=0.022)
b
ULN = Upper limit of normal range
c
Patients could have reported more than one adverse event; therefore, the sum of adverse events exceeds
the number of patients
Laboratory toxicities were generally manageable with dose modification of
trimetrexate/leucovorin (see DOSAGE AND ADMINISTRATION).
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19
Table 4 lists the adverse events resulting in discontinuation of study therapy in the Neutrexin
Comparative Study with TMP/SMX. Twenty-nine percent of the patients on the TMP/SMX arm
discontinued therapy due to adverse events compared to 10% of the patients treated with TMTX/LV (p
< 0.001).
TABLE 4
NEUTREXIN COMPARATIVE TRIAL
Adverse Events Resulting in Discontinuation of Therapy
Number and Percent (%) of
Patients Discontinued for
Adverse Eventsb
Adverse Events
TMTX/LV
(n = 109)
TMP/SMX
(n = 111)
Non-Laboratory Adverse Events:
Rash/Pruritus
Fever
Nausea/Vomiting
Neurologic Toxicity
3
2
1
1
(2.8)
(1.8)
(0.9)
(0.9)c
5
4
8
2
(4.5)
(3.6)
(7.2)
(1.8)
Hematologic Toxicity:
Neutropenia (<1000/mm3)
Thrombocytopenia (<75,000/mm3)
Anemia (Hgb <8 g/dL)
4
0
0
(3.7)
(0.0)
(0.0)
6
4
4
(5.4)
(3.6)
(3.6)
Hepatotoxicity:
Increased AST (>5 x ULNa)
Increased ALT (>5 x ULN)
Increased Alkaline Phosphatase (>5 x ULN)
3
1
0
(2.8)
(0.9)
(0.0)
9
4
1
(8.1)
(3.6)
(0.9)
Electrolyte Imbalance:
Hyponatremia
0
(0.0)
3
(2.7)
No. of Patients Discontinuing Therapy Due to an
Adverse Eventb
11
(10.1)d
32
(28.8)d
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20
a
ULN = Upper limit of normal range
b
Patients could discontinue therapy due to more than one toxicity; therefore the sum exceeds
number of patients who discontinued due to toxicity
c
Patient discontinued TMTX/LV due to seizure, though causal relationship could not be established.
d
Statistically significant difference between treatment groups (Chi-square: p < 0.001)
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21
Hematologic toxicity was the principal dose-limiting side effect.
OVERDOSAGE
Neutrexin (trimetrexate glucuronate for injection) administered without concurrent
leucovorin can cause lethal complications. There has been no extensive experience in humans receiving
single intravenous doses of trimetrexate greater than 90 mg/m2/day with concurrent leucovorin. The
toxicities seen at this dose were primarily hematologic. In the event of overdose, Neutrexin should be
stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. The LD50
of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2).
DOSAGE AND ADMINISTRATION
Caution: Neutrexin (trimetrexate glucuronate for injection) must be administered with concurrent
leucovorin (leucovorin protection) to avoid potentially serious or life-threatening toxicities.
Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
Neutrexin (trimetrexate glucuronate for injection) is administered at a dose of 45 mg/m2 once daily by
intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment with
Neutrexin and for 72 hours past the last dose of Neutrexin. Leucovorin may be administered intravenously
at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or orally as
4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be rounded up to the next
higher 25 mg increment. The recommended course of therapy is 21 days of Neutrexin and 24 days of
leucovorin.
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22
Neutrexin and leucovorin may alternatively be dosed on a mg/kg basis, depending on the patient’s body
weight, using the conversion factors shown in the table below:
Body Weight (kg)
Neutrexin Dose
(mg/kg/day)
Leucovorin Dose (mg/kg/qid)
<50
1.5
0.6
50-80
1.2
0.5
>80
1.0
0.5
Dosage Modifications
Hematologic toxicity: Neutrexin (trimetrexate glucuronate for injection) and leucovorin doses should be
modified based on the worst hematologic toxicity according to the following table. If leucovorin is given
orally, doses should be rounded up to the next higher 25 mg increment.
TABLE 5
DOSE MODIFICATIONS FOR HEMATOLOGIC TOXICITY
Recommended Dosages of
Toxicity
Grade
Neutrophils
(Polys and Bands)
Platelets
Neutrexin
Leucovorin
1
>1000/mm3
>75,000/mm3
45 mg/m2 once daily
20 mg/m2 every 6 hours
2
750-1000/mm3
50,000-75,000/mm3
45 mg/m2 once daily
40 mg/m2 every 6 hours
3
500-749/mm3
25,000-49,999/mm3
22 mg/m2 once daily
40 mg/m2 every 6 hours
4
<500/mm3
<25,000/mm3
Day 1-9 Discontinue
Day 10-21 Interrupt up to 96 hours a
40 mg/m2 every 6 hours
a
If Grade 4 hematologic toxicity occurs prior to Day 10, Neutrexin should be discontinued. Leucovorin (40 mg/m2, q6h)
should be administered for an additional 72 hours. If Grade 4 hematologic toxicity occurs at Day 10 or later, Neutrexin
may be held up to 96 hours to allow counts to recover. If counts recover to Grade 3 within 96 hours, Neutrexin should
be administered at a dose of 22 mg/m2 and leucovorin maintained at 40 mg/m2, q6h. When counts recover to Grade 2
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23
toxicity, Neutrexin dose may be increased to 45 mg/m2, but the leucovorin dose should be maintained at 40 mg/m2 for the
duration of treatment. If counts do not improve to ≤ Grade 3 toxicity within 96 hours, Neutrexin should be discontinued.
Leucovorin at a dose of 40 mg/m2, q6h should be administered for 72 hours following the last dose of Neutrexin.
Hepatic toxicity: Transient elevations of transaminases and alkaline phosphatase have been observed in
patients treated with Neutrexin. Interruption of treatment is advisable if transaminase levels or alkaline
phosphatase levels increase to >5 times the upper limit of normal range.
Renal toxicity: Interruption of Neutrexin is advisable if serum creatinine levels increase to > 2.5 mg/dL and
the elevation is considered to be secondary to Neutrexin.
Other toxicities: Interruption of treatment is advisable in patients who experience severe mucosal toxicity
that interferes with oral intake. Treatment should be discontinued for fever (oral temperature ≥
105°F/40.5°C) that cannot be controlled with antipyretics.
Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
RECONSTITUTION AND DILUTION
Each vial of Neutrexin (trimetrexate glucuronate for injection) should be reconstituted in accordance with
labeled instructions with either 5% Dextrose Injection, USP, or Sterile Water for Injection, USP, to yield
a concentration of 12.5 mg of trimetrexate per mL (complete dissolution should occur within 30 seconds).
The reconstituted product will appear as a pale greenish-yellow solution and must be inspected visually
prior to dilution. Do not use if cloudiness or precipitate is observed. Neutrexin should not be
reconstituted with solutions containing either chloride ion or leucovorin, since precipitation occurs instantly.
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After reconstitution, the solution should be used immediately; however, the solution is stable for 6 hours at
room temperature (20 to 25ºC), or 24 hours under refrigeration (2-8°C).
Prior to administration, the reconstituted solution should be further diluted with 5% Dextrose Injection,
USP, to yield a final concentration of 0.25 to 2 mg of trimetrexate per mL. The diluted solution should be
administered by intravenous infusion over 60 minutes. Neutrexin should not be mixed with solutions
containing either chloride ion or leucovorin, since precipitation occurs instantly. The diluted solution is stable
under refrigeration or at room temperature for up to 24 hours. Do not freeze. Discard any unused portion
after 24 hours. The intravenous line must be flushed thoroughly with at least 10 mL of 5% Dextrose
Injection, USP, before and after administering Neutrexin.
Leucovorin protection may be administered prior to or following Neutrexin. In either case, the intravenous
line must be flushed thoroughly with at least 10 mL of 5% Dextrose Injection, USP. Leucovorin calcium
for injection should be diluted according to the instructions in the leucovorin package insert, and
administered over 5 to 10 minutes every 6 hours.
Caution: Parenteral products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Neutrexin forms a precipitate
instantly upon contact with chloride ion or leucovorin, therefore it should not be added to solutions
containing sodium chloride or other anions. Neutrexin and leucovorin solutions must be
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25
administered separately. Intravenous lines should be flushed with at least 10 mL of 5% Dextrose
Injection, USP, between Neutrexin and leucovorin infusions.
HANDLING AND DISPOSAL
If Neutrexin (trimetrexate glucuronate for injection) contacts the skin or mucosa, immediately wash
thoroughly with soap and water. Procedures for proper disposal of cytotoxic drugs should be considered.
Several guidelines on this subject have been published (1-5).
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26
HOW SUPPLIED
Neutrexin (trimetrexate glucuronate for injection) is supplied as a sterile lyophilized powder in either 5 mL
or 30 mL vials. Each 5 mL vial contains trimetrexate glucuronate equivalent to 25 mg of trimetrexate. Each
30 mL vial contains trimetrexate glucuronate equivalent to 200 mg of trimetrexate. The 5 mL vials are
packaged and available in two market presentations as listed below:
10 Pack - 10 vials in a white chip-board carton (NDC 58178-020-10)
50 Pack - 2 trays of 25 vials per shrink-wrapped tray (NDC 58178-020-50)
The 30 mL vials are packaged and available as listed below:
Single Pack - 1 vial (NDC 58178-021-01)
Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from exposure to light.
U.S. Patents 4,376,858; 4,694,007; 6,017,922
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27
REFERENCES
1.
AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. Journal of the
American Medical Association March 15, 1985.
2.
Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of
Antineoplastic Agents. Medical Journal of Australia 1: 426-428, 1983.
3.
Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai
Medical Center. CA - A Cancer Journal for Clinicians Sept/Oct, 258-263, 1983.
4.
American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic
Drugs in Hospitals. American Journal of Hospital Pharmacy 42: 131-137, 1985.
5.
OSHA Work Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs.
American Journal of Hospital Pharmacy 43: 1193-1204, 1986.
Manufactured by:
Marketed by:
Ben Venue Laboratories, Inc.
MedImmune Oncology, Inc.
Bedford, OH 44146
a subsidiary of MedImmune Inc.
Gaithersburg, MD 20878
Or:
1-877-633-4411
MedImmune Pharma B.V.
6545 CG Nijmegen
The Netherlands
© 2000, MedImmune Oncology, Inc.
Revision Date 11/2000
N-LB3020 PG
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For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
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this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Renata Albrecht
6/26/02 02:02:14 PM
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|
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----------------------------------------------------
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10/11/2012
Reference ID: 3202076
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1
NEUTREXIN® (trimetrexate glucuronate for injection)
1
2
Black Box
3
WARNINGS
4
NEUTREXIN (TRIMETREXATE GLUCURONATE FOR INJECTION) MUST BE USED
5
WITH CONCURRENT LEUCOVORIN (LEUCOVORIN PROTECTION) TO AVOID
6
POTENTIALLY SERIOUS OR LIFE-THREATENING TOXICITIES (SEE PRECAUTIONS
7
AND DOSAGE AND ADMINISTRATION).
8
9
DESCRIPTION
10
Neutrexin is the brand name for trimetrexate glucuronate. Trimetrexate, a 2,4-diaminoquinazoline,
11
non-classical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase
12
(DHFR). Neutrexin is available as a sterile lyophilized powder, containing trimetrexate glucuronate
13
equivalent to either 200mg or 25mg of trimetrexate without any preservatives or excipients. The
14
powder is reconstituted prior to intravenous infusion (see DOSAGE AND ADMINISTRATION,
15
RECONSTITUTION AND DILUTION).
16
17
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2
Trimetrexate
glucuronate
is
chemically
known
as
2,4-diamino-5-methyl-6-[(3,4,5-
18
trimethoxyanilino)methyl] quinazoline mono-D-glucuronate, and has the following structure:
19
20
OCH3
CH3O
CH3O
N
N
N
CH3
NH2
NH2
H
CHO
OH
H
H
HO
OH
H
OH
H
COOH
21
22
The empirical formula for trimetrexate glucuronate is C19H23N5O3 • C6H10O7 with a molecular
23
weight of 563.56. The active ingredient, trimetrexate free base, has an empirical formula of
24
C19H23N5O3 with a molecular weight of 369.42. Trimetrexate glucuronate for injection is a pale
25
greenish-yellow powder or cake. Trimetrexate glucuronate is soluble in water (>50 mg/mL),
26
whereas trimetrexate free base is practically insoluble in water (<0.1 mg/mL). The pKa of
27
trimetrexate free base in 50% methanol/water is 8.0. The logarithm10 of the partition coefficient of
28
trimetrexate free base between octanol and water is 1.63.
29
30
CLINICAL PHARMACOLOGY
31
Mechanism of Action
32
In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase
33
(DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of
34
intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the
35
depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as
36
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3
inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis.
37
The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.
38
Leucovorin (folinic acid) is readily transported into mammalian cells by an active, carrier-mediated
39
process and can be assimilated into cellular folate pools following its metabolism. In vitro studies
40
have shown that leucovorin provides a source of reduced folates necessary for normal cellular
41
biosynthetic processes. Because the Pneumocystis carinii organism lacks the reduced folate carrier-
42
mediated transport system, leucovorin is prevented from entering the organism. Therefore, at
43
concentrations achieved with therapeutic doses of trimetrexate plus leucovorin, the selective
44
transport of trimetrexate, but not leucovorin, into the Pneumocystis carinii organism allows the
45
concurrent administration of leucovorin to protect normal host cells from the cytotoxicity of
46
trimetrexate without inhibiting the antifolate's inhibition of Pneumocystis carinii. It is not known if
47
considerably higher doses of leucovorin would affect trimetrexate's effect on Pneumocystis carinii.
48
49
Microbiology
50
Trimetrexate inhibits, in a dose-related manner, in vitro growth of the trophozoite stage of rat
51
Pneumocystis carinii cultured on human embryonic lung fibroblast cells. Trimetrexate
52
concentrations between 3 and 54.1 µM were shown to inhibit the growth of trophozoites.
53
Leucovorin alone at a concentration of 10 µM did not alter either the growth of the trophozoites or
54
the anti-pneumocystis activity of trimetrexate. Resistance to trimetrexate's antimicrobial activity
55
against Pneumocystis carinii has not been studied.
56
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Pharmacokinetics
57
Trimetrexate pharmacokinetics were assessed in six patients with acquired immunodeficiency
58
syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2
59
patients). Trimetrexate was administered intravenously as a bolus injection at a dose of
60
30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days. Trimetrexate clearance
61
(mean ± SD) was 38 ± 15 mL/min/m2 and volume of distribution at steady state (Vdss) was 20 ± 8
62
L/m2. The plasma concentration time profile declined in a biphasic manner over 24 hours with a
63
terminal half-life of 11 ± 4 hours.
64
65
The pharmacokinetics of trimetrexate without the concomitant administration of leucovorin have
66
been evaluated in cancer patients with advanced solid tumors using various dosage regimens. The
67
decline in plasma concentrations over time has been described by either biexponential or
68
triexponential equations. Following the single-dose administration of 10 to 130 mg/m2 to 37
69
patients, plasma concentrations were obtained for 72 hours. Nine plasma concentration time profiles
70
were described as biexponential. The alpha phase half-life was 57 ± 28 minutes, followed by a
71
terminal phase with a half-life of 16 ± 3 hours. The plasma concentrations in the remaining patients
72
exhibited a triphasic decline with half-lives of 8.6 ± 6.5 minutes, 2.4 ± 1.3 hours, and 17.8 ± 8.2
73
hours.
74
75
Trimetrexate clearance in cancer patients has been reported as 53 ± 41 mL/min (14 patients) and 32
76
± 18 mL/min/m2 (23 patients) following single-dose administration. After a five-day infusion of
77
trimetrexate to 16 patients, plasma clearance was 30 ± 8 mL/min/m2.
78
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5
Renal clearance of trimetrexate in cancer patients has varied from about 4 ± 2 mL/min/m2 to 10 ± 6
79
mL/min/m2. Ten to 30% of the administered dose is excreted unchanged in the urine. Considering
80
the free fraction of trimetrexate, active tubular secretion may possibly contribute to the renal
81
clearance of trimetrexate. Renal clearance has been associated with urine flow, suggesting the
82
possibility of tubular reabsorption as well.
83
84
The Vdss of trimetrexate in cancer patients after single-dose administration and for whom plasma
85
concentrations were obtained for 72 hours was 36.9 ± 17.6 L/m2 (n=23) and 0.62 ± 0.24 L/kg
86
(n=14). Following a constant infusion of trimetrexate for five days, Vdss was 32.8 ± 16.6 L/m2. The
87
volume of the central compartment has been estimated as 0.17 ± 0.08 L/kg and 4.0 ± 2.9 L/m2.
88
89
There have been inconsistencies in the reporting of trimetrexate protein binding. The in vitro plasma
90
protein binding of trimetrexate using ultrafiltration is approximately 95% over the concentration
91
range of 18.75 to 1000 ng/mL. There is a suggestion of capacity limited binding (saturable binding)
92
at concentrations greater than about 1000 ng/mL, with free fraction progressively increasing to about
93
9.3% as concentration is increased to 15 µg/mL. Other reports have declared trimetrexate to be
94
greater than 98% bound at concentrations of 0.1 to 10 µg/mL; however, specific free fractions were
95
not stated. The free fraction of trimetrexate also has been reported to be about 15 to 16% at a
96
concentration of 60 ng/mL, increasing to about 20% at a trimetrexate concentration of 6 µg/mL.
97
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6
Trimetrexate metabolism in man has not been characterized. Preclinical data strongly suggest that
98
the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either
99
glucuronide or the sulfate. N-demethylation and oxidation is a related minor pathway. Preliminary
100
findings in humans indicate the presence of a glucuronide conjugate with DHFR inhibition and a
101
demethylated metabolite in urine.
102
103
The presence of metabolite(s) in human plasma following the administration of trimetrexate is
104
suggested by the differences seen in trimetrexate plasma concentrations when measured by HPLC
105
and a nonspecific DHFR inhibition assay. The profiles are similar initially, but diverge with time;
106
concentrations determined by DHFR being higher than those determined by HPLC. This suggests
107
the presence of one or more metabolites with DHFR inhibition activity. After intravenous
108
administration of trimetrexate to humans, urinary recovery averaged about 40%, using a DHFR
109
assay, in comparison to 10% urinary recovery as determined by HPLC, suggesting the presence of
110
one or more metabolites that retain inhibitory activity against DHFR. Fecal recovery of trimetrexate
111
over 48 hours after intravenous administration ranged from 0.09 to 7.6% of the dose as determined
112
by DHFR inhibition and 0.02 to 5.2% of the dose as determined by HPLC.
113
114
The pharmacokinetics of trimetrexate have not been determined in patients with renal insufficiency
115
or hepatic dysfunction.
116
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7
INDICATIONS AND USAGE
117
Neutrexin (trimetrexate glucuronate for injection) with concurrent leucovorin administration
118
(leucovorin protection) is indicated as an alternative therapy for the treatment of moderate-to-severe
119
Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the
120
acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to,
121
trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is
122
contraindicated.
123
124
This indication is based on the results of a randomized, controlled double-blind trial comparing
125
Neutrexin with concurrent leucovorin protection (TMTX/LV) to trimethoprim-sulfamethoxazole
126
(TMP/SMX) in patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results
127
of a Treatment IND. These studies are summarized below:
128
129
Neutrexin Comparative Study with TMP/SMX: This double-blind, randomized trial initiated by
130
the AIDS Clinical Trials Group (ACTG) in 1988 was designed to compare the safety and efficacy of
131
TMTX/LV to that of TMP/SMX for the treatment of histologically confirmed, moderate-to-severe
132
PCP, defined as (A-a) baseline gradient >30 mmHg, in patients with AIDS.
133
134
Of the 220 patients with histologically confirmed PCP, 109 were randomized to receive TMTX/LV
135
and 111 to TMP/SMX. Study patients randomized to TMTX/LV treatment were to receive 45
136
mg/m2 of TMTX daily for 21 days plus 20 mg/m2 of LV every 6 hours for 24 days. Those
137
randomized to TMP/SMX were to receive 5 mg/kg TMP plus 25 mg/kg SMX four times daily for 21
138
days.
139
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8
Response to therapy, defined as alive and off ventilatory support at completion of therapy, with no
140
change in anti-pneumocystis therapy, or addition of supraphysiologic doses of steroids, occurred in
141
fifty percent of patients in each treatment group.
142
143
The observed mortality in the TMTX/LV treatment group was approximately twice that in the
144
TMP/SMX treatment group (95% CI: 0.99 - 4.11). Thirty of 109 (27%) patients treated with
145
TMTX/LV and 18 of 111 (16%) patients receiving TMP/SMX died during the 21-day treatment
146
course or 4-week follow-up period. Twenty-seven of 30 deaths in the TMTX/LV arm were
147
attributed to PCP; all 18 deaths in the TMP/SMX arm were attributed to PCP.
148
A significantly smaller proportion of patients who received TMTX/LV compared to TMP/SMX
149
failed therapy due to toxicity (10% vs. 25%), and a significantly greater proportion of patients failed
150
due to lack of efficacy (40% vs. 24%). Six patients (12%) who responded to TMTX/LV relapsed
151
during the one-month follow-up period; no patient responding to TMP/SMX relapsed during this
152
period. Information is not available as to whether these patients received prophylaxis therapy for
153
PCP.
154
155
Treatment IND: The FDA granted a Treatment IND for Neutrexin with leucovorin protection in
156
February 1988 to make Neutrexin therapy available to HIV-infected patients with histologically
157
confirmed PCP who had disease refractory to or who were intolerant of TMP/SMX and/or
158
intravenous pentamidine.
159
160
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9
Over 500 physicians in the United States participated in the Treatment IND. Of the first 753 patients
161
enrolled, 577 were evaluable for efficacy. Of these, 227 patients were intolerant of both TMP/SMX
162
and pentamidine (IST - patients intolerant of both standard therapies), 146 were intolerant of one
163
therapy and refractory to the other (RIST - patients refractory to one therapy and intolerant of the
164
other) and 204 were refractory to both therapies (RST - refractory to both standard therapies). This
165
was a very ill patient population; 38% required ventilatory support at entry (Table 1). These studies
166
did not have concurrent control groups.
167
168
TABLE 1
169
170
TREATMENT IND
171
172
Baseline Characteristics
173
IST
(n = 227)
RIST
(n = 146)
RST
(n = 204)
TOTAL
(n = 577)
Ventilatory Support Required
n (%)
39
(17)
50
(34)
129
(63)
218
(38)
Median Days on Standard Therapy
10
12
16
14
First Episode of PCP
n (%)
104
(46)
103
(71)
190
(93)
397
(69)
174
175
The overall survival rate one month after completion of TMTX/LV as salvage therapy was 48%.
176
Patients who had not responded to treatment with both TMP/SMX and pentamidine, of whom 63%
177
required mechanical ventilation at entry, achieved a survival rate of 25% following treatment with
178
TMTX/LV. Survival was 67% in patients who were intolerant to both TMP/SMX and pentamidine
179
(Table 2).
180
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10
TABLE 2
181
182
TREATMENT IND
183
184
Survival Rate One Month After Completion of Neutrexin
185
Therapy
186
IST
RIST
RST
All Patients
153/227
(67%)
73/146
(50%)
50/204
(25%)
Baseline Ventilatory
Support
No Baseline Ventilatory
Support
9/39
144/188
(23%)
(77%)
15/50
58/96
(30%)
(60%)
18/129
32/75
(14%)
(43%)
187
188
189
190
In the Treatment IND, 12% of the patients discontinued Neutrexin therapy (with leucovorin
191
protection) for toxicity.
192
193
CONTRAINDICATIONS
194
Neutrexin (trimetrexate glucuronate for injection) is contraindicated in patients with clinically
195
significant sensitivity to trimetrexate, leucovorin, or methotrexate.
196
197
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11
WARNINGS
198
Neutrexin (trimetrexate glucuronate for injection) must be used with concurrent leucovorin to avoid
199
potentially serious or life-threatening complications including bone marrow suppression, oral and
200
gastrointestinal mucosal ulceration, and renal and hepatic dysfunction. Leucovorin therapy must
201
extend for 72 hours past the last dose of Neutrexin. Patients should be informed that failure to take
202
the recommended dose and duration of leucovorin can lead to fatal toxicity. Patients should be
203
closely monitored for the development of serious hematologic adverse reactions (see
204
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
205
206
Neutrexin can cause fetal harm when administered to a pregnant woman. Trimetrexate has been
207
shown to be fetotoxic and teratogenic in rats and rabbits. Rats administered 1.5 and 2.5 mg/kg/day
208
intravenously on gestational days 6-15 showed substantial postimplantation loss and severe
209
inhibition of maternal weight gain. Trimetrexate administered intravenously to rats at 0.5 and 1.0
210
mg/kg/day on gestational days 6-15 retarded normal fetal development and was teratogenic. Rabbits
211
administered trimetrexate intravenously at daily doses of 2.5 and 5.0 mg/kg/day on gestational days
212
6-18 resulted in significant maternal and fetal toxicity. In rabbits, trimetrexate at 0.1 mg/kg/day was
213
teratogenic in the absence of significant maternal toxicity. These effects were observed using doses
214
1/20 to 1/2 the equivalent human therapeutic dose based on a mg/m2 basis. Teratogenic effects
215
included skeletal, visceral, ocular, and cardiovascular abnormalities. If Neutrexin is used during
216
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised
217
of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid
218
becoming pregnant.
219
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12
PRECAUTIONS
220
General
221
Patients receiving Neutrexin (trimetrexate glucuronate for injection) may experience severe
222
hematologic, hepatic, renal, and gastrointestinal toxicities. Caution should be used in treating
223
patients with impaired hematologic, renal, or hepatic function. Patients who require concomitant
224
therapy with nephrotoxic, myelosuppressive, or hepatotoxic drugs should be treated with Neutrexin
225
at the discretion of the physician and monitored carefully. To allow for full therapeutic doses of
226
Neutrexin, treatment with zidovudine should be discontinued during Neutrexin therapy.
227
228
Neutrexin-associated myelosuppression, stomatitis, and gastrointestinal toxicities generally can be
229
ameliorated by adjusting the dose of leucovorin. Mild elevations in transaminases and alkaline
230
phosphatase have been observed with Neutrexin administration and are usually not cause for
231
modification of Neutrexin therapy (see DOSAGE AND ADMINISTRATION). Seizures have
232
been reported rarely (< 1%) in AIDS patients receiving Neutrexin; however, a causal relationship
233
has not been established. Trimetrexate is a known inhibitor of histamine metabolism.
234
Hypersensitivity/allergic type reactions including but not limited to rash, chills/rigors, fever,
235
diaphoresis and dypsnea have occurred with trimetrexate primarily when it is administered as a bolus
236
infusion or at doses higher than those recommended for PCP, and most frequently in combination
237
with 5FU and leucovorin. In rare cases, anaphylactoid reactions, including acute hypotension and
238
loss of consciousness have occurred. Neutrexin infusion should be permanently discontinued in all
239
patients with severe hypersensitivity reactions. Epinephrine should be available for treatment of
240
acute allergic symptoms.
241
242
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13
Neutrexin has not been evaluated clinically for the treatment of concurrent pulmonary conditions
243
such as bacterial, viral, or fungal pneumonia or mycobacterial diseases. In vitro activity has been
244
observed against Toxoplasma gondii, Mycobacterium avium complex, gram positive cocci, and gram
245
negative rods. If clinical deterioration is observed in patients, they should be carefully evaluated for
246
other possible causes of pulmonary disease and treated with additional agents as appropriate.
247
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14
Laboratory Tests
248
Patients receiving Neutrexin with leucovorin protection should be seen frequently by a physician.
249
Blood tests to assess the following parameters should be performed at least twice a week during
250
therapy: hematology (absolute neutrophil counts [ANC], platelets), renal function (serum creatinine,
251
BUN), and hepatic function (AST, ALT, alkaline phosphatase).
252
253
Drug Interactions
254
Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug
255
metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate
256
plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for
257
other indications that could elicit this activity include erythromycin, rifampin, rifabutin,
258
ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine
259
caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative
260
concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on
261
an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole,
262
miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated
263
with these drugs and trimetrexate should be carefully monitored.
264
265
Carcinogenesis, Mutagenesis, Impairment of Fertility
266
Carcinogenesis: Long term studies in animals to evaluate the carcinogenic potential of trimetrexate
267
have not been performed.
268
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15
Mutagenesis: Trimetrexate was not mutagenic when tested using the standard Ames Salmonella
269
mutagenicity assay with and without metabolic activation. Trimetrexate did not induce mutations in
270
Chinese hamster lung cells or sister-chromatid exchange in Chinese hamster ovary cells.
271
Trimetrexate did induce an increase in the chromosomal aberration frequency of cultured Chinese
272
hamster lung cells; however, trimetrexate showed no clastogenic activity in a mouse micronucleus
273
assay.
274
275
Impairment of fertility: No studies have been conducted to evaluate the potential of trimetrexate to
276
impair fertility. However, during standard toxicity studies conducted in mice and rats, degeneration
277
of the testes and spermatocytes including the arrest of spermatogenesis was observed.
278
279
Pregnancy, Teratogenic Effects
280
See WARNINGS.
281
Pregnancy Category D
282
Nursing Mothers
283
It is not known if trimetrexate is excreted in human milk. Because many drugs are excreted in
284
human milk and because of the potential for serious adverse reactions in nursing infants from
285
trimetrexate, it is recommended that breast feeding be discontinued if the mother is treated with
286
Neutrexin.
287
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16
Pediatric Use
288
The safety and effectiveness of Neutrexin for the treatment of histologically confirmed PCP has not
289
been established for patients under 18 years of age. Two children, ages 15 months and 9 months,
290
were treated with trimetrexate and leucovorin using a dose of 45 mg/m2 of trimetrexate per day for
291
21 days and 20 mg/m2 of leucovorin every 6 hours for 24 days. There were no serious or unexpected
292
adverse effects.
293
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17
ADVERSE REACTIONS
294
Because many patients who participated in clinical trials of Neutrexin (trimetrexate glucuronate for
295
injection) had complications of advanced HIV disease, it is difficult to distinguish adverse events
296
caused by Neutrexin from those resulting from underlying medical conditions.
297
298
Table 3 lists the adverse events that occurred in ≥ 1% of the patients who participated in the
299
Comparative Study of Neutrexin plus leucovorin versus TMP/SMX.
300
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18
TABLE 3
NEUTREXIN COMPARATIVE TRIAL
Comparison of Adverse Events Reported for ≥≥≥≥ 1% of Patients
Number and Percent (%) of
Patients with Adverse Events
Adverse Events
TMTX/LV
(n = 109)
TMP/SMX
(n = 111)
Non-Laboratory Adverse Events:
Fever
Rash/Pruritus
Nausea/Vomiting
Confusion
Fatigue
9
6
5
3
2
(8.3)
(5.5)
(4.6)a
(2.8)
(1.8)
14
14
15
3
0
(12.6)
(12.6)
(13.5)a
(2.7)
(0.0)
Hematologic Toxicity:
Neutropenia (<1000/mm3)
Thrombocytopenia (<75,000/mm3)
Anemia (Hgb <8 g/dL)
33
11
8
(30.3)
(10.1)
(7.3)
37
17
10
(33.3)
(15.3)
(9.0)
Hepatotoxicity:
Increased AST (>5 x ULNb)
Increased ALT (>5 x ULN)
Increased Alkaline Phosphatase (>5 x ULN)
Increased Bilirubin (2.5 x ULN)
15
12
5
2
(13.8)
(11.0)
(4.6)
(1.8)
10
13
3
1
(9.0)
(11.7)
(2.7)
(0.9)
Renal:
Increased Serum Creatinine (>3 x ULN)
1
(0.9)
2
(1.8)
Electrolyte Imbalance:
Hyponatremia
Hypocalcemia
5
2
(4.6)
(1.8)
10
0
(9.0)
(0.0)
No. of Patients With at Least one Adverse Eventc
58
(53.2)
60
(54.1)
a
Statistically significant difference between treatment groups (Chi-square: p=0.022)
b
ULN = Upper limit of normal range
c
Patients could have reported more than one adverse event; therefore, the sum of adverse events exceeds
the number of patients
301
Laboratory toxicities were generally manageable with dose modification of
302
trimetrexate/leucovorin (see DOSAGE AND ADMINISTRATION).
303
Table 4 lists the adverse events resulting in discontinuation of study therapy in the Neutrexin
304
Comparative Study with TMP/SMX. Twenty-nine percent of the patients on the TMP/SMX arm
305
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19
discontinued therapy due to adverse events compared to 10% of the patients treated with
306
TMTX/LV (p < 0.001).
307
308
TABLE 4
NEUTREXIN COMPARATIVE TRIAL
Adverse Events Resulting in Discontinuation of Therapy
Number and Percent (%) of
Patients Discontinued for
Adverse Eventsb
Adverse Events
TMTX/LV
(n = 109)
TMP/SMX
(n = 111)
Non-Laboratory Adverse Events:
Rash/Pruritus
Fever
Nausea/Vomiting
Neurologic Toxicity
3
2
1
1
(2.8)
(1.8)
(0.9)
(0.9)c
5
4
8
2
(4.5)
(3.6)
(7.2)
(1.8)
Hematologic Toxicity:
Neutropenia (<1000/mm3)
Thrombocytopenia (<75,000/mm3)
Anemia (Hgb <8 g/dL)
4
0
0
(3.7)
(0.0)
(0.0)
6
4
4
(5.4)
(3.6)
(3.6)
Hepatotoxicity:
Increased AST (>5 x ULNa)
Increased ALT (>5 x ULN)
Increased Alkaline Phosphatase (>5 x ULN)
3
1
0
(2.8)
(0.9)
(0.0)
9
4
1
(8.1)
(3.6)
(0.9)
Electrolyte Imbalance:
Hyponatremia
0
(0.0)
3
(2.7)
No. of Patients Discontinuing Therapy Due to an
Adverse Eventb
11
(10.1)d
32
(28.8)d
a
ULN = Upper limit of normal range
b
Patients could discontinue therapy due to more than one toxicity; therefore the sum exceeds
number of patients who discontinued due to toxicity
c
Patient discontinued TMTX/LV due to seizure, though causal relationship could not be established.
d
Statistically significant difference between treatment groups (Chi-square: p < 0.001)
309
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20
Hematologic toxicity was the principal dose-limiting side effect.
309
310
OVERDOSAGE
311
Neutrexin (trimetrexate glucuronate for injection) administered without concurrent
312
leucovorin can cause lethal complications. There has been no extensive experience in humans
313
receiving single intravenous doses of trimetrexate greater than 90 mg/m2/day with concurrent
314
leucovorin. The toxicities seen at this dose were primarily hematologic. In the event of overdose,
315
Neutrexin should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6
316
hours for 3 days. The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2).
317
318
DOSAGE AND ADMINISTRATION
319
Caution: Neutrexin (trimetrexate glucuronate for injection) must be administered with
320
concurrent leucovorin (leucovorin protection) to avoid potentially serious or life-threatening
321
toxicities. Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
322
323
Neutrexin (trimetrexate glucuronate for injection) is administered at a dose of 45 mg/m2 once daily
324
by intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment
325
with Neutrexin and for 72 hours past the last dose of Neutrexin. Leucovorin may be administered
326
intravenously at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80
327
mg/m2, or orally as 4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be
328
rounded up to the next higher 25 mg increment. The recommended course of therapy is 21 days of
329
Neutrexin and 24 days of leucovorin.
330
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21
Neutrexin and leucovorin may alternatively be dosed on a mg/kg basis, depending on the patient’s
331
body weight, using the conversion factors shown in the table below:
332
333
Body Weight
(kg)
Neutrexin Dose
(mg/kg/day)
Leucovorin Dose
(mg/kg/qid)
<50
1.5
0.6
50-80
1.2
0.5
>80
1.0
0.5
334
Dosage Modifications
335
Hematologic toxicity: Neutrexin (trimetrexate glucuronate for injection) and leucovorin doses
336
should be modified based on the worst hematologic toxicity according to the following table. If
337
leucovorin is given orally, doses should be rounded up to the next higher 25 mg increment.
338
339
TABLE 5
DOSE MODIFICATIONS FOR HEMATOLOGIC TOXICITY
Recommended Dosages of
Toxicity
Grade
Neutrophils
(Polys and Bands)
Platelets
Neutrexin
Leucovorin
1
>1000/mm3
>75,000/mm3
45 mg/m2 once daily
20 mg/m2 every 6 hours
2
750-1000/mm3
50,000-75,000/mm3
45 mg/m2 once daily
40 mg/m2 every 6 hours
3
500-749/mm3
25,000-49,999/mm3
22 mg/m2 once daily
40 mg/m2 every 6 hours
4
<500/mm3
<25,000/mm3
Day 1-9 Discontinue
Day 10-21 Interrupt up to 96 hoursa
40 mg/m2 every 6 hours
a
If Grade 4 hematologic toxicity occurs prior to Day 10, Neutrexin should be discontinued. Leucovorin (40 mg/m2, q6h)
should be administered for an additional 72 hours. If Grade 4 hematologic toxicity occurs at Day 10 or later, Neutrexin
may be held up to 96 hours to allow counts to recover. If counts recover to Grade 3 within 96 hours, Neutrexin should
be administered at a dose of 22 mg/m2 and leucovorin maintained at 40 mg/m2, q6h. When counts recover to Grade 2
toxicity, Neutrexin dose may be increased to 45 mg/m2, but the leucovorin dose should be maintained at 40 mg/m2 for
the duration of treatment. If counts do not improve to ≤ Grade 3 toxicity within 96 hours, Neutrexin should be
discontinued. Leucovorin at a dose of 40 mg/m2, q6h should be administered for 72 hours following the last dose of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Neutrexin.
340
341
Hepatic toxicity: Transient elevations of transaminases and alkaline phosphatase have been
342
observed in patients treated with Neutrexin. Interruption of treatment is advisable if transaminase
343
levels or alkaline phosphatase levels increase to >5 times the upper limit of normal range.
344
345
Renal toxicity: Interruption of Neutrexin is advisable if serum creatinine levels increase to > 2.5
346
mg/dL and the elevation is considered to be secondary to Neutrexin.
347
348
Other toxicities: Interruption of treatment is advisable in patients who experience severe mucosal
349
toxicity that interferes with oral intake. Treatment should be discontinued for fever (oral
350
temperature ≥ 105°F/40.5°C) that cannot be controlled with antipyretics.
351
Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
352
353
RECONSTITUTION AND DILUTION
354
Each vial of Neutrexin (trimetrexate glucuronate for injection) should be reconstituted in accordance
355
with labeled instructions with either 5% Dextrose Injection, USP, or Sterile Water for Injection,
356
USP, to yield a concentration of 12.5 mg of trimetrexate per mL (complete dissolution should occur
357
within 30 seconds). The reconstituted product will appear as a pale greenish-yellow solution and
358
must be inspected visually prior to dilution. Do not use if cloudiness or precipitate is observed.
359
Neutrexin should not be reconstituted with solutions containing either chloride ion or leucovorin,
360
since precipitation occurs instantly.
361
362
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
After reconstitution, the solution should be used immediately; however, the solution is stable for 6
363
hours at room temperature (20 to 25ºC), or 24 hours under refrigeration (2-8°C).
364
365
Prior to administration, the reconstituted solution should be further diluted with 5% Dextrose
366
Injection, USP, to yield a final concentration of 0.25 to 2 mg of trimetrexate per mL. The diluted
367
solution should be administered by intravenous infusion over 60 minutes. Neutrexin should not be
368
mixed with solutions containing either chloride ion or leucovorin, since precipitation occurs
369
instantly. The diluted solution is stable under refrigeration or at room temperature for up to 24
370
hours. Do not freeze. Discard any unused portion after 24 hours. The intravenous line must be
371
flushed thoroughly with at least 10 mL of 5% Dextrose Injection, USP, before and after
372
administering Neutrexin.
373
374
Leucovorin protection may be administered prior to or following Neutrexin. In either case, the
375
intravenous line must be flushed thoroughly with at least 10 mL of 5% Dextrose Injection, USP.
376
Leucovorin calcium for injection should be diluted according to the instructions in the leucovorin
377
package insert, and administered over 5 to 10 minutes every 6 hours.
378
379
Caution: Parenteral products should be inspected visually for particulate matter and
380
discoloration prior to administration, whenever solution and container permit. Neutrexin
381
forms a precipitate instantly upon contact with chloride ion or leucovorin, therefore it should
382
not be added to solutions containing sodium chloride or other anions. Neutrexin and
383
leucovorin solutions must be administered separately. Intravenous lines should be flushed
384
with at least 10 mL of 5% Dextrose Injection, USP, between Neutrexin and leucovorin
385
infusions.
386
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
387
HANDLING AND DISPOSAL
388
If Neutrexin (trimetrexate glucuronate for injection) contacts the skin or mucosa, immediately wash
389
thoroughly with soap and water. Procedures for proper disposal of cytotoxic drugs should be
390
considered. Several guidelines on this subject have been published (1-5).
391
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
HOW SUPPLIED
392
Neutrexin (trimetrexate glucuronate for injection) is supplied as a sterile lyophilized powder in
393
either 5 mL or 30 mL vials. Each 5 mL vial contains trimetrexate glucuronate equivalent to 25 mg
394
of trimetrexate. Each 30 mL vial contains trimetrexate glucuronate equivalent to 200 mg of
395
trimetrexate. The 5 mL vials are packaged and available in two market presentations as listed below:
396
10 Pack - 10 vials in a white chip-board carton (NDC 58178-020-10)
397
50 Pack - 2 trays of 25 vials per shrink-wrapped tray (NDC 58178-020-50)
398
The 30 mL vials are packaged and available as listed below:
399
Single Pack - 1 vial (NDC 58178-021-01)
400
Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from exposure to light.
401
U.S. Patents 4,376,858; 4,694,007; 6,017,922
402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
REFERENCES
403
404
1.
AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. Journal of the
405
American Medical Association March 15, 1985.
406
407
2.
Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe
408
Handling of Antineoplastic Agents. Medical Journal of Australia 1: 426-428, 1983.
409
410
3.
Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount
411
Sinai Medical Center. CA - A Cancer Journal for Clinicians Sept/Oct, 258-263, 1983.
412
413
4.
American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling
414
Cytotoxic Drugs in Hospitals. American Journal of Hospital Pharmacy 42: 131-137, 1985.
415
416
5.
OSHA Work Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic)
417
Drugs. American Journal of Hospital Pharmacy 43: 1193-1204, 1986.
418
419
420
Manufactured by:
Marketed by:
421
Ben Venue Laboratories, Inc.
MedImmune Oncology, Inc.
422
Bedford, OH 44146
a subsidiary of MedImmune Inc.
423
Gaithersburg, MD 20878
424
Or:
1-877-633-4411
425
MedImmune Pharma B.V.
426
6545 CG Nijmegen
427
The Netherlands
428
429
© 2000, MedImmune Oncology, Inc.
430
Revision Date 1/2005
N-LB3020 PH
431
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020326s015lbl.pdf', 'application_number': 20326, 'submission_type': 'SUPPL ', 'submission_number': 15}
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12,444
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
VALERIE S PRATT
06/08/2016
Reference ID: 3942868
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020325Orig1s030lbl.pdf', 'application_number': 20325, 'submission_type': 'SUPPL ', 'submission_number': 30}
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NDA 20-327; ISOVUE Multipack® (Iopamidol Injection)
Revised labeling to FDA_JULY-2012_CLEAN.doc
Bracco Diagnostics
F1/6065347 company logo
Isovue Multipack®
Pharmacy Bulk Package -
Not for Direct Infusion
ISOVUE Multipack®-250
lopamidol injection 51%
ISOVUE Multipack®-300
lopamidol injection 61%
ISOVUE Multipack®-370
lopamidol injection 76%
NOT FOR INTRATHECAL USE
ISOVUE 250, 300 and 370 are NOT FOR INTRATHECAL USE.
See Indications, and Dosage and Administration sections for further details
on proper use
DIAGNOSTIC
NONIONIC RADIOPAQUE CONTRAST MEDIA
For Angiography Throughout the Cardiovascular
System, Including Cerebral and Peripheral Arteriography,
Coronary Arteriography and Ventriculography,
Pediatric Angiocardiography, Selective Visceral
Arteriography and Aortography,
Peripheral Venography (Phlebography), and
Adult and Pediatric Intravenous Excretory
Urography and Intravenous Adult and Pediatric
Contrast Enhancement of Computed Tomographic
(CECT) Head and Body Imaging
DESCRIPTION
ISOVUE (lopamidol Injection) formulations are stable, aqueous, sterile, and nonpyrogenic solutions for
intravascular administration. Each bottle is to be used as a Pharmacy Bulk Package for dispensing
multiple single dose preparations utilizing a suitable transfer device.
Each mL of ISOVUE Multipack-250 (lopamidol Injection 51%) provides 510 mg iopamidol with 1 mg
tromethamine and 0.33 mg edetate calcium disodium. The solution contains approximately 0.036 mg
(0.002 mEq) sodium and 250 mg organically bound iodine per mL.
Each mL of ISOVUE Multipack-300 (lopamidol Injection 61%) provides 612 mg iopamidol with 1 mg
tromethamine and 0.39 mg edetate calcium disodium. The solution contains approximately 0.043 mg
(0.002 mEq) sodium and 300 mg organically bound iodine per mL.
Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each mL of ISOVUE Multipack-370 (lopamidol Injection 76%) provides 755 mg iopamidol with 1 mg
tromethamine and 0.48 mg edetate calcium disodium. The solution contains approximately 0.053 mg
(0.002 mEq) sodium and 370 mg organically bound iodine per mL.
The pH of ISOVUE contrast media has been adjusted to 6.5-7.5 with hydrochloric acid and/or
sodium hydroxide. Pertinent physicochemical data are noted below. ISOVUE (lopamidol Injection) is
hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water,
respectively).
Iopamidol
Parameter
51%
61%
76%
Concentration (mgl/mL)
250
300
370
Osmolality @ 37° C (mOsm/kg water)
524
616
796
Viscosity (cP) @ 37° C
3.0
4.7
9.4
@ 20° C
5.1
8.8
20.9
Specific Gravity @ 37° C
1.281
1.339
1.405
lopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo
5-lactamidoisophthalamide. Structural formula: structural formula
CLINICAL PHARMACOLOGY
Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of flow of the
contrast medium, permitting radiographic visualization of the internal structures of the human body until
significant hemodilution occurs.
Following intravascular injection, radiopaque diagnostic agents are immediately diluted in the
circulating plasma. Calculations of apparent volume of distribution at steady-state indicate that
iopamidol is distributed between the circulating blood volume and other extracellular fluid; there appears
to be no significant deposition of iopamidol in tissues. Uniform distribution of iopamidol in extracellular
fluid is reflected by its demonstrated utility in contrast enhancement of computed tomographic imaging of
the head and body following intravenous administration.
The pharmacokinetics of intravenously administered iopamidol in normal subjects conform to an
open two-compartment model with first order elimination (a rapid alpha phase for drug distribution and a
slow beta phase for drug elimination). The elimination serum or plasma half-life is approximately two
hours; the half-life is not dose dependent. No significant metabolism, deiodination, or biotransformation
occurs.
Iopamidol is excreted mainly through the kidneys following intravascular administration. In patients
with impaired renal function, the elimination half-life is prolonged dependent upon the degree of
impairment. In the absence of renal dysfunction, the cumulative urinary excretion for iopamidol,
expressed as a percentage of administered intravenous dose, is approximately 35 to 40 percent at 60
minutes, 80 to 90 percent at 8 hours, and 90 percent or more in the 72- to 96-hour period after
administration. In normal subjects, approximately one percent or less of the administered dose appears
in cumulative 72- to 96-hour fecal specimens.
2
Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ISOVUE may be visualized in the renal parenchyma within 30-60 seconds following rapid
intravenous administration. Opacification of the calyces and pelves in patients with normal renal
function becomes apparent within 1 to 3 minutes, with optimum contrast occurring between 5 and 15
minutes. In patients with renal impairment, contrast visualization may be delayed.
Iopamidol displays little tendency to bind to serum or plasma proteins.
No evidence of in vivo complement activation has been found in normal subjects.
Animal studies indicate that iopamidol does not cross the blood-brain barrier to any significant extent
following intravascular administration.
ISOVUE (lopamidol Injection) enhances computed tomographic brain imaging through
augmentation of radiographic efficiency. The degree of enhancement of visualization of tissue density
is directly related to the iodine content in an administered dose; peak iodine blood levels occur
immediately following rapid injection of the dose. These levels fall rapidly within five to ten minutes. This
can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes
an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached
in about ten minutes, thereafter, the fall becomes exponential. Maximum contrast enhancement
frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast
enhancement can range from five to forty minutes depending on the peak iodine levels achieved and
the cell type of the lesion. This lag suggests that radiographic contrast enhancement is at least in part
dependent on the accumulation of iodine within the lesion and outside the blood pool, although the
mechanism by which this occurs is not clear. The radiographic enhancement of nontumoral lesions,
such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of
the circulating blood pool.
In CECT head imaging, ISOVUE (lopamidol Injection) does not accumulate in normal brain tissue due
to the presence of the “blood-brain” barrier. The increase in x-ray absorption in normal brain is due to the
presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in
malignant tumors of the brain allows the accumulation of the contrast medium within the interstitial tissue
of the tumor. Adjacent normal brain tissue does not contain the contrast medium.
In nonneural tissues (during computed tomography of the body), iopamidol diffuses rapidly from the
vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration
of the contrast medium, and extraction of the contrast medium by interstitial tissue of tumors since no
barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion
between normal and abnormal tissue, quite different from that in the brain.
The pharmacokinetics of iopamidol in both normal and abnormal tissue have been shown to be
variable. Contrast enhancement appears to be greatest soon after administration of the contrast
medium, and following intra-arterial rather than intravenous administration. Thus, greatest
enhancement can be detected by a series of consecutive two- to three-second scans performed just
after injection (within 30 to 90 seconds), i.e., dynamic computed tomographic imaging.
INDICATIONS AND USAGE
ISOVUE (lopamidol Injection) is indicated for angiography throughout the cardiovascular system,
including cerebral and peripheral arteriography, coronary arteriography and ventriculography, pediatric
angiocardiography, selective visceral arteriography and aortography, peripheral venography
(phlebography), and adult and pediatric intravenous excretory urography and intravenous adult and
pediatric contrast enhancement of computed tomographic (CECT) head and body imaging (see below).
CECT Head Imaging
ISOVUE may be used to refine diagnostic precision in areas of the brain which may not otherwise have
been satisfactorily visualized.
Tumors
ISOVUE may be useful to investigate the presence and extent of certain malignancies such as: gliomas
including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas,
ependymomas, medulloblastomas, meningiomas, neuromas, pinealomas, pituitary adenomas,
craniopharyngiomas, germinomas, and metastatic lesions. The usefulness of contrast enhancement for
the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been
demonstrated.
3
Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In calcified lesions, there is less likelihood of enhancement. Following therapy, tumors may show
decreased or no enhancement.
The opacification of the inferior vermis following contrast media administration has resulted in false-
positive diagnosis in a number of otherwise normal studies.
Nonneoplastic Conditions
ISOVUE may be beneficial in the image enhancement of nonneoplastic lesions. Cerebral infarctions of
recent onset may be better visualized with contrast enhancement, while some infarctions are obscured
if contrast media are used. The use of iodinated contrast media results in contrast enhancement in
about 60 percent of cerebral infarctions studied from one to four weeks from the onset of symptoms.
Sites of active infection may also be enhanced following contrast media administration.
Arteriovenous malformations and aneurysms will show contrast enhancement. For these vascular
lesions, the enhancement is probably dependent on the iodine content of the circulating blood pool.
Hematomas and intraparenchymal bleeders seldom demonstrate any contrast enhancement.
However, in cases of intraparenchymal clot, for which there is no obvious clinical explanation, contrast
media administration may be helpful in ruling out the possibility of associated arteriovenous
malformation.
CECT Body Imaging
ISOVUE (lopamidol Injection) may be used for enhancement of computed tomographic images for
detection and evaluation of lesions in the liver, pancreas, kidneys, aorta, mediastinum, abdominal
cavity, pelvis and retroperitoneal space.
Enhancement of computed tomography with ISOVUE may be of benefit in establishing diagnoses
of certain lesions in these sites with greater assurance than is possible with CT alone, and in supplying
additional features of the lesions (e.g., hepatic abscess delineation prior to percutaneous drainage). In
other cases, the contrast agent may allow visualization of lesions not seen with CT alone (e.g. tumor
extension), or may help to define suspicious lesions seen with unenhanced CT (e.g., pancreatic cyst).
Contrast enhancement appears to be greatest within 60 to 90 seconds after bolus administration of
contrast agent. Therefore, utilization of a continuous scanning technique (“dynamic CT scanning”) may
improve enhancement and diagnostic assessment of tumor and other lesions
such as an abscess, occasionally revealing unsuspected or more extensive disease. For example, a cyst
may be distinguished from a vascularized solid lesion when precontrast and enhanced scans are compared;
the nonperfused mass shows unchanged x-ray absorption (CT number). A vascularized lesion is
characterized by an increase in CT number in the few minutes after a bolus of intravascular contrast agent; it
may be malignant, benign, or normal tissue, but would probably not be a cyst, hematoma, or other
nonvascular lesion.
Because unenhanced scanning may provide adequate diagnostic information in the individual
patient, the decision to employ contrast enhancement, which may be associated with risk and increased
radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and
unenhanced CT findings.
CONTRAINDICATIONS
None.
WARNINGS
Severe Adverse Events-lnadvertent Intrathecal Administration
Serious adverse reactions have been reported due to the inadvertent intrathecal
administration of iodinated contrast media that are not indicated for intrathecal use.
These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma,
paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis,
hyperthermia, and brain edema. Special attention must be given to insure that this drug product
is not inadvertently administered intrathecally.
General
Nonionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media.
Clotting has been reported when blood remains in contact with syringes containing nonionic contrast
media.
4
Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been
reported during angiographic procedures with both ionic and nonionic contrast media. Therefore,
meticulous intravascular administration technique is necessary, particularly during angiographic
procedures, to minimize thromboembolic events. Numerous factors, including length of procedure,
catheter and syringe material, underlying disease state, and concomitant medications may contribute to
the development of thromboembolic events. For these reasons, meticulous angiographic techniques
are recommended including close attention to guidewire and catheter manipulation, use of manifold
systems and/or three way stopcocks, frequent catheter flushing with heparinized saline solutions, and
minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been
reported to decrease but not eliminate the likelihood of in vitro clotting.
Caution must be exercised in patients with severely impaired renal function, those with combined
renal and hepatic disease, or anuria, particularly when larger or repeat doses are administered.
Radiopaque diagnostic contrast agents are potentially hazardous in patients with multiple myeloma
or other paraproteinemia, particularly in those with therapeutically resistant anuria. Myeloma occurs
most commonly in persons over age 40. Although neither the contrast agent nor dehydration has been
proved separately to be the cause of anuria in myelomatous patients, it has been speculated that the
combination of both may be causative. The risk in myelomatous patients is not a contraindication;
however, special precautions are required.
Contrast media may promote sickling in individuals who are homozygous for sickle cell disease
when injected intravenously or intraarterially.
Administration of radiopaque materials to patients known or suspected of having
pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the
possible benefits of such procedures outweigh the considered risks, the procedures may be performed;
however, the amount of radiopaque medium injected should be kept to an absolute minimum. The
blood pressure should be assessed throughout the procedure and measures for treatment of a
hypertensive crisis should be available. These patients should be monitored very closely during
contrast enhanced procedures.
Reports of thyroid storm following the use of iodinated radiopaque diagnostic agents in patients with
hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be
evaluated in such patients before use of any contrast medium.
PRECAUTIONS
General
Diagnostic procedures which involve the use of any radiopaque agent should be carried out under the
direction of personnel with the prerequisite training and with a thorough knowledge of the particular
procedure to be performed. Appropriate facilities should be available for coping with any complication of
the procedure, as well as for emergency treatment of severe reaction to the contrast agent itself. After
parenteral administration of a radiopaque agent, competent personnel and emergency facilities should
be available for at least 30 to 60 minutes since severe delayed reactions may occur. Caution should be
exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, such
as congestive heart failure.
Diabetic nephropathy may predispose to acute renal impairment following intravascular contrast
media administration. Acute renal impairment following contrast media administration may precipitate
lactic acidosis in patients who are taking biguanides.
The administration of iodinated contrast media may aggravate the symptoms of myasthenia gravis.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with
advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with
pre-existing renal disease). Patients should be well hydrated prior to and following iopamidol
administration.
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular
reactions, should always be considered (see ADVERSE REACTIONS). Patients at increased risk include
those with a history of a previous reaction to a contrast medium, patients with a known sensitivity to
iodine per se, and patients with a known clinical hypersensitivity (bronchial asthma, hay fever, and food
allergies). The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting
5
Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be
hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and
hypersensitivity, prior to the injection of any contrast medium, may be more accurate than pretesting in
predicting potential adverse reactions. A positive history of allergies or hypersensitivity does not arbitrarily
contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution
should be exercised. Premedication with antihistamines or corticosteroids to avoid or minimize possible
allergic reactions in such patients should be considered. Recent reports indicate that such pretreatment
does not prevent serious life-threatening reactions but may reduce both their incidence and severity.
Pre-existing conditions, such as pacemakers or cardiac medications, specifically beta-blockers, may
mask or alter the signs or symptoms of an anaphylactoid reaction, as well as masking or altering the
response to particular medications used for treatment. For example, beta-blockers inhibit a tachycardiac
response, and can lead to the incorrect diagnosis of a vasovagal rather than an anaphylactoid reaction.
Special attention to this possibility is particularly critical in patients suffering from serious, life-threatening
reactions.
General anesthesia may be indicated in the performance of some procedures in selected patients;
however, a higher incidence of adverse reactions has been reported with radiopaque media in
anesthetized patients, which may be attributable to the inability of the patient to identify untoward
symptoms, or to the hypotensive effect of anesthesia which can reduce cardiac output and increase the
duration of exposure to the contrast agent.
Even though the osmolality of iopamidol is low compared to diatrizoate or iothalamate based ionic
agents of comparable iodine concentration, the potential transitory increase in the circulatory osmotic
load in patients with congestive heart failure requires caution during injection. These patients should be
observed for several hours following the procedure to detect delayed hemodynamic disturbances.
Injection site pain and swelling may occur. In the majority of cases it is due to extravasation of contrast
medium. Reactions are usually transient and recover without sequelae. However, inflammation and
even skin necrosis have been seen on very rare occasions.
In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel
wall, or inducing vasospasm, and or subsequent ischemic events, should be borne in mind during catheter
manipulations and contrast medium injection. Test injections to ensure proper catheter placement are
suggested.
Selective coronary arteriography should be performed only in selected patients and those in whom
the expected benefits outweigh the procedural risk. The inherent risks of angiocardiography in patients
with pulmonary hypertension must be weighed against the necessity for performing this procedure.
Angiography should be avoided whenever possible in patients with homocystinuria, because of the risk
of inducing thrombosis and embolism.
See also Pediatric Use.
In addition to the general precautions previously described, special care is required when
venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease,
local infection or a totally obstructed venous system.
Extreme caution during injection of contrast media is necessary to avoid extravasation and
fluoroscopy is recommended. This is especially important in patients with severe arterial or venous
disease.
Information for Patients
Patients receiving injectable radiopaque diagnostic agents should be instructed to:
1. Inform your physician if you are pregnant.
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma,
homozygous sickle cell disease, or known thyroid disorder (see WARNINGS).
3. Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous
injections of substances used for x-ray procedures (see PRECAUTIONS-General).
4. Inform your physician about any other medications you are currently taking, including nonprescription
drugs, before you have this procedure.
Drug Interactions
Renal toxicity has been reported in a few patients with liver dysfunction who were given oral
cholecystographic agents followed by intravascular contrast agents. Administration of intravascular
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Reference ID: 3167853
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agents should therefore be postponed in any patient with a known or suspected hepatic or biliary
disorder who has recently received a cholecystographic contrast agent.
Other drugs should not be admixed with iopamidol.
Drug/Laboratory Test Interactions
The results of PBI and radioactive iodine uptake studies, which depend on iodine estimations, will not
accurately reflect thyroid function for up to 16 days following administration of iodinated contrast media.
However, thyroid function tests not depending on iodine estimations, e.g., T3 resin uptake and total or
free thyroxine (T4) assays are not affected.
Any test which might be affected by contrast media should be performed prior to administration of
the contrast medium.
Laboratory Test Findings
In vitro studies with animal blood showed that many radiopaque contrast agents, including iopamidol,
produced a slight depression of plasma coagulation factors including prothrombin time, partial
thromboplastin time, and fibrinogen, as well as a slight tendency to cause platelet and/or red blood cell
aggregation (see PRECAUTIONS-General).
Transitory changes may occur in red cell and leucocyte counts, serum calcium, serum creatinine,
serum glutamic oxaloacetic transaminase (SGOT), and uric acid in urine; transient albuminuria may
occur.
These findings have not been associated with clinical manifestations.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. No evidence
of genetic toxicity was obtained in in vitro tests.
Pregnancy: Teratogenic Effects
Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to
2.7 and 1.4 times the maximum recommended human dose (1.48 gl/kg in a 50 kg individual),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to iopamidol.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when iopamidol is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children has been established in pediatric angiocardiography, computed
tomography (head and body) and excretory urography. Pediatric patients at higher risk of experiencing
adverse events during contrast medium administration may include those having asthma, a sensitivity
to medication and/or allergens, cyanotic heart disease, congestive heart failure, a serum creatinine
greater than 1.5 mg/dL or those less than 12 months of age.
ADVERSE REACTIONS
Adverse reactions following the use of iopamidol are usually mild to moderate, self-limited, and
transient.
In angiocardiography (597 patients), the adverse reactions with an estimated incidence of one
percent or higher are: hot flashes 3.4%; angina pectoris 3.0%; flushing 1.8%; bradycardia 1.3%;
hypotension 1.0%; hives 1.0%.
In a clinical trial with 76 pediatric patients undergoing angiocardiography, 2 adverse reactions (2.6%)
both remotely attributed to the contrast media were reported. Both patients were less than 2 years of age,
both had cyanotic heart disease with underlying right ventricular abnormalities and abnormal pulmonary
circulation. In one patient pre-existing cyanosis was transiently intensified following contrast media
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Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
administration. In the second patient pre-existing decreased peripheral perfusion was intensified for 24
hours following the examination. (See “PRECAUTIONS” Section for information on high risk nature of these
patients.)
Intravascular injection of contrast media is frequently associated with the sensation of warmth and
pain especially in peripheral arteriography and venography; pain and warmth are less frequent and less
severe with ISOVUE (lopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium
injection.
The following table of incidence of reactions is based on clinical studies with ISOVUE in about 2246
patients.
Adverse Reactions
Estimated Overall Incidence
System
> 1%
≤ 1%
Cardiovascular
none
tachycardia
hypotension
hypertension
myocardial ischemia
circulatory collapse
S-T segment depression
bigeminy
extrasystoles
ventricular fibrillation
angina pectoris
bradycardia
transient ischemic attack
thrombophlebitis
Nervous
pain (2.8%)
burning sensation (1.4%)
vasovagal reaction
tingling in arms
grimace
faintness
Digestive
nausea (1.2%)
vomiting
anorexia
Respiratory
none
throat constriction
dyspnea
pulmonary edema
Skin and Appendages
none
rash
urticaria
pruritus
flushing
Body as a Whole
hot flashes (1.5%)
headache
fever
chills
excessive sweating
back spasm
Special Senses
warmth (1.1%)
taste alterations
nasal congestion
visual disturbances
Urogenital
none
urinary retention
Regardless of the contrast agent employed, the overall estimated incidence of serious adverse
reactions is higher with coronary arteriography than with other procedures. Cardiac decompensation,
serious arrhythmias, or myocardial ischemia or infarction have been reported with Isovue and may
8
Reference ID: 3167853
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occur during coronary arteriography and left ventriculography. Following coronary and ventricular
injections, certain electrocardiographic changes (increased QTc, increased R-R, T-wave amplitude) and
certain hemodynamic changes (decreased systolic pressure) occurred less frequently with ISOVUE
(lopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium injection; increased
LVEDP occurred less frequently after ventricular iopamidol injections.
In aortography, the risks of procedures also include injury to the aorta and neighboring organs, pleural
puncture, renal damage including infarction and acute tabular necrosis with oliguria and anuria, accidental
selective filling of the right renal artery during the translumbar procedure in the presence of pre-existing renal
disease, retroperitoneal hemorrhage from the translumbar approach, and spinal cord injury and pathology
associated with the syndrome of transverse myelitis.
The following adverse reactions have been reported for lopamidol: Cardiovascular: arrhythmia,
arterial spasms, flushing, vasodilation, chest pain, cardiopulmonary arrest; Nervous: confusion,
paresthesia, dizziness, temporary cortical blindness, temporary amnesia, convulsions, paralysis, coma;
Respiratory: increased cough, sneezing, asthma, apnea, laryngeal edema, chest tightness, rhinitis;
Skin and Appendages: injection site pain usually due to extravasation and/or erythematous swelling,
pallor, periorbital edema, facial edema; Urogenital: pain, hematuria; Special Senses: watery itchy eyes,
lacrimation, conjunctivitis; Musculoskeletal: muscle spasm, involuntary leg movement; Body as a whole:
tremors, malaise, anaphylactoid reaction (characterized by cardiovascular, respiratory and cutaneous
symptoms), pain; Digestive: severe retching and choking, abdominal cramps. Some of these may occur
as a consequence of the procedure. Other reactions may also occur with the use of any contrast agent
as a consequence of the procedural hazard; these include hemorrhage or pseudoaneurysms at the
puncture site, brachial plexus palsy following axillary artery injections, chest pain, myocardial infarction,
and transient changes in hepatorenal chemistry tests. Arterial thrombosis, displacement of arterial
plaques, venous thrombosis, dissection of the coronary vessels and transient sinus arrest are rare
complications.
General Adverse Reactions To Contrast Media
Reactions known to occur with parenteral administration of iodinated ionic contrast agents (see the
listing below) are possible with any nonionic agent. Approximately 95 percent of adverse reactions
accompanying the use of other water-soluble intravascularly administered contrast agents are mild to
moderate in degree. However, life-threatening reactions and fatalities, mostly of cardiovascular origin,
have occurred. Reported incidences of death from the administration of other iodinated contrast media
range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Most deaths occur
during injection or 5 to 10 minutes later, the main feature being cardiac arrest with cardiovascular
disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in
the literature. The incidence of shock is estimated to be 1 out of 20,000 (0.005 percent) patients.
Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and
idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast
medium, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or
vessels perfused by the contrast medium are included in this category. Experience with iopamidol
suggests there is much less discomfort (e.g. pain and/or warmth) with peripheral arteriography. Fewer
changes are noted in ventricular function after ventriculography and coronary arteriography.
Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40
years old. Idiosyncratic reactions may or may not be dependent on the amount of drug injected, the
speed of injection, the mode of injection, and the radiographic procedure. Idiosyncratic reactions are
subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short
duration; the severe reactions are life-threatening and treatment is urgent and mandatory.
The reported incidence of adverse reactions to contrast media in patients with a history of allergy is
twice that for the general population. Patients with a history of previous reactions to a contrast medium
are three times more susceptible than other patients. However, sensitivity to contrast media does not
appear to increase with repeated examinations. Most adverse reactions to intravascular contrast agents
appear within one to three minutes after the start of injection, but delayed reactions may occur. Delayed
reactions, usually involving the skin, may uncommonly occur within 2-3 days (range 1-7 days) after the
administration of contrast (see PRECAUTIONS-General). Delayed allergic reactions are more frequent
in patients treated with immunostimulants, such as interleukin-2.
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Reference ID: 3167853
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In addition to the adverse drug reactions reported for iopamidol, the following additional adverse
reactions have been reported with the use of other intravascular contrast agents and are possible with
the use of any water-soluble iodinated contrast agent:
Cardiovascular: cerebral hematomas, petechiae; Hematologic: neutropenia; Skin and Appendages:
skin necrosis; Urogenital: osmotic nephrosis of proximal tubular cells, renal failure; Special Senses:
conjunctival chemosis with infection.
OVERDOSAGE
Treatment of an overdose of an injectable radiopaque contrast medium is directed toward the support
of all vital functions, and prompt institution of symptomatic therapy.
DOSAGE AND ADMINISTRATION
General
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Iopamidol solutions should be
used only if clear and within the normal colorless to pale yellow range. Discard any product
which shows signs of crystallization or damage to the container-closure system, which includes
the glass container, stopper and/or crimp.
It is desirable that solutions of radiopaque diagnostic agents for intravascular use be at body
temperature when injected. Withdrawal of contrast agents from their containers should be
accomplished under aseptic conditions with sterile syringes. Sterile techniques must be used
with any intravascular injection, and with catheters and guidewires.
The transferring of ISOVUE from ISOVUE Multipack should be performed in a suitable work
area, such as a laminar flow hood, utilizing aseptic technique. The container closure may be
penetrated only one time, utilizing a suitable transfer device.
Patients should be well hydrated prior to and following ISOVUE (lopamidol Injection)
administration.
As with all radiopaque contrast agents, only the lowest dose of ISOVUE necessary to obtain
adequate visualization should be used. A lower dose reduces the possibility of an adverse
reaction. Most procedures do not require use of either a maximum dose or the highest available
concentration of ISOVUE; the combination of dose and ISOVUE concentration to be used should
be carefully individualized, and factors such as age, body size, size of the vessel and its blood
flow rate, anticipated pathology and degree and extent of opacification required, structure(s) or
area to be examined, disease processes affecting the patient, and equipment and technique to
be employed should be considered.
Cerebral Arteriography
ISOVUE-300 (lopamidol Injection, 300 mgl/mL) should be used. The usual individual injection by carotid
puncture or transfemoral catheterization is 8 to 12 mL, with total multiple doses ranging to 90 mL.
Peripheral Arteriograghy
ISOVUE-300 usually provides adequate visualization. For injection into the femoral artery or subclavian
artery, 5 to 40 mL may be used; for injection into the aorta for a distal runoff, 25 to 50 mL may be used.
Doses up to a total of 250 mL of ISOVUE-300 have been administered during peripheral arteriography.
Selective Visceral Arteriography and Aortography
ISOVUE-370 (lopamidol Injection, 370 mgl/mL) should be used. Doses up to 50 mL may be required for
injection into the larger vessels such as the aorta or celiac artery; doses up to 10 mL may be required
for injection into the renal arteries. Often, lower doses will be sufficient. The combined total dose for
multiple injections has not exceeded 225 mL.
Pediatric Angiocardiography
ISOVUE-370 should be used. Pediatric angiocardiography may be performed by injection into a large
peripheral vein or by direct catheterization of the heart.
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Reference ID: 3167853
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The usual dose range for single injections is provided in the following table:
Single Injection
Usual Dose Range
Age
mL
< 2 years
10-15
2-9 years
15-30
10-18 years
20-50
The usual recommended dose for cumulative injections is provided in the following table:
Cumulative Injection
Usual Recommended Dose
Age
mL
< 2 years
40
2-4 years
50
5-9 years
100
10-18 years
125
Coronary Arteriography and Ventriculography
ISOVUE-370 should be used. The usual dose for selective coronary artery injections is 2 to 10 mL. The
usual dose for ventriculography, or for nonselective opacification of multiple coronary arteries following
injection at the aortic root is 25 to 50 mL. The total dose for combined procedures has not exceeded
200 mL. EKG monitoring is essential.
Excretory Urography
ISOVUE-250 ISOVUE-300 or ISOVUE-370 may be used. The usual adult dose for ISOVUE-250 is 50
to 100 mL, for ISOVUE-300 is 50 mL and for ISOVUE-370 is 40 mL administered by rapid intravenous
injection.
Pediatric Excretory Urography
ISOVUE-250 or ISOVUE-300 may be used. The dosage recommended for use in children for excretory
urography is 1.2 mL/kg to 3.6 mL/kg for ISOVUE-250 and 1.0 mL/kg to 3.0 mL/kg for ISOVUE-300. It
should not be necessary to exceed a total dose of 30 grams of iodine.
Computed Tomography
ISOVUE-250 or ISOVUE-300 may be used.
CECT OF THE HEAD: The suggested dose for ISOVUE-250 is 130 to 240 mL and for ISOVUE-300 is
100 to 200 mL by intravenous administration. Imaging may be performed immediately after completion
of administration.
CECT OF THE BODY: The usual adult dose range for ISOVUE-250 is 130 to 240 mL and for ISOVUE
300 is 100 to 200 mL administered by rapid intravenous infusion or bolus injection.
Equivalent doses of ISOVUE-370 based on organically bound iodine content may also be used.
The total dose for either CECT procedure should not exceed 60 grams of iodine.
Pediatric Computed Tomography
ISOVUE-250 or ISOVUE-300 may be used. The dosage recommended for use in children for contrast
enhanced computed tomography is 1.2 mL/kg to 3.6 mL/kg for ISOVUE-250 and 1.0 mL/kg to 3.0
mL/kg for ISOVUE-300. It should not be necessary to exceed a total dose of 30 grams of iodine.
Drug Incompatibilities
Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other
drugs; therefore, no other pharmaceuticals should be admixed with contrast agents.
Reference ID: 3167853
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DRUG HANDLING
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Iopamidol solutions should be
used only if clear and within the normal colorless to pale yellow range.
Discard any product which shows signs of crystallization or damage to the container-closure
system, which includes the glass container, stopper and/or crimp.
Directions for Proper Use of ISOVUE Multipack
The pharmacy bulk package is used as a multiple dose container with an appropriate transfer
device to fill empty sterile syringes.
ISOVUE Multipack injection should be drawn into the syringe and administered using sterile
technique. Unused portions of the drug must be discarded.
a. The transferring ISOVUE (Iopamidol Injection) from the Pharmacy Bulk Package should be
performed in a suitable work area, such as a laminar flow hood, utilizing aseptic technique.
b. The container closure may be penetrated only one time, utilizing a suitable transfer device.
Once the pharmacy bulk package is punctured, it should not be removed from the aseptic
work area during the entire period of use.
c. The withdrawal of container contents should be accomplished without delay. However, should
this not be possible, a maximum time of 10 hours from initial closure entry is permitted to
complete fluid transfer operation. Any unused ISOVUE Multipack injection must be discarded
10 hours after initial puncture of the bulk package.
d. Storage temperature of container after the closure has been entered should not exceed 25° C
(77° F).
HOW SUPPLIED
ISOVUE Multipack-250 (lopamidol Injection 51%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1317-41)
ISOVUE Multipack-300 (lopamidol Injection 61%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1315-41)
Six 500 mL Pharmacy Bulk Packages
(NDC 0270-1315-98)
ISOVUE Multipack-370 (lopamidol Injection 76%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1316-41)
Six 500 mL Pharmacy Bulk Packages
(NDC 0270-1316-98)
Storage
Store at 20-25° C (68-77° F). [See USP]. Protect from light.
Rx Only
Manufactured for
Bracco Diagnostic Inc. - Princeton, NJ 08543
by BIPSO GmbH
78224 Singen (Germany)
Revised August 2012
F1/6065347
Reference ID: 3167853
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-327; ISOVUE Multipack® (Iopamidol Injection)
Revised labeling to FDA_JULY-2012_CLEAN.doc
Bracco Diagnostics
255615 company logo
Isovue Multipack®
Pharmacy Bulk Package -
Not for Direct Infusion
ISOVUE Multipack®-250
lopamidol injection 51%
ISOVUE Multipack®-300
lopamidol injection 61%
ISOVUE Multipack®-370
lopamidol injection 76%
NOT FOR INTRATHECAL USE
ISOVUE 250, 300 and 370 are NOT FOR INTRATHECAL USE.
See Indications, and Dosage and Administration sections for further details
on proper use
DIAGNOSTIC
NONIONIC RADIOPAQUE CONTRAST MEDIA
For Angiography Throughout the Cardiovascular
System, Including Cerebral and Peripheral Arteriography,
Coronary Arteriography and Ventriculography,
Pediatric Angiocardiography, Selective Visceral
Arteriography and Aortography,
Peripheral Venography (Phlebography), and
Adult and Pediatric Intravenous Excretory
Urography and Intravenous Adult and Pediatric
Contrast Enhancement of Computed Tomographic
(CECT) Head and Body Imaging
DESCRIPTION
ISOVUE (lopamidol Injection) formulations are stable, aqueous, sterile, and nonpyrogenic solutions for
intravascular administration. Each bottle is to be used as a Pharmacy Bulk Package for dispensing
multiple single dose preparations utilizing a suitable transfer device.
Each mL of ISOVUE Multipack-250 (lopamidol Injection 51%) provides 510 mg iopamidol with 1 mg
tromethamine and 0.33 mg edetate calcium disodium. The solution contains approximately 0.036 mg
(0.002 mEq) sodium and 250 mg organically bound iodine per mL.
Each mL of ISOVUE Multipack-300 (lopamidol Injection 61%) provides 612 mg iopamidol with 1 mg
tromethamine and 0.39 mg edetate calcium disodium. The solution contains approximately 0.043 mg
(0.002 mEq) sodium and 300 mg organically bound iodine per mL.
Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Each mL of ISOVUE Multipack-370 (lopamidol Injection 76%) provides 755 mg iopamidol with 1 mg
tromethamine and 0.48 mg edetate calcium disodium. The solution contains approximately 0.053 mg
(0.002 mEq) sodium and 370 mg organically bound iodine per mL.
The pH of ISOVUE contrast media has been adjusted to 6.5-7.5 with hydrochloric acid and/or
sodium hydroxide. Pertinent physicochemical data are noted below. ISOVUE (lopamidol Injection) is
hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water,
respectively).
Iopamidol
Parameter
51%
61%
76%
Concentration (mgl/mL)
250
300
370
Osmolality @ 37° C (mOsm/kg water)
524
616
796
Viscosity (cP) @ 37° C
3.0
4.7
9.4
@ 20° C
5.1
8.8
20.9
Specific Gravity @ 37° C
1.281
1.339
1.405
lopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo
5-lactamidoisophthalamide. Structural formula: structural formula
CLINICAL PHARMACOLOGY
Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of flow of the
contrast medium, permitting radiographic visualization of the internal structures of the human body until
significant hemodilution occurs.
Following intravascular injection, radiopaque diagnostic agents are immediately diluted in the
circulating plasma. Calculations of apparent volume of distribution at steady-state indicate that
iopamidol is distributed between the circulating blood volume and other extracellular fluid; there appears
to be no significant deposition of iopamidol in tissues. Uniform distribution of iopamidol in extracellular
fluid is reflected by its demonstrated utility in contrast enhancement of computed tomographic imaging of
the head and body following intravenous administration.
The pharmacokinetics of intravenously administered iopamidol in normal subjects conform to an
open two-compartment model with first order elimination (a rapid alpha phase for drug distribution and a
slow beta phase for drug elimination). The elimination serum or plasma half-life is approximately two
hours; the half-life is not dose dependent. No significant metabolism, deiodination, or biotransformation
occurs.
Iopamidol is excreted mainly through the kidneys following intravascular administration. In patients
with impaired renal function, the elimination half-life is prolonged dependent upon the degree of
impairment. In the absence of renal dysfunction, the cumulative urinary excretion for iopamidol,
expressed as a percentage of administered intravenous dose, is approximately 35 to 40 percent at 60
minutes, 80 to 90 percent at 8 hours, and 90 percent or more in the 72- to 96-hour period after
administration. In normal subjects, approximately one percent or less of the administered dose appears
in cumulative 72- to 96-hour fecal specimens.
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Reference ID: 3167853
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ISOVUE may be visualized in the renal parenchyma within 30-60 seconds following rapid
intravenous administration. Opacification of the calyces and pelves in patients with normal renal
function becomes apparent within 1 to 3 minutes, with optimum contrast occurring between 5 and 15
minutes. In patients with renal impairment, contrast visualization may be delayed.
Iopamidol displays little tendency to bind to serum or plasma proteins.
No evidence of in vivo complement activation has been found in normal subjects.
Animal studies indicate that iopamidol does not cross the blood-brain barrier to any significant extent
following intravascular administration.
ISOVUE (lopamidol Injection) enhances computed tomographic brain imaging through
augmentation of radiographic efficiency. The degree of enhancement of visualization of tissue density
is directly related to the iodine content in an administered dose; peak iodine blood levels occur
immediately following rapid injection of the dose. These levels fall rapidly within five to ten minutes. This
can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes
an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached
in about ten minutes, thereafter, the fall becomes exponential. Maximum contrast enhancement
frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast
enhancement can range from five to forty minutes depending on the peak iodine levels achieved and
the cell type of the lesion. This lag suggests that radiographic contrast enhancement is at least in part
dependent on the accumulation of iodine within the lesion and outside the blood pool, although the
mechanism by which this occurs is not clear. The radiographic enhancement of nontumoral lesions,
such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of
the circulating blood pool.
In CECT head imaging, ISOVUE (lopamidol Injection) does not accumulate in normal brain tissue due
to the presence of the “blood-brain” barrier. The increase in x-ray absorption in normal brain is due to the
presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in
malignant tumors of the brain allows the accumulation of the contrast medium within the interstitial tissue
of the tumor. Adjacent normal brain tissue does not contain the contrast medium.
In nonneural tissues (during computed tomography of the body), iopamidol diffuses rapidly from the
vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration
of the contrast medium, and extraction of the contrast medium by interstitial tissue of tumors since no
barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion
between normal and abnormal tissue, quite different from that in the brain.
The pharmacokinetics of iopamidol in both normal and abnormal tissue have been shown to be
variable. Contrast enhancement appears to be greatest soon after administration of the contrast
medium, and following intra-arterial rather than intravenous administration. Thus, greatest
enhancement can be detected by a series of consecutive two- to three-second scans performed just
after injection (within 30 to 90 seconds), i.e., dynamic computed tomographic imaging.
INDICATIONS AND USAGE
ISOVUE (lopamidol Injection) is indicated for angiography throughout the cardiovascular system,
including cerebral and peripheral arteriography, coronary arteriography and ventriculography, pediatric
angiocardiography, selective visceral arteriography and aortography, peripheral venography
(phlebography), and adult and pediatric intravenous excretory urography and intravenous adult and
pediatric contrast enhancement of computed tomographic (CECT) head and body imaging (see below).
CECT Head Imaging
ISOVUE may be used to refine diagnostic precision in areas of the brain which may not otherwise have
been satisfactorily visualized.
Tumors
ISOVUE may be useful to investigate the presence and extent of certain malignancies such as: gliomas
including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas,
ependymomas, medulloblastomas, meningiomas, neuromas, pinealomas, pituitary adenomas,
craniopharyngiomas, germinomas, and metastatic lesions. The usefulness of contrast enhancement for
the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been
demonstrated.
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Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In calcified lesions, there is less likelihood of enhancement. Following therapy, tumors may show
decreased or no enhancement.
The opacification of the inferior vermis following contrast media administration has resulted in false-
positive diagnosis in a number of otherwise normal studies.
Nonneoplastic Conditions
ISOVUE may be beneficial in the image enhancement of nonneoplastic lesions. Cerebral infarctions of
recent onset may be better visualized with contrast enhancement, while some infarctions are obscured
if contrast media are used. The use of iodinated contrast media results in contrast enhancement in
about 60 percent of cerebral infarctions studied from one to four weeks from the onset of symptoms.
Sites of active infection may also be enhanced following contrast media administration.
Arteriovenous malformations and aneurysms will show contrast enhancement. For these vascular
lesions, the enhancement is probably dependent on the iodine content of the circulating blood pool.
Hematomas and intraparenchymal bleeders seldom demonstrate any contrast enhancement.
However, in cases of intraparenchymal clot, for which there is no obvious clinical explanation, contrast
media administration may be helpful in ruling out the possibility of associated arteriovenous
malformation.
CECT Body Imaging
ISOVUE (lopamidol Injection) may be used for enhancement of computed tomographic images for
detection and evaluation of lesions in the liver, pancreas, kidneys, aorta, mediastinum, abdominal
cavity, pelvis and retroperitoneal space.
Enhancement of computed tomography with ISOVUE may be of benefit in establishing diagnoses
of certain lesions in these sites with greater assurance than is possible with CT alone, and in supplying
additional features of the lesions (e.g., hepatic abscess delineation prior to percutaneous drainage). In
other cases, the contrast agent may allow visualization of lesions not seen with CT alone (e.g. tumor
extension), or may help to define suspicious lesions seen with unenhanced CT (e.g., pancreatic cyst).
Contrast enhancement appears to be greatest within 60 to 90 seconds after bolus administration of
contrast agent. Therefore, utilization of a continuous scanning technique (“dynamic CT scanning”) may
improve enhancement and diagnostic assessment of tumor and other lesions
such as an abscess, occasionally revealing unsuspected or more extensive disease. For example, a cyst
may be distinguished from a vascularized solid lesion when precontrast and enhanced scans are compared;
the nonperfused mass shows unchanged x-ray absorption (CT number). A vascularized lesion is
characterized by an increase in CT number in the few minutes after a bolus of intravascular contrast agent; it
may be malignant, benign, or normal tissue, but would probably not be a cyst, hematoma, or other
nonvascular lesion.
Because unenhanced scanning may provide adequate diagnostic information in the individual
patient, the decision to employ contrast enhancement, which may be associated with risk and increased
radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and
unenhanced CT findings.
CONTRAINDICATIONS
None.
WARNINGS
Severe Adverse Events-lnadvertent Intrathecal Administration
Serious adverse reactions have been reported due to the inadvertent intrathecal
administration of iodinated contrast media that are not indicated for intrathecal use.
These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma,
paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis,
hyperthermia, and brain edema. Special attention must be given to insure that this drug product
is not inadvertently administered intrathecally.
General
Nonionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media.
Clotting has been reported when blood remains in contact with syringes containing nonionic contrast
media.
4
Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been
reported during angiographic procedures with both ionic and nonionic contrast media. Therefore,
meticulous intravascular administration technique is necessary, particularly during angiographic
procedures, to minimize thromboembolic events. Numerous factors, including length of procedure,
catheter and syringe material, underlying disease state, and concomitant medications may contribute to
the development of thromboembolic events. For these reasons, meticulous angiographic techniques
are recommended including close attention to guidewire and catheter manipulation, use of manifold
systems and/or three way stopcocks, frequent catheter flushing with heparinized saline solutions, and
minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been
reported to decrease but not eliminate the likelihood of in vitro clotting.
Caution must be exercised in patients with severely impaired renal function, those with combined
renal and hepatic disease, or anuria, particularly when larger or repeat doses are administered.
Radiopaque diagnostic contrast agents are potentially hazardous in patients with multiple myeloma
or other paraproteinemia, particularly in those with therapeutically resistant anuria. Myeloma occurs
most commonly in persons over age 40. Although neither the contrast agent nor dehydration has been
proved separately to be the cause of anuria in myelomatous patients, it has been speculated that the
combination of both may be causative. The risk in myelomatous patients is not a contraindication;
however, special precautions are required.
Contrast media may promote sickling in individuals who are homozygous for sickle cell disease
when injected intravenously or intraarterially.
Administration of radiopaque materials to patients known or suspected of having
pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the
possible benefits of such procedures outweigh the considered risks, the procedures may be performed;
however, the amount of radiopaque medium injected should be kept to an absolute minimum. The
blood pressure should be assessed throughout the procedure and measures for treatment of a
hypertensive crisis should be available. These patients should be monitored very closely during
contrast enhanced procedures.
Reports of thyroid storm following the use of iodinated radiopaque diagnostic agents in patients with
hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be
evaluated in such patients before use of any contrast medium.
PRECAUTIONS
General
Diagnostic procedures which involve the use of any radiopaque agent should be carried out under the
direction of personnel with the prerequisite training and with a thorough knowledge of the particular
procedure to be performed. Appropriate facilities should be available for coping with any complication of
the procedure, as well as for emergency treatment of severe reaction to the contrast agent itself. After
parenteral administration of a radiopaque agent, competent personnel and emergency facilities should
be available for at least 30 to 60 minutes since severe delayed reactions may occur. Caution should be
exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, such
as congestive heart failure.
Diabetic nephropathy may predispose to acute renal impairment following intravascular contrast
media administration. Acute renal impairment following contrast media administration may precipitate
lactic acidosis in patients who are taking biguanides.
The administration of iodinated contrast media may aggravate the symptoms of myasthenia gravis.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with
advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with
pre-existing renal disease). Patients should be well hydrated prior to and following iopamidol
administration.
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular
reactions, should always be considered (see ADVERSE REACTIONS). Patients at increased risk include
those with a history of a previous reaction to a contrast medium, patients with a known sensitivity to
iodine per se, and patients with a known clinical hypersensitivity (bronchial asthma, hay fever, and food
allergies). The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting
5
Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be
hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and
hypersensitivity, prior to the injection of any contrast medium, may be more accurate than pretesting in
predicting potential adverse reactions. A positive history of allergies or hypersensitivity does not arbitrarily
contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution
should be exercised. Premedication with antihistamines or corticosteroids to avoid or minimize possible
allergic reactions in such patients should be considered. Recent reports indicate that such pretreatment
does not prevent serious life-threatening reactions but may reduce both their incidence and severity.
Pre-existing conditions, such as pacemakers or cardiac medications, specifically beta-blockers, may
mask or alter the signs or symptoms of an anaphylactoid reaction, as well as masking or altering the
response to particular medications used for treatment. For example, beta-blockers inhibit a tachycardiac
response, and can lead to the incorrect diagnosis of a vasovagal rather than an anaphylactoid reaction.
Special attention to this possibility is particularly critical in patients suffering from serious, life-threatening
reactions.
General anesthesia may be indicated in the performance of some procedures in selected patients;
however, a higher incidence of adverse reactions has been reported with radiopaque media in
anesthetized patients, which may be attributable to the inability of the patient to identify untoward
symptoms, or to the hypotensive effect of anesthesia which can reduce cardiac output and increase the
duration of exposure to the contrast agent.
Even though the osmolality of iopamidol is low compared to diatrizoate or iothalamate based ionic
agents of comparable iodine concentration, the potential transitory increase in the circulatory osmotic
load in patients with congestive heart failure requires caution during injection. These patients should be
observed for several hours following the procedure to detect delayed hemodynamic disturbances.
Injection site pain and swelling may occur. In the majority of cases it is due to extravasation of contrast
medium. Reactions are usually transient and recover without sequelae. However, inflammation and
even skin necrosis have been seen on very rare occasions.
In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel
wall, or inducing vasospasm, and or subsequent ischemic events, should be borne in mind during catheter
manipulations and contrast medium injection. Test injections to ensure proper catheter placement are
suggested.
Selective coronary arteriography should be performed only in selected patients and those in whom
the expected benefits outweigh the procedural risk. The inherent risks of angiocardiography in patients
with pulmonary hypertension must be weighed against the necessity for performing this procedure.
Angiography should be avoided whenever possible in patients with homocystinuria, because of the risk
of inducing thrombosis and embolism.
See also Pediatric Use.
In addition to the general precautions previously described, special care is required when
venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease,
local infection or a totally obstructed venous system.
Extreme caution during injection of contrast media is necessary to avoid extravasation and
fluoroscopy is recommended. This is especially important in patients with severe arterial or venous
disease.
Information for Patients
Patients receiving injectable radiopaque diagnostic agents should be instructed to:
1. Inform your physician if you are pregnant.
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma,
homozygous sickle cell disease, or known thyroid disorder (see WARNINGS).
3. Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous
injections of substances used for x-ray procedures (see PRECAUTIONS-General).
4. Inform your physician about any other medications you are currently taking, including nonprescription
drugs, before you have this procedure.
Drug Interactions
Renal toxicity has been reported in a few patients with liver dysfunction who were given oral
cholecystographic agents followed by intravascular contrast agents. Administration of intravascular
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Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
agents should therefore be postponed in any patient with a known or suspected hepatic or biliary
disorder who has recently received a cholecystographic contrast agent.
Other drugs should not be admixed with iopamidol.
Drug/Laboratory Test Interactions
The results of PBI and radioactive iodine uptake studies, which depend on iodine estimations, will not
accurately reflect thyroid function for up to 16 days following administration of iodinated contrast media.
However, thyroid function tests not depending on iodine estimations, e.g., T3 resin uptake and total or
free thyroxine (T4) assays are not affected.
Any test which might be affected by contrast media should be performed prior to administration of
the contrast medium.
Laboratory Test Findings
In vitro studies with animal blood showed that many radiopaque contrast agents, including iopamidol,
produced a slight depression of plasma coagulation factors including prothrombin time, partial
thromboplastin time, and fibrinogen, as well as a slight tendency to cause platelet and/or red blood cell
aggregation (see PRECAUTIONS-General).
Transitory changes may occur in red cell and leucocyte counts, serum calcium, serum creatinine,
serum glutamic oxaloacetic transaminase (SGOT), and uric acid in urine; transient albuminuria may
occur.
These findings have not been associated with clinical manifestations.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. No evidence
of genetic toxicity was obtained in in vitro tests.
Pregnancy: Teratogenic Effects
Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to
2.7 and 1.4 times the maximum recommended human dose (1.48 gl/kg in a 50 kg individual),
respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to iopamidol.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when iopamidol is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children has been established in pediatric angiocardiography, computed
tomography (head and body) and excretory urography. Pediatric patients at higher risk of experiencing
adverse events during contrast medium administration may include those having asthma, a sensitivity
to medication and/or allergens, cyanotic heart disease, congestive heart failure, a serum creatinine
greater than 1.5 mg/dL or those less than 12 months of age.
ADVERSE REACTIONS
Adverse reactions following the use of iopamidol are usually mild to moderate, self-limited, and
transient.
In angiocardiography (597 patients), the adverse reactions with an estimated incidence of one
percent or higher are: hot flashes 3.4%; angina pectoris 3.0%; flushing 1.8%; bradycardia 1.3%;
hypotension 1.0%; hives 1.0%.
In a clinical trial with 76 pediatric patients undergoing angiocardiography, 2 adverse reactions (2.6%)
both remotely attributed to the contrast media were reported. Both patients were less than 2 years of age,
both had cyanotic heart disease with underlying right ventricular abnormalities and abnormal pulmonary
circulation. In one patient pre-existing cyanosis was transiently intensified following contrast media
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Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
administration. In the second patient pre-existing decreased peripheral perfusion was intensified for 24
hours following the examination. (See “PRECAUTIONS” Section for information on high risk nature of these
patients.)
Intravascular injection of contrast media is frequently associated with the sensation of warmth and
pain especially in peripheral arteriography and venography; pain and warmth are less frequent and less
severe with ISOVUE (lopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium
injection.
The following table of incidence of reactions is based on clinical studies with ISOVUE in about 2246
patients.
Adverse Reactions
Estimated Overall Incidence
System
> 1%
≤ 1%
Cardiovascular
none
tachycardia
hypotension
hypertension
myocardial ischemia
circulatory collapse
S-T segment depression
bigeminy
extrasystoles
ventricular fibrillation
angina pectoris
bradycardia
transient ischemic attack
thrombophlebitis
Nervous
pain (2.8%)
burning sensation (1.4%)
vasovagal reaction
tingling in arms
grimace
faintness
Digestive
nausea (1.2%)
vomiting
anorexia
Respiratory
none
throat constriction
dyspnea
pulmonary edema
Skin and Appendages
none
rash
urticaria
pruritus
flushing
Body as a Whole
hot flashes (1.5%)
headache
fever
chills
excessive sweating
back spasm
Special Senses
warmth (1.1%)
taste alterations
nasal congestion
visual disturbances
Urogenital
none
urinary retention
Regardless of the contrast agent employed, the overall estimated incidence of serious adverse
reactions is higher with coronary arteriography than with other procedures. Cardiac decompensation,
serious arrhythmias, or myocardial ischemia or infarction have been reported with Isovue and may
8
Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
occur during coronary arteriography and left ventriculography. Following coronary and ventricular
injections, certain electrocardiographic changes (increased QTc, increased R-R, T-wave amplitude) and
certain hemodynamic changes (decreased systolic pressure) occurred less frequently with ISOVUE
(lopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium injection; increased
LVEDP occurred less frequently after ventricular iopamidol injections.
In aortography, the risks of procedures also include injury to the aorta and neighboring organs, pleural
puncture, renal damage including infarction and acute tabular necrosis with oliguria and anuria, accidental
selective filling of the right renal artery during the translumbar procedure in the presence of pre-existing renal
disease, retroperitoneal hemorrhage from the translumbar approach, and spinal cord injury and pathology
associated with the syndrome of transverse myelitis.
The following adverse reactions have been reported for lopamidol: Cardiovascular: arrhythmia,
arterial spasms, flushing, vasodilation, chest pain, cardiopulmonary arrest; Nervous: confusion,
paresthesia, dizziness, temporary cortical blindness, temporary amnesia, convulsions, paralysis, coma;
Respiratory: increased cough, sneezing, asthma, apnea, laryngeal edema, chest tightness, rhinitis;
Skin and Appendages: injection site pain usually due to extravasation and/or erythematous swelling,
pallor, periorbital edema, facial edema; Urogenital: pain, hematuria; Special Senses: watery itchy eyes,
lacrimation, conjunctivitis; Musculoskeletal: muscle spasm, involuntary leg movement; Body as a whole:
tremors, malaise, anaphylactoid reaction (characterized by cardiovascular, respiratory and cutaneous
symptoms), pain; Digestive: severe retching and choking, abdominal cramps. Some of these may occur
as a consequence of the procedure. Other reactions may also occur with the use of any contrast agent
as a consequence of the procedural hazard; these include hemorrhage or pseudoaneurysms at the
puncture site, brachial plexus palsy following axillary artery injections, chest pain, myocardial infarction,
and transient changes in hepatorenal chemistry tests. Arterial thrombosis, displacement of arterial
plaques, venous thrombosis, dissection of the coronary vessels and transient sinus arrest are rare
complications.
General Adverse Reactions To Contrast Media
Reactions known to occur with parenteral administration of iodinated ionic contrast agents (see the
listing below) are possible with any nonionic agent. Approximately 95 percent of adverse reactions
accompanying the use of other water-soluble intravascularly administered contrast agents are mild to
moderate in degree. However, life-threatening reactions and fatalities, mostly of cardiovascular origin,
have occurred. Reported incidences of death from the administration of other iodinated contrast media
range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Most deaths occur
during injection or 5 to 10 minutes later, the main feature being cardiac arrest with cardiovascular
disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in
the literature. The incidence of shock is estimated to be 1 out of 20,000 (0.005 percent) patients.
Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and
idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast
medium, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or
vessels perfused by the contrast medium are included in this category. Experience with iopamidol
suggests there is much less discomfort (e.g. pain and/or warmth) with peripheral arteriography. Fewer
changes are noted in ventricular function after ventriculography and coronary arteriography.
Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40
years old. Idiosyncratic reactions may or may not be dependent on the amount of drug injected, the
speed of injection, the mode of injection, and the radiographic procedure. Idiosyncratic reactions are
subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short
duration; the severe reactions are life-threatening and treatment is urgent and mandatory.
The reported incidence of adverse reactions to contrast media in patients with a history of allergy is
twice that for the general population. Patients with a history of previous reactions to a contrast medium
are three times more susceptible than other patients. However, sensitivity to contrast media does not
appear to increase with repeated examinations. Most adverse reactions to intravascular contrast agents
appear within one to three minutes after the start of injection, but delayed reactions may occur. Delayed
reactions, usually involving the skin, may uncommonly occur within 2-3 days (range 1-7 days) after the
administration of contrast (see PRECAUTIONS-General). Delayed allergic reactions are more frequent
in patients treated with immunostimulants, such as interleukin-2.
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Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In addition to the adverse drug reactions reported for iopamidol, the following additional adverse
reactions have been reported with the use of other intravascular contrast agents and are possible with
the use of any water-soluble iodinated contrast agent:
Cardiovascular: cerebral hematomas, petechiae; Hematologic: neutropenia; Skin and Appendages:
skin necrosis; Urogenital: osmotic nephrosis of proximal tubular cells, renal failure; Special Senses:
conjunctival chemosis with infection.
OVERDOSAGE
Treatment of an overdose of an injectable radiopaque contrast medium is directed toward the support
of all vital functions, and prompt institution of symptomatic therapy.
DOSAGE AND ADMINISTRATION
General
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Iopamidol solutions should be
used only if clear and within the normal colorless to pale yellow range. Discard any product
which shows signs of crystallization or damage to the container-closure system, which includes
the glass container, stopper and/or crimp.
It is desirable that solutions of radiopaque diagnostic agents for intravascular use be at body
temperature when injected. Withdrawal of contrast agents from their containers should be
accomplished under aseptic conditions with sterile syringes. Sterile techniques must be used
with any intravascular injection, and with catheters and guidewires.
The transferring of ISOVUE from ISOVUE Multipack should be performed in a suitable work
area, such as a laminar flow hood, utilizing aseptic technique. The container closure may be
penetrated only one time, utilizing a suitable transfer device.
Patients should be well hydrated prior to and following ISOVUE (lopamidol Injection)
administration.
As with all radiopaque contrast agents, only the lowest dose of ISOVUE necessary to obtain
adequate visualization should be used. A lower dose reduces the possibility of an adverse
reaction. Most procedures do not require use of either a maximum dose or the highest available
concentration of ISOVUE; the combination of dose and ISOVUE concentration to be used should
be carefully individualized, and factors such as age, body size, size of the vessel and its blood
flow rate, anticipated pathology and degree and extent of opacification required, structure(s) or
area to be examined, disease processes affecting the patient, and equipment and technique to
be employed should be considered.
Cerebral Arteriography
ISOVUE-300 (lopamidol Injection, 300 mgl/mL) should be used. The usual individual injection by carotid
puncture or transfemoral catheterization is 8 to 12 mL, with total multiple doses ranging to 90 mL.
Peripheral Arteriograghy
ISOVUE-300 usually provides adequate visualization. For injection into the femoral artery or subclavian
artery, 5 to 40 mL may be used; for injection into the aorta for a distal runoff, 25 to 50 mL may be used.
Doses up to a total of 250 mL of ISOVUE-300 have been administered during peripheral arteriography.
Selective Visceral Arteriography and Aortography
ISOVUE-370 (lopamidol Injection, 370 mgl/mL) should be used. Doses up to 50 mL may be required for
injection into the larger vessels such as the aorta or celiac artery; doses up to 10 mL may be required
for injection into the renal arteries. Often, lower doses will be sufficient. The combined total dose for
multiple injections has not exceeded 225 mL.
Pediatric Angiocardiography
ISOVUE-370 should be used. Pediatric angiocardiography may be performed by injection into a large
peripheral vein or by direct catheterization of the heart.
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Reference ID: 3167853
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The usual dose range for single injections is provided in the following table:
Single Injection
Usual Dose Range
Age
mL
< 2 years
10-15
2-9 years
15-30
10-18 years
20-50
The usual recommended dose for cumulative injections is provided in the following table:
Cumulative Injection
Usual Recommended Dose
Age
mL
< 2 years
40
2-4 years
50
5-9 years
100
10-18 years
125
Coronary Arteriography and Ventriculography
ISOVUE-370 should be used. The usual dose for selective coronary artery injections is 2 to 10 mL. The
usual dose for ventriculography, or for nonselective opacification of multiple coronary arteries following
injection at the aortic root is 25 to 50 mL. The total dose for combined procedures has not exceeded
200 mL. EKG monitoring is essential.
Excretory Urography
ISOVUE-250 ISOVUE-300 or ISOVUE-370 may be used. The usual adult dose for ISOVUE-250 is 50
to 100 mL, for ISOVUE-300 is 50 mL and for ISOVUE-370 is 40 mL administered by rapid intravenous
injection.
Pediatric Excretory Urography
ISOVUE-250 or ISOVUE-300 may be used. The dosage recommended for use in children for excretory
urography is 1.2 mL/kg to 3.6 mL/kg for ISOVUE-250 and 1.0 mL/kg to 3.0 mL/kg for ISOVUE-300. It
should not be necessary to exceed a total dose of 30 grams of iodine.
Computed Tomography
ISOVUE-250 or ISOVUE-300 may be used.
CECT OF THE HEAD: The suggested dose for ISOVUE-250 is 130 to 240 mL and for ISOVUE-300 is
100 to 200 mL by intravenous administration. Imaging may be performed immediately after completion
of administration.
CECT OF THE BODY: The usual adult dose range for ISOVUE-250 is 130 to 240 mL and for ISOVUE
300 is 100 to 200 mL administered by rapid intravenous infusion or bolus injection.
Equivalent doses of ISOVUE-370 based on organically bound iodine content may also be used.
The total dose for either CECT procedure should not exceed 60 grams of iodine.
Pediatric Computed Tomography
ISOVUE-250 or ISOVUE-300 may be used. The dosage recommended for use in children for contrast
enhanced computed tomography is 1.2 mL/kg to 3.6 mL/kg for ISOVUE-250 and 1.0 mL/kg to 3.0
mL/kg for ISOVUE-300. It should not be necessary to exceed a total dose of 30 grams of iodine.
Drug Incompatibilities
Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other
drugs; therefore, no other pharmaceuticals should be admixed with contrast agents.
Reference ID: 3167853
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DRUG HANDLING
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Iopamidol solutions should be
used only if clear and within the normal colorless to pale yellow range.
Discard any product which shows signs of crystallization or damage to the container-closure
system, which includes the glass container, stopper and/or crimp.
Directions for Proper Use of ISOVUE Multipack
The pharmacy bulk package is used as a multiple dose container with an appropriate transfer
device to fill empty sterile syringes.
ISOVUE Multipack injection should be drawn into the syringe and administered using sterile
technique. Unused portions of the drug must be discarded.
a. The transferring ISOVUE (Iopamidol Injection) from the Pharmacy Bulk Package should be
performed in a suitable work area, such as a laminar flow hood, utilizing aseptic technique.
b. The container closure may be penetrated only one time, utilizing a suitable transfer device.
Once the pharmacy bulk package is punctured, it should not be removed from the aseptic
work area during the entire period of use.
c. The withdrawal of container contents should be accomplished without delay. However, should
this not be possible, a maximum time of 10 hours from initial closure entry is permitted to
complete fluid transfer operation. Any unused ISOVUE Multipack injection must be discarded
10 hours after initial puncture of the bulk package.
d. Storage temperature of container after the closure has been entered should not exceed 25° C
(77° F).
HOW SUPPLIED
ISOVUE Multipack-250 (lopamidol Injection 51%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1317-41)
ISOVUE Multipack-300 (lopamidol Injection 61%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1315-41)
Six 500 mL Pharmacy Bulk Packages
(NDC 0270-1315-98)
ISOVUE Multipack-370 (lopamidol Injection 76%)
Ten 200 mL Pharmacy Bulk Packages
(NDC 0270-1316-41)
Six 500 mL Pharmacy Bulk Packages
(NDC 0270-1316-98)
Storage
Store at 20-25° C (68-77° F). [See USP]. Protect from light.
Rx Only
Manufactured for
Bracco Diagnostics Inc.
Princeton, NJ 08543
by Patheon Italia S.p.A.
03013 Ferentino (Italy)
Revised August 2012
255615
Reference ID: 3167853
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
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----------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
RAFEL D RIEVES
08/01/2012
Reference ID: 3167853
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020327s007lbl.pdf', 'application_number': 20327, 'submission_type': 'SUPPL ', 'submission_number': 7}
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GLUCOTROL XL - glipizide tablet, extended release
Roerig
GLUCOTROL XL®
(glipizide)
Extended Release Tablets
For Oral Use
DESCRIPTION
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea. The
molecular formula is C21H27N5O4S; the molecular weight is 445.55; the structural formula is shown below: Chemical Structure
Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely
soluble in dimethylformamide. GLUCOTROL XL® is a registered trademark for glipizide GITS. Glipizide GITS (Gastrointestinal
Therapeutic System) is formulated as a once-a-day controlled release tablet for oral use and is designed to deliver 2.5, 5, or 10 mg of
glipizide.
Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: polyethylene oxide, hypromellose, magnesium stearate, sodium
chloride, red ferric oxide, cellulose acetate, polyethylene glycol, Opadry® blue (OY-LS-20921)(2.5 mg tablets), Opadry® white
(YS-2-7063)(5 mg and 10 mg tablet) and black ink (S-1-8106).
System Components and Performance
GLUCOTROL XL Extended Release Tablet is similar in appearance to a conventional tablet. It consists, however, of an osmotically
active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an "active" layer containing
the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the
tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure
increases in the osmotic layer and "pushes" against the drug layer, resulting in the release of drug through a small, laser-drilled orifice
in the membrane on the drug side of the tablet.
The GLUCOTROL XL Extended Release Tablet is designed to provide a controlled rate of delivery of glipizide into the
gastrointestinal lumen which is independent of pH or gastrointestinal motility. The function of the GLUCOTROL XL Extended
Release Tablet depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI
tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. The
biologically inert components of the tablet remain intact during GI transit and are eliminated in the feces as an insoluble shell.
CLINICAL PHARMACOLOGY
Mechanism of Action
Glipizide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent
upon functioning beta cells in the pancreatic islets. Extrapancreatic effects also may play a part in the mechanism of action of oral
sulfonylurea hypoglycemic drugs. Two extrapancreatic effects shown to be important in the action of glipizide are an increase in
insulin sensitivity and a decrease in hepatic glucose production. However, the mechanism by which glipizide lowers blood glucose
during long-term administration has not been clearly established. Stimulation of insulin secretion by glipizide in response to a meal is
of major importance. The insulinotropic response to a meal is enhanced with GLUCOTROL XL administration in diabetic patients.
The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In 2 randomized,
double-blind, dose-response studies comprising a total of 347 patients, there was no significant increase in fasting insulin in all
GLUCOTROL XL-treated patients combined compared to placebo, although minor elevations were observed at some doses. There
was no increase in fasting insulin over the long term.
Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively,
glipizide may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas.
Effects on Blood Glucose
The effectiveness of GLUCOTROL XL Extended Release Tablets in type 2 diabetes at doses from 5–60 mg once daily has
been evaluated in 4 therapeutic clinical trials each with long-term open extensions involving a total of 598 patients. Once daily
administration of 5, 10 and 20 mg produced statistically significant reductions from placebo in hemoglobin A1C, fasting plasma
glucose and postprandial glucose in patients with mild to severe type 2 diabetes. In a pooled analysis of the patients treated with 5 mg
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and 20 mg, the relationship between dose and GLUCOTROL XL's effect of reducing hemoglobin A1C was not established. However,
in the case of fasting plasma glucose patients treated with 20 mg had a statistically significant reduction of fasting plasma glucose
compared to the 5 mg-treated group.
The reductions in hemoglobin A1C and fasting plasma glucose were similar in younger and older patients. Efficacy of GLUCOTROL
XL was not affected by gender, race or weight (as assessed by body mass index). In long term extension trials, efficacy of
GLUCOTROL XL was maintained in 81% of patients for up to 12 months.
In an open, two-way crossover study 132 patients were randomly assigned to either GLUCOTROL XL or Glucotrol® for 8 weeks and
then crossed over to the other drug for an additional 8 weeks. GLUCOTROL XL administration resulted in significantly lower fasting
plasma glucose levels and equivalent hemoglobin A1C levels, as compared to Glucotrol.
In 12 week, well-controlled studies there was a maximal average net reduction in hemoglobin A1c of 1.7% in absolute units between
placebo-treated and GLUCOTROL XL-treated patients.
Other Effects
It has been shown that GLUCOTROL XL therapy is effective in controlling blood glucose without deleterious changes in the plasma
lipoprotein profiles of patients treated for type 2 diabetes.
In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity, and, in fact, led to a slight increase
in free water clearance.
Pharmacokinetics and Metabolism
Glipizide is rapidly and completely absorbed following oral administration in an immediate release dosage form. The absolute
bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes. Beginning 2 to 3 hours after
administration of GLUCOTROL XL Extended Release Tablets, plasma drug concentrations gradually rise reaching maximum
concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of GLUCOTROL XL Extended Release Tablets,
effective plasma glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to trough fluctuation
than that observed with twice daily dosing of immediate release glipizide. The mean relative bioavailability of glipizide in 21 males
with type 2 diabetes after administration of 20 mg GLUCOTROL XL Extended Release Tablets, compared to immediate release
Glucotrol (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth
day of dosing with GLUCOTROL XL Extended Release Tablets in 21 males with type 2 diabetes and patients younger than 65 years.
Approximately 1 to 2 days longer were required to reach steady-state in 24 elderly (≥65 years) males and females with type 2 diabetes.
No accumulation of drug was observed in patients with type 2 diabetes during chronic dosing with GLUCOTROL XL Extended
Release Tablets. Administration of GLUCOTROL XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a
single dose, food effect study in 21 healthy male subjects, the administration of GLUCOTROL XL immediately before a high fat
breakfast resulted in a 40% increase in the glipizide mean Cmax value, which was significant, but the effect on the AUC was not
significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the
GLUCOTROL XL tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug
and potentially result in lower plasma concentrations. In a multiple dose study in 26 males with type 2 diabetes, the pharmacokinetics
of glipizide were linear over the dose range of 5 to 60 mg of GLUCOTROL XL in that the plasma drug concentrations increased
proportionately with dose. In a single dose study in 24 healthy subjects, four 5 mg, two 10 mg, and one 20 mg GLUCOTROL XL
Extended Release Tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg GLUCOTROL XL
Extended Release Tablets were bioequivalent to one 10-mg GLUCOTROL XL Extended Release Tablet.
Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and
feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%). The major metabolites
of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts for less
than 2% of a dose, an acetylamino-ethyl benzene derivative, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the
parent compound. The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in
patients with type 2 diabetes. The mean apparent volume of distribution was approximately 10 liters. Glipizide is 98–99% bound to
serum proteins, primarily to albumin. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or
multiple doses in patients with type 2 diabetes. There were no significant differences in the pharmacokinetics of glipizide after single
dose administration to older diabetic subjects compared to younger healthy subjects. There is only limited information regarding the
effects of renal impairment on the disposition of glipizide, and no information regarding the effects of hepatic disease. However, since
glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or
pharmacodynamics of glipizide may be altered in patients with renal or hepatic impairment.
In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the
fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given
labelled drug.
INDICATIONS AND USAGE
GLUCOTROL XL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
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CONTRAINDICATIONS
Glipizide is contraindicated in patients with:
1.
Known hypersensitivity to glipizide or any excipients in the GITS tablets.
2.
Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
WARNINGS
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality
as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University
Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-
lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes. The study involved 823
patients who were randomly assigned to one of four treatment groups (Diabetes, 19, SUPP. 2: 747–830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had
a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase
in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular
mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding
the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient
should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety
standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close
similarities in mode of action and chemical structure.
As with any other non-deformable material, caution should be used when administering GLUCOTROL XL Extended Release Tablets
in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive
symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable sustained release
formulation.
PRECAUTIONS
General
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOTROL XL or any
other anti-diabetic drug.
Renal and Hepatic Disease
The pharmacokinetics and/or pharmacodynamics of glipizide may be affected in patients with impaired renal or hepatic function. If
hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted.
GI Disease
Markedly reduced GI retention times of the GLUCOTROL XL Extended Release Tablets may influence the pharmacokinetic profile
and hence the clinical efficacy of the drug.
Hypoglycemia
All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important
to avoid hypoglycemic episodes. Renal or hepatic insufficiency may affect the disposition of glipizide and the latter may also diminish
gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished
patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering
drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested,
or when more than one glucose-lowering drug is used. Therapy with a combination of glucose-lowering agents may increase the
potential for hypoglycemia.
Loss of Control of Blood Glucose
When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control
may occur. At such times, it may be necessary to discontinue glipizide and administer insulin.
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The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many
patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the
drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an
individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient
as a secondary failure.
Laboratory Tests
Blood and urine glucose should be monitored periodically. Measurement of hemoglobin A1C may be useful.
Information for Patients
Patients should be informed that GLUCOTROL XL Extended Release Tablets should be swallowed whole. Patients should not chew,
divide or crush tablets. Patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
In the GLUCOTROL XL Extended Release Tablet, the medication is contained within a nonabsorbable shell that has been specially
designed to slowly release the drug so the body can absorb it. When this process is completed, the empty tablet is eliminated from the
body.
Patients should be informed of the potential risks and advantages of GLUCOTROL XL and of alternative modes of therapy. They
should also be informed about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing
of urine and/or blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to
patients and responsible family members. Primary and secondary failure also should be explained.
Physician Counseling Information for Patients
In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight
loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose
and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors
should be identified and corrective measures taken where possible. Use of GLUCOTROL XL or other antidiabetic medications must
be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism
for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term
administration of GLUCOTROL XL or other antidiabetic medications. Maintenance or discontinuation of GLUCOTROL XL or other
antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.
Drug Interactions
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and
other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase
inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving glipizide, the patient should
be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide, the patient should be
observed closely for loss of control. In vitro binding studies with human serum proteins indicate that glipizide binds differently than
tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to
the clinical situation and in the use of glipizide with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics,
corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium
channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide, the patient should be closely
observed for loss of control. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely
for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported.
Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of
concomitant administration of Diflucan® (fluconazole) and Glucotrol has been demonstrated in a placebo-controlled crossover study
in normal volunteers. All subjects received Glucotrol alone and following treatment with 100 mg of Diflucan® as a single daily oral
dose for 7 days. The mean percentage increase in the Glucotrol AUC after fluconazole administration was 56.9% (range: 35 to 81%).
Carcinogenesis, Mutagenesis, Impairment of Fertility
A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum human dose revealed no
evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both
sexes at doses up to 75 times the human dose showed no effects on fertility.
Pregnancy
Pregnancy Category C
Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5–50 mg/kg). This fetotoxicity has been
similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related
to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits no teratogenic effects were found. There are
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no adequate and well controlled studies in pregnant women. Glipizide should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Because recent information suggests that abnormal blood-glucose levels during pregnancy are associated with a higher incidence of
congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood-glucose levels as close to
normal as possible.
Nonteratogenic Effects
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug
at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glipizide is used
during pregnancy, it should be discontinued at least one month before the expected delivery date.
Nursing Mothers
Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human
milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued and if diet alone is
inadequate for controlling blood glucose, insulin therapy should be considered.
Pediatric Use
Safety and effectiveness in children have not been established.
Geriatric Use
Of the total number of patients in clinical studies of GLUCOTROL XL, 33 percent were 65 and over. Approximately 1–2 days longer
were required to reach steady-state in the elderly. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
There were no overall differences in effectiveness or safety between younger and older patients, but greater sensitivity of some
individuals cannot be ruled out. As such, it should be noted that elderly, debilitated or malnourished patients, and those with adrenal
or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be
difficult to recognize in the elderly. In addition, in elderly, debilitated or malnourished patients, and patients with impaired renal or
hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.
ADVERSE REACTIONS
In U.S. controlled studies the frequency of serious adverse experiences reported was very low and causal relationship has not been
established.
The 580 patients from 31 to 87 years of age who received GLUCOTROL XL Extended Release Tablets in doses from 5 mg to 60
mg in both controlled and open trials were included in the evaluation of adverse experiences. All adverse experiences reported were
tabulated independently of their possible causal relation to medication.
Hypoglycemia
See PRECAUTIONS and OVERDOSAGE sections.
Only 3.4% of patients receiving GLUCOTROL XL Extended Release Tablets had hypoglycemia documented by a blood-glucose
measurement <60 mg/dL and/or symptoms believed to be associated with hypoglycemia. In a comparative efficacy study of
GLUCOTROL XL and Glucotrol, hypoglycemia occurred rarely with an incidence of less than 1% with both drugs.
In double-blind, placebo-controlled studies the adverse experiences reported with an incidence of 3% or more in GLUCOTROL XL-
treated patients include:
GLUCOTROL XL (%)
Placebo (%)
(N=278)
(N=69)
Adverse Effect
Asthenia
10.1
13.0
Headache
8.6
8.7
Dizziness
6.8
5.8
Nervousness
3.6
2.9
Tremor
3.6
0.0
Diarrhea
5.4
0.0
Flatulence
3.2
1.4
The following adverse experiences occurred with an incidence of less than 3% in GLUCOTROL XL-treated patients:
Body as a whole–pain
Nervous system–insomnia, paresthesia, anxiety, depression and hypesthesia
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Gastrointestinal–nausea, dyspepsia, constipation and vomiting
Metabolic–hypoglycemia
Musculoskeletal–arthralgia, leg cramps and myalgia
Cardiovascular–syncope
Skin–sweating and pruritus
Respiratory–rhinitis
Special senses–blurred vision
Urogenital–polyuria
Other adverse experiences occurred with an incidence of less than 1% in GLUCOTROL XL-treated patients:
Body as a whole–chills
Nervous system–hypertonia, confusion, vertigo, somnolence, gait abnormality and decreased libido
Gastrointestinal–anorexia and trace blood in stool
Metabolic–thirst and edema
Cardiovascular–arrhythmia, migraine, flushing and hypertension
Skin–rash and urticaria
Respiratory–pharyngitis and dyspnea
Special senses–pain in the eye, conjunctivitis and retinal hemorrhage
Urogenital–dysuria
Although these adverse experiences occurred in patients treated with GLUCOTROL XL, a causal relationship to the medication has
not been established in all cases.
There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable
sustained release formulation, although causal relationship to the drug is uncertain.
In post-marketing experience of GLUCOTROL XL, the additional adverse reaction of abdominal pain has been reported.
The following are adverse experiences reported with immediate release glipizide and other sulfonylureas, but have not been observed
with GLUCOTROL XL:
Hematologic
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with
sulfonylureas.
Metabolic
Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. In the mouse, glipizide pretreatment did
not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide has an
extremely low incidence of disulfiram-like alcohol reactions.
Endocrine Reactions
Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with glipizide
and other sulfonylureas.
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Laboratory Tests
The pattern of laboratory test abnormalities observed with glipizide was similar to that for other sulfonylureas. Occasional mild to
moderate elevations of SGOT, LDH, alkaline phosphatase, BUN and creatinine were noted. One case of jaundice was reported. The
relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated with clinical symptoms.
OVERDOSAGE
There is no well-documented experience with GLUCOTROL XL overdosage in humans. There have been no known suicide
attempts associated with purposeful overdosing with GLUCOTROL XL. In nonclinical studies the acute oral toxicity of glipizide
was extremely low in all species tested (LD50 greater than 4 g/kg). Overdosage of sulfonylureas including glipizide can produce
hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with
oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that
the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently,
but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient
should be given rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion
of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should
be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of
glipizide from plasma may be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is
unlikely to be of benefit.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with GLUCOTROL XL Extended Release Tablet or any
other hypoglycemic agent. Glycemic control should be monitored with hemoglobin A1C and/or blood-glucose levels to determine
the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum
recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after
an initial period of effectiveness. Home blood-glucose monitoring may also provide useful information to the patient and physician.
Short-term administration of GLUCOTROL XL Extended Release Tablet may be sufficient during periods of transient loss of control
in patients usually controlled on diet.
In general, GLUCOTROL XL should be given with breakfast.
Recommended Dosing
The usual starting dose of GLUCOTROL XL as initial therapy is 5 mg per day, given with breakfast. Those patients who may be more
sensitive to hypoglycemic drugs may be started at a lower dose.
Dosage adjustment should be based on laboratory measures of glycemic control. While fasting blood-glucose levels generally reach
steady-state following initiation or change in GLUCOTROL XL dosage, a single fasting glucose determination may not accurately
reflect the response to therapy. In most cases, hemoglobin A1C level measured at three month intervals is the preferred means of
monitoring response to therapy.
Hemoglobin A1C should be measured as GLUCOTROL XL therapy is initiated and repeated approximately three months later. If the
result of this test suggests that glycemic control over the preceding three months was inadequate, the GLUCOTROL XL dose may be
increased. Subsequent dosage adjustments should be made on the basis of hemoglobin A1C levels measured at three month intervals.
If no improvement is seen after three months of therapy with a higher dose, the previous dose should be resumed. Decisions which
utilize fasting blood glucose to adjust GLUCOTROL XL therapy should be based on at least two or more similar, consecutive values
obtained seven days or more after the previous dose adjustment.
Most patients will be controlled with 5 mg to 10 mg taken once daily. However, some patients may require up to the maximum
recommended daily dose of 20 mg. While the glycemic control of selected patients may improve with doses which exceed 10 mg,
clinical studies conducted to date have not demonstrated an additional group average reduction of hemoglobin A1C beyond what was
achieved with the 10 mg dose.
Based on the results of a randomized crossover study, patients receiving immediate release glipizide may be switched safely to
GLUCOTROL XL Extended Release Tablets once-a-day at the nearest equivalent total daily dose. Patients receiving immediate
release Glucotrol also may be titrated to the appropriate dose of GLUCOTROL XL starting with 5 mg once daily. The decision to
switch to the nearest equivalent dose or to titrate should be based on clinical judgment.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and
maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section).
Combination Use
When adding other blood-glucose-lowering agents to GLUCOTROL XL for combination therapy, the agent should be initiated at the
lowest recommended dose, and patients should be observed carefully for hypoglycemia. Refer to the product information supplied
with the oral agent for additional information.
When adding GLUCOTROL XL to other blood-glucose-lowering agents, GLUCOTROL XL can be initiated at 5 mg. Those patients
who may be more sensitive to hypoglycemic drugs may be started at a lower dose. Titration should be based on clinical judgment.
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Patients Receiving Insulin
As with other sulfonylurea-class hypoglycemics, many patients with stable type 2 diabetes receiving insulin may be transferred safely
to treatment with GLUCOTROL XL Extended Release Tablets. When transferring patients from insulin to GLUCOTROL XL, the
following general guidelines should be considered:
For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and GLUCOTROL XL therapy may
begin at usual dosages. Several days should elapse between titration steps.
For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and GLUCOTROL
XL therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response.
Several days should elapse between titration steps.
During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily.
Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when the
patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition
period.
Patients Receiving Other Oral Hypoglycemic Agents
As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to GLUCOTROL XL
Extended Release Tablets. Patients should be observed carefully (1–2 weeks) for hypoglycemia when being transferred from longer
half-life sulfonylureas (e.g., chlorpropamide) to GLUCOTROL XL due to potential overlapping of drug effect.
HOW SUPPLIED
GLUCOTROL XL (glipizide) Extended Release Tablets are supplied as 2.5 mg, 5 mg, and 10 mg round, biconvex tablets and
imprinted with black ink as follows:
2.5 mg tablets are blue and imprinted with "GLUCOTROL XL 2.5" on one side.
Bottles of 30: NDC 0049-1620-30
5 mg tablets are white and imprinted with "GLUCOTROL XL 5" on one side.
Bottles of 100: NDC 0049-1550-66
Bottles of 500: NDC 0049-1550-73
10 mg tablets are white and imprinted with "GLUCOTROL XL 10" on one side.
Bottles of 100: NDC 0049-1560-66
Bottles of 500: NDC 0049-1560-73
Recommended Storage
The tablets should be protected from moisture and humidity and stored at controlled room temperature, 59° to 86°F (15° to 30°C).
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LAB-0113-4.4
September 2008
PATIENT INFORMATION
GLUCOTROL XL
(glipizide) extended release tablets
Read this information carefully before you start taking this medicine. Read the information you get with your medicine each time you
refill your prescription. There may be new information. This information does not take the place of your healthcare provider's advice.
Ask your healthcare provider or pharmacist if you do not understand some of this information or if you want to know more about this
medicine.
What is GLUCOTROL XL?
GLUCOTROL XL (glue-kuh-troll-ex-el) is a medicine you take by mouth. It is used to treat type 2 diabetes (also called non-insulin
dependant diabetes mellitus). Your healthcare provider has prescribed GLUCOTROL XL because your current treatment, including
diet and exercise, has not been able to bring your blood sugar level under good control.
Your body makes insulin to keep the amount of sugar (glucose) in your blood at the right level. With type 2 diabetes:
•
your body may not be making enough insulin
•
your body may not be using the insulin that you have already made
•
the level of sugar in your blood is too high
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If your blood sugar level is not under control, it can lead to serious medical problems, such as kidney damage, nerve damage,
blindness, problems with circulation (blood movement in your body), loss of feet, legs or other limbs, high blood pressure, heart
attack, or stroke.
GLUCOTROL XL works mainly by:
•
helping the body release more of its own insulin
•
helping the body respond better to its own insulin
•
lowering the amount of sugar (glucose) made by the body
Even after you start taking GLUCOTROL XL, you must continue to follow your program of diet and exercise.
Who Should Not Use GLUCOTROL XL?
Do not use GLUCOTROL XL if you:
•
have a condition called diabetic ketoacidosis
•
have ever had an allergic reaction to glipizide or any of the other ingredients in GLUCOTROL XL. Ask your healthcare provider
or pharmacist for a list of these ingredients.
Only your healthcare provider can decide if GLUCOTROL XL is right for you. Before you start GLUCOTROL XL, tell the healthcare
provider if you:
•
are taking or using any prescription medicines or non-prescription medicines, including natural or herbal remedies. Other
medications can increase your chance of getting low blood sugar or high blood sugar. Be sure to tell your healthcare provider if
you take the medicines miconazole or fluconazole, used to fight fungus infections.
•
have ever had a condition called diabetic ketoacidosis
•
have kidney or liver problems
•
have had blockage or narrowing of your intestines due to illness or past surgery
•
have chronic (continuing) diarrhea
•
are pregnant or might be pregnant. Your healthcare provider may switch you to insulin injections some time during your
pregnancy. You should not take GLUCOTROL XL during the last month of pregnancy.
•
are breast-feeding. GLUCOTROL XL may pass to the baby through your milk and cause harm.
How Should I Take GLUCOTROL XL?
GLUCOTROL XL tablets come in three different strengths (2.5 mg, 5 mg and 10 mg). Your healthcare provider will prescribe the
dose that is right for you.
•
Take GLUCOTROL XL once a day with breakfast. The tablet is designed to release the medicine slowly over 24 hours. This is
why you have to take it only once a day.
•
Swallow the tablet whole. Never chew, crush or cut the tablet in half. This would damage the tablet and release too much
medicine into your body at one time.
•
After all of the medicine has been released, the empty tablet shell will pass out of the body normally in a bowel movement. Do
not be concerned if you see the empty tablet shell in your stool (bowel movement).
It is important to take GLUCOTROL XL every day to help keep your blood sugar level under good control. Your healthcare provider
may adjust your dose depending on your blood glucose test results. If your blood sugar level is not under control, call your healthcare
provider. Do not change your dose without your healthcare provider's approval.
In case of overdose, call the poison control center or your healthcare provider right away, or have someone drive you to the nearest
emergency room.
You must continue your diet and exercise program while taking GLUCOTROL XL. You must also have your blood and urine tested
regularly to be sure GLUCOTROL XL is working.
GLUCOTROL XL may not work for everyone. If it does work, you may find that GLUCOTROL XL is not working as well for you
after you have used it for a while. Tell your healthcare provider if GLUCOTROL XL is not working well.
What Should I Avoid While Taking GLUCOTROL XL?
Some medicines can affect how well GLUCOTROL XL works or may affect your blood sugar level. Check with your healthcare
provider or pharmacist before you start or stop taking prescription or over-the-counter medicines, including natural/herbal remedies,
while on GLUCOTROL XL.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the Possible Side Effects of GLUCOTROL XL?
Low blood sugar. GLUCOTROL XL may lower your blood sugar to low levels that are dangerous (hypoglycemia). This can happen
if you do not follow your diet, exercise too much, drink alcohol, are under stress, or get sick. This could also happen if your dose of
GLUCOTROL XL is higher than you need. Your healthcare provider may need to adjust it. Do not adjust the dose on your own.
Be sure you know how to recognize your body's signs that your blood sugar is too low. These signs include:
•
a cold clammy feeling
•
unusual sweating
•
dizziness
•
weakness
•
trembling
•
shakiness
•
hunger
•
fast heartbeat
•
headache
•
blurred vision
•
slurred speech
•
tingling in the lips or hands
If you notice any of these signs, eat or drink something with sugar in it right away, such as a regular (not diet) soft drink, orange juice,
honey, sugar candy. You can also keep glucose tablets on hand that are available at your pharmacy. If you do not feel better shortly
or your blood sugar level does not go up, call your healthcare provider. If you cannot reach your healthcare provider in an emergency,
call 911 or have someone drive you to the nearest emergency room.
Other side effects. GLUCOTROL XL may cause other side effects in some people. However, the incidence of serious side effects
with GLUCOTROL XL is very low. Other than the signs of low blood sugar listed above, possible side effects include:
•
feeling jittery
•
diarrhea
•
gas
GLUCOTROL XL may cause other less common side effects besides those listed here. For a list of all side effects that have been
reported, ask your healthcare provider or pharmacist.
While it has never been reported with GLUCOTROL XL, another similar type of diabetes medicine has been linked to a higher risk of
heart attacks. If you have risk factors for heart disease and take GLUCOTROL XL, be sure to see your healthcare provider for regular
checkups.
How To Store GLUCOTROL XL
Keep GLUCOTROL XL and all medicines out of reach of children. Store GLUCOTROL XL in a dry place, in its original container,
and at room temperature (between 59°–86° F or 15°–30° C).
General Advice About Prescription Medicines
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. If you have any concerns
about GLUCOTROL XL, ask your healthcare provider. Your healthcare provider or pharmacist can give you information about
GLUCOTROL XL that was written for healthcare professionals. Do not use GLUCOTROL XL for a condition for which it was not
prescribed. Do not share GLUCOTROL XL with other people. For more information about GLUCOTROL XL, you can visit the
Pfizer internet site at www.pfizer.com. logo
LAB-0115-2.0
September 2006
Revised: 09/2008
Distributed by: Roerig
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:47:27.861834
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020329s22lbl.pdf', 'application_number': 20329, 'submission_type': 'SUPPL ', 'submission_number': 22}
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NDA 20-329/S-002
Page 3
GLUCOTROL XL®
(glipizide)
Extended Release Tablets
For Oral Use
Rx only
DESCRIPTION
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-
methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea. The molecular formula is C21H27N5O4S; the
molecular weight is 445.55; the structural formula is shown below:
N
N
H3C
CONHCH2CH2
SO2NHCONH
Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but
soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. GLUCOTROL XL® is a
registered trademark for glipizide GITS. Glipizide GITS (Gastrointestinal Therapeutic System) is
formulated as a once-a-day controlled release tablet for oral use and is designed to deliver 2.5, 5, or
10 mg of glipizide.
Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: polyethylene oxide,
hydroxypropyl methylcellulose, magnesium stearate, sodium chloride, red ferric oxide, cellulose
acetate, polyethylene glycol, opadry blue (OY-LS-20921)(2.5 mg tablets), opadry white
(YS-2-7063)(5 mg and 10 mg tablet) and black ink (S-1-8106).
System Components and Performance
GLUCOTROL XL Extended Release Tablet is similar in appearance to a conventional tablet. It
consists, however, of an osmotically active drug core surrounded by a semipermeable membrane.
The core itself is divided into two layers: an “active” layer containing the drug, and a “push” layer
containing pharmacologically inert (but osmotically active) components. The membrane surrounding
the tablet is permeable to water but not to drug or osmotic excipients. As water from the
gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against
the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane
on the drug side of the tablet.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-329/S-002
Page 4
The GLUCOTROL XL Extended Release Tablet is designed to provide a controlled rate of delivery
of glipizide into the gastrointestinal lumen which is independent of pH or gastrointestinal motility.
The function of the GLUCOTROL XL Extended Release Tablet depends upon the existence of an
osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. Drug delivery is
essentially constant as long as the osmotic gradient remains constant, and then gradually falls to
zero. The biologically inert components of the tablet remain intact during GI transit and are
eliminated in the feces as an insoluble shell.
CLINICAL PHARMACOLOGY
Mechanism of Action: Glipizide appears to lower blood glucose acutely by stimulating the release
of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets.
Extrapancreatic effects also may play a part in the mechanism of action of oral sulfonylurea
hypoglycemic drugs. Two extrapancreatic effects shown to be important in the action of glipizide are
an increase in insulin sensitivity and a decrease in hepatic glucose production. However, the
mechanism by which glipizide lowers blood glucose during long-term administration has not been
clearly established. Stimulation of insulin secretion by glipizide in response to a meal is of major
importance. The insulinotropic response to a meal is enhanced with GLUCOTROL XL
administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be
enhanced after at least 6 months of treatment. In 2 randomized, double-blind, dose-response studies
comprising a total of 347 patients, there was no significant increase in fasting insulin in all
GLUCOTROL XL-treated patients combined compared to placebo, although minor elevations were
observed at some doses. There was no increase in fasting insulin over the long term.
Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs,
including glipizide. Alternatively, glipizide may be effective in some patients who have not
responded or have ceased to respond to other sulfonylureas.
Effects on Blood Glucose
The effectiveness of GLUCOTROL XL Extended Release Tablets in type 2 diabetes at doses from
5-60 mg once daily has been evaluated in 4 therapeutic clinical trials each with long-term open
extensions involving a total of 598 patients. Once daily administration of 5, 10 and 20 mg produced
statistically significant reductions from placebo in hemoglobin A1C, fasting plasma glucose and
postprandial glucose in patients with mild to severe type 2 diabetes. In a pooled analysis of the
patients treated with 5 mg and 20 mg, the relationship between dose and GLUCOTROL XL’s effect
of reducing hemoglobin A1C was not established. However, in the case of fasting plasma glucose
patients treated with 20 mg had a statistically significant reduction of fasting plasma glucose
compared to the 5 mg-treated group.
The reductions in hemoglobin A1C and fasting plasma glucose were similar in younger and older
patients. Efficacy of GLUCOTROL XL was not affected by gender, race or weight (as assessed by
body mass index). In long term extension trials, efficacy of GLUCOTROL XL was maintained in
81% of patients for up to 12 months.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-329/S-002
Page 5
In an open, two-way crossover study 132 patients were randomly assigned to either GLUCOTROL
XL or Glucotrol® for 8 weeks and then crossed over to the other drug for an additional 8 weeks.
GLUCOTROL XL administration resulted in significantly lower fasting plasma glucose levels and
equivalent hemoglobin A1C levels, as compared to Glucotrol.
Other Effects: It has been shown that GLUCOTROL XL therapy is effective in controlling blood
glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for type 2
diabetes.
In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity,
and, in fact, led to a slight increase in free water clearance.
Pharmacokinetics and Metabolism: Glipizide is rapidly and completely absorbed following oral
administration in an immediate release dosage form. The absolute bioavailability of glipizide was
100% after single oral doses in patients with type 2 diabetes. Beginning 2 to 3 hours after
administration of GLUCOTROL XL Extended Release Tablets, plasma drug concentrations
gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent
once daily dosing of GLUCOTROL XL Extended Release Tablets, effective plasma glipizide
concentrations are maintained throughout the 24 hour dosing interval with less peak to trough
fluctuation than that observed with twice daily dosing of immediate release glipizide. The mean
relative bioavailability of glipizide in 21 males with type 2 diabetes after administration of 20 mg
GLUCOTROL XL Extended Release Tablets, compared to immediate release Glucotrol (10 mg
given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at
least the fifth day of dosing with GLUCOTROL XL Extended Release Tablets in 21 males with
type 2 diabetes and patients younger than 65 years. Approximately 1 to 2 days longer were required
to reach steady-state in 24 elderly (≥65 years) males and females with type 2 diabetes. No
accumulation of drug was observed in patients with type 2 diabetes during chronic dosing with
GLUCOTROL XL Extended Release Tablets. Administration of GLUCOTROL XL with food has
no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food effect study in 21
healthy male subjects, the administration of GLUCOTROL XL immediately before a high fat
breakfast resulted in a 40% increase in the glipizide mean Cmax value, which was significant, but
the effect on the AUC was not significant. There was no change in glucose response between the fed
and fasting state. Markedly reduced GI retention times of the GLUCOTROL XL tablets over
prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the
drug and potentially result in lower plasma concentrations. In a multiple dose study in 26 males with
type 2 diabetes, the pharmacokinetics of glipizide were linear over the dose range of 5 to 60 mg of
GLUCOTROL XL in that the plasma drug concentrations increased proportionately with dose. In a
single dose study in 24 healthy subjects, four 5 mg, two 10 mg, and one 20 mg GLUCOTROL XL
Extended Release Tablets were bioequivalent. In a separate single dose study in 36 healthy subjects,
four 2.5-mg GLUCOTROL XL Extended Release Tablets were bioequivalent to one 10-mg
GLUCOTROL XL Extended Release Tablet.
Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as
unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation
products in urine (80%) and feces (10%). The major metabolites of glipizide are products of
aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts for
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-329/S-002
Page 6
less than 2% of a dose, an acetylamino-ethyl benzene derivative, is reported to have 1/10 to 1/3 as
much hypoglycemic activity as the parent compound. The mean total body clearance of glipizide was
approximately 3 liters per hour after single intravenous doses in patients with type 2 diabetes. The
mean apparent volume of distribution was approximately 10 liters. Glipizide is 98-99% bound to
serum proteins, primarily to albumin. The mean terminal elimination half-life of glipizide ranged
from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes. There were no
significant differences in the pharmacokinetics of glipizide after single dose administration to older
diabetic subjects compared to younger healthy subjects. There is only limited information regarding
the effects of renal impairment on the disposition of glipizide, and no information regarding the
effects of hepatic disease. However, since glipizide is highly protein bound and hepatic
biotransformation is the predominant route of elimination, the pharmacokinetics and/or
pharmacodynamics of glipizide may be altered in patients with renal or hepatic impairment.
In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord
of males or females, nor in the fetuses of pregnant females. In another study, however, very small
amounts of radioactivity were detected in the fetuses of rats given labelled drug.
INDICATIONS AND USAGE
GLUCOTROL XL is indicated as an adjunct to diet for the control of hyperglycemia and its
associated symptomatology in patients with type 2 diabetes formerly known as non-insulin-dependent
diabetes mellitus (NIDDM) or maturity-onset diabetes, after an adequate trial of dietary therapy has
proved unsatisfactory. GLUCOTROL XL is indicated when diet alone has been unsuccessful in
correcting hyperglycemia, but even after the introduction of the drug in the patient’s regimen,
dietary measures should continue to be considered as important. In 12 week, well-controlled studies
there was a maximal average net reduction in hemoglobin A1C of 1.7% in absolute units between
placebo-treated and GLUCOTROL XL-treated patients.
In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of
treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper
dietary management alone may be effective in controlling blood glucose and symptoms of
hyperglycemia. The importance of regular physical activity should also be stressed, cardiovascular
risk factors should be identified, and corrective measures taken where possible.
If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral
sulfonylurea should be considered. If additional reduction of symptoms and/or blood glucose is
required, the addition of insulin to the treatment regimen should be considered. Use of
GLUCOTROL XL must be viewed by both the physician and patient as a treatment in addition to
diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint.
Furthermore, loss of blood-glucose control on diet alone also may be transient, thus requiring only
short-term administration of glipizide.
Some patients fail to respond initially or gradually lose their responsiveness to sulfonylurea drugs,
including GLUCOTROL XL. In these cases, concomitant use of GLUCOTROL XL with other oral
blood-glucose-lowering agents can be considered. Other approaches that can be considered include
substitution of GLUCOTROL XL therapy with that of another oral blood-glucose-lowering agent or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-329/S-002
Page 7
insulin. GLUCOTROL XL should be discontinued if it no longer contributes to glucose lowering.
Judgment of response to therapy should be based on regular clinical and laboratory evaluations.
In considering the use of GLUCOTROL XL in asymptomatic patients, it should be recognized that
controlling blood glucose in type 2 diabetes has not been definitely established to be effective in
preventing the long-term cardiovascular or neural complications of diabetes. However, in
insulin-dependent diabetes mellitus controlling blood glucose has been effective in slowing the
progression of diabetic retinopathy, nephropathy, and neuropathy.
CONTRAINDICATIONS
Glipizide is contraindicated in patients with:
1. Known hypersensitivity to the drug.
2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
WARNINGS
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY: The
administration of oral hypoglycemic drugs has been reported to be associated with increased
cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This
warning is based on the study conducted by the University Group Diabetes Program (UGDP), a
long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering
drugs in preventing or delaying vascular complications in patients with type 2 diabetes. The
study involved 823 patients who were randomly assigned to one of four treatment groups
(Diabetes, 19, SUPP. 2: 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide
(1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of
patients treated with diet alone. A significant increase in total mortality was not observed, but
the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus
limiting the opportunity for the study to show an increase in overall mortality. Despite
controversy regarding the interpretation of these results, the findings of the UGDP study
provide an adequate basis for this warning. The patient should be informed of the potential
risks and advantages of glipizide and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is
prudent from a safety standpoint to consider that this warning may also apply to other oral
hypoglycemic drugs in this class, in view of their close similarities in mode of action and
chemical structure.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-329/S-002
Page 8
As with any other non-deformable material, caution should be used when administering
GLUCOTROL XL Extended Release Tablets in patients with preexisting severe gastrointestinal
narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in
patients with known strictures in association with the ingestion of another drug in this non-
deformable sustained release formulation.
PRECAUTIONS
General
Renal and Hepatic Disease: The pharmacokinetics and/or pharmacodynamics of glipizide may be
affected in patients with impaired renal or hepatic function. If hypoglycemia should occur in such
patients, it may be prolonged and appropriate management should be instituted.
GI Disease: Markedly reduced GI retention times of the GLUCOTROL XL Extended Release
Tablets may influence the pharmacokinetic profile and hence the clinical efficacy of the drug.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper
patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal or
hepatic insufficiency may affect the disposition of glipizide and the latter may also diminish
gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly,
debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are particularly
susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to
recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged
exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Therapy
with a combination of glucose-lowering agents may increase the potential for hypoglycemia.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to
stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it
may be necessary to discontinue glipizide and administer insulin.
The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a
desired level decreases in many patients over a period of time, which may be due to progression of
the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known
as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an
individual patient when first given. Adequate adjustment of dose and adherence to diet should be
assessed before classifying a patient as a secondary failure.
Laboratory Tests: Blood and urine glucose should be monitored periodically. Measurement of
hemoglobin A1C may be useful.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-329/S-002
Page 9
Information for Patients: Patients should be informed that GLUCOTROL XL Extended Release
Tablets should be swallowed whole. Patients should not chew, divide or crush tablets. Patients
should not be concerned if they occasionally notice in their stool something that looks like a tablet.
In the GLUCOTROL XL Extended Release Tablet, the medication is contained within a
nonabsorbable shell that has been specially designed to slowly release the drug so the body can
absorb it. When this process is completed, the empty tablet is eliminated from the body.
Patients should be informed of the potential risks and advantages of GLUCOTROL XL and of
alternative modes of therapy. They should also be informed about the importance of adhering to
dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood
glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its
development should be explained to patients and responsible family members. Primary and
secondary failure also should be explained.
Drug Interactions: The hypoglycemic action of sulfonylureas may be potentiated by certain drugs
including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound,
salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors,
and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving
glipizide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn
from a patient receiving glipizide, the patient should be observed closely for loss of control. In vitro
binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide
and does not interact with salicylate or dicumarol. However, caution must be exercised in
extrapolating these findings to the clinical situation and in the use of glipizide with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include
the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral
contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and
isoniazid. When such drugs are administered to a patient receiving glipizide, the patient should be
closely observed for loss of control. When such drugs are withdrawn from a patient receiving
glipizide, the patient should be observed closely for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical,
or vaginal preparations of miconazole is not known. The effect of concomitant administration of
Diflucan® (fluconazole) and Glucotrol has been demonstrated in a placebo-controlled crossover study
in normal volunteers. All subjects received Glucotrol alone and following treatment with 100 mg of
Diflucan® as a single daily oral dose for 7 days. The mean percentage increase in the Glucotrol AUC
after fluconazole administration was 56.9% (range: 35 to 81%).
Carcinogenesis, Mutagenesis, Impairment of Fertility: A twenty month study in rats and an
eighteen month study in mice at doses up to 75 times the maximum human dose revealed no evidence
of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative.
Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-329/S-002
Page 10
Pregnancy: Pregnancy Category C: Glipizide was found to be mildly fetotoxic in rat reproductive
studies at all dose levels (5-50 mg/kg). This fetotoxicity has been similarly noted with other
sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly
related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits no
teratogenic effects were found. There are no adequate and well controlled studies in pregnant
women. Glipizide should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Because recent information suggests that abnormal blood-glucose levels during pregnancy are
associated with a higher incidence of congenital abnormalities, many experts recommend that insulin
be used during pregnancy to maintain blood-glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has
been reported more frequently with the use of agents with prolonged half-lives. If glipizide is used
during pregnancy, it should be discontinued at least one month before the expected delivery date.
Nursing Mothers: Although it is not known whether glipizide is excreted in human milk, some
sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia
in nursing infants may exist, 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. If the drug is
discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be
considered.
Pediatric Use: Safety and effectiveness in children have not been established.
Geriatric Use: Of the total number of patients in clinical studies of GLUCOTROL XL, 33 percent
were 65 and over. Approximately 1-2 days longer were required to reach steady-state in the elderly.
(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) There were no
overall differences in effectiveness or safety between younger and older patients, but greater
sensitivity of some individuals cannot be ruled out. As such, it should be noted that elderly,
debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are
particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may
be difficult to recognize in the elderly. In addition, in elderly, debilitated or malnourished patients,
and patients with impaired renal or hepatic function, the initial and maintenance dosing should be
conservative to avoid hypoglycemic reactions.
ADVERSE REACTIONS
In U.S. controlled studies the frequency of serious adverse experiences reported was very low and
causal relationship has not been established.
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NDA 20-329/S-002
Page 11
The 580 patients from 31 to 87 years of age who received GLUCOTROL XL Extended Release
Tablets in doses from 5 mg to 60 mg in both controlled and open trials were included in the
evaluation of adverse experiences. All adverse experiences reported were tabulated independently of
their possible causal relation to medication.
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.
Only 3.4% of patients receiving GLUCOTROL XL Extended Release Tablets had hypoglycemia
documented by a blood-glucose measurement <60 mg/dL and/or symptoms believed to be
associated with hypoglycemia. In a comparative efficacy study of GLUCOTROL XL and Glucotrol,
hypoglycemia occurred rarely with an incidence of less than 1% with both drugs.
In double-blind, placebo-controlled studies the adverse experiences reported with an incidence of 3%
or more in GLUCOTROL XL-treated patients include:
GLUCOTROL XL (%)
Placebo (%)
(N=278)
(N=69)
Adverse Effect
Asthenia
10.1
13.0
Headache
8.6
8.7
Dizziness
6.8
5.8
Nervousness
3.6
2.9
Tremor
3.6
0.0
Diarrhea
5.4
0.0
Flatulence
3.2
1.4
The following adverse experiences occurred with an incidence of less than 3% in
GLUCOTROL XL-treated patients:
Body as a whole–pain
Nervous system–insomnia, paresthesia, anxiety, depression and hypesthesia
Gastrointestinal–nausea, dyspepsia, constipation and vomiting
Metabolic–hypoglycemia
Musculoskeletal–arthralgia, leg cramps and myalgia
Cardiovascular–syncope
Skin–sweating and pruritus
Respiratory–rhinitis
Special senses–blurred vision
Urogenital–polyuria
Other adverse experiences occurred with an incidence of less than 1% in GLUCOTROL XL-treated
patients:
Body as a whole–chills
Nervous system–hypertonia, confusion, vertigo, somnolence, gait abnormality and decreased
libido
Gastrointestinal–anorexia and trace blood in stool
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NDA 20-329/S-002
Page 12
Metabolic–thirst and edema
Cardiovascular–arrhythmia, migraine, flushing and hypertension
Skin–rash and urticaria
Respiratory–pharyngitis and dyspnea
Special senses–pain in the eye, conjunctivitis and retinal hemorrhage
Urogenital–dysuria
Although these adverse experiences occurred in patients treated with GLUCOTROL XL, a causal
relationship to the medication has not been established in all cases.
There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of
another drug in this non-deformable sustained release formulation, although causal relationship to the
drug is uncertain.
The following are adverse experiences reported with immediate release glipizide and other
sulfonylureas, but have not been observed with GLUCOTROL XL:
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia,
and pancytopenia have been reported with sulfonylureas.
Metabolic: Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.
In the mouse, glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol
administration. Clinical experience to date has shown that glipizide has an extremely low incidence
of disulfiram-like alcohol reactions.
Endocrine Reactions: Cases of hyponatremia and the syndrome of inappropriate antidiuretic
hormone (SIADH) secretion have been reported with glipizide and other sulfonylureas.
Laboratory Tests: The pattern of laboratory test abnormalities observed with glipizide was similar
to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH, alkaline
phosphatase, BUN and creatinine were noted. One case of jaundice was reported. The relationship of
these abnormalities to glipizide is uncertain, and they have rarely been associated with clinical
symptoms.
OVERDOSAGE
There is no well-documented experience with GLUCOTROL XL overdosage in humans. There have
been no known suicide attempts associated with purposeful overdosing with GLUCOTROL XL. In
nonclinical studies the acute oral toxicity of glipizide was extremely low in all species tested (LD50
greater than 4 g/kg). Overdosage of sulfonylureas including glipizide can produce hypoglycemia.
Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated
aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close
monitoring should continue until the physician is assured that the patient is out of danger. Severe
hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but
constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is
diagnosed or suspected, the patient should be given rapid intravenous injection of concentrated
(50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%)
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NDA 20-329/S-002
Page 13
glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients
should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after
apparent clinical recovery. Clearance of glipizide from plasma may be prolonged in persons with
liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of
benefit.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with GLUCOTROL XL
Extended Release Tablet or any other hypoglycemic agent. Glycemic control should be monitored
with hemoglobin A1C and/or blood-glucose levels to determine the minimum effective dose for the
patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum
recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate
blood-glucose-lowering response after an initial period of effectiveness. Home blood-glucose
monitoring may also provide useful information to the patient and physician. Short-term
administration of GLUCOTROL XL Extended Release Tablet may be sufficient during periods of
transient loss of control in patients usually controlled on diet.
In general, GLUCOTROL XL should be given with breakfast.
Recommended Dosing: The usual starting dose of GLUCOTROL XL as initial therapy is 5 mg per
day, given with breakfast. Those patients who may be more sensitive to hypoglycemic drugs may be
started at a lower dose.
Dosage adjustment should be based on laboratory measures of glycemic control. While fasting
blood-glucose levels generally reach steady-state following initiation or change in GLUCOTROL XL
dosage, a single fasting glucose determination may not accurately reflect the response to therapy. In
most cases, hemoglobin A1C level measured at three month intervals is the preferred means of
monitoring response to therapy.
Hemoglobin A1C should be measured as GLUCOTROL XL therapy is initiated and repeated
approximately three months later. If the result of this test suggests that glycemic control over the
preceding three months was inadequate, the GLUCOTROL XL dose may be increased. Subsequent
dosage adjustments should be made on the basis of hemoglobin A1C levels measured at three month
intervals. If no improvement is seen after three months of therapy with a higher dose, the previous
dose should be resumed. Decisions which utilize fasting blood glucose to adjust GLUCOTROL XL
therapy should be based on at least two or more similar, consecutive values obtained seven days or
more after the previous dose adjustment.
Most patients will be controlled with 5 mg to 10 mg taken once daily. However, some patients may
require up to the maximum recommended daily dose of 20 mg. While the glycemic control of
selected patients may improve with doses which exceed 10 mg, clinical studies conducted to date
have not demonstrated an additional group average reduction of hemoglobin A1C beyond what was
achieved with the 10 mg dose.
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NDA 20-329/S-002
Page 14
Based on the results of a randomized crossover study, patients receiving immediate release glipizide
may be switched safely to GLUCOTROL XL Extended Release Tablets once-a-day at the nearest
equivalent total daily dose. Patients receiving immediate release Glucotrol also may be titrated to the
appropriate dose of GLUCOTROL XL starting with 5 mg once daily. The decision to switch to the
nearest equivalent dose or to titrate should be based on clinical judgment.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic
function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions
(see PRECAUTIONS section).
Combination Use: When adding other blood-glucose-lowering agents to GLUCOTROL XL for
combination therapy, the agent should be initiated at the lowest recommended dose, and patients
should be observed carefully for hypoglycemia. Refer to the product information supplied with the
oral agent for additional information.
When adding GLUCOTROL XL to other blood-glucose-lowering agents, GLUCOTROL XL can be
initiated at 5 mg. Those patients who may be more sensitive to hypoglycemic drugs may be started at
a lower dose. Titration should be based on clinical judgment.
Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many patients with
stable type 2 diabetes receiving insulin may be transferred safely to treatment with GLUCOTROL
XL Extended Release Tablets. When transferring patients from insulin to GLUCOTROL XL, the
following general guidelines should be considered:
For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and
GLUCOTROL XL therapy may begin at usual dosages. Several days should elapse between titration
steps.
For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be
reduced by 50% and GLUCOTROL XL therapy may begin at usual dosages. Subsequent reductions
in insulin dosage should depend on individual patient response. Several days should elapse between
titration steps.
During the insulin withdrawal period, the patient should test urine samples for sugar and ketone
bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if
these tests are abnormal. In some cases, especially when the patient has been receiving greater than
40 units of insulin daily, it may be advisable to consider hospitalization during the transition period.
Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class
hypoglycemics, no transition period is necessary when transferring patients to GLUCOTROL XL
Extended Release Tablets. Patients should be observed carefully
(1-2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g.,
chlorpropamide) to GLUCOTROL XL due to potential overlapping of drug effect.
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NDA 20-329/S-002
Page 15
HOW SUPPLIED
GLUCOTROL XL® (glipizide) Extended Release Tablets are supplied as 2.5 mg, 5 mg, and 10 mg
round, biconvex tablets and imprinted with black ink as follows:
2.5 mg tablets are blue and imprinted with “GLUCOTROL XL 2.5” on one side.
Bottles of 30: NDC 0049-1620-30
5 mg tablets are white and imprinted with “GLUCOTROL XL 5” on one side.
Bottles of 100: NDC 0049-1550-66
Bottles of 500: NDC 0049-1550-73
10 mg tablets are white and imprinted with “GLUCOTROL XL 10” on one side.
Bottles of 100: NDC 0049-1560-66
Bottles of 500: NDC 0049-1560-73
Recommended Storage: The tablets should be protected from moisture and humidity and stored at
controlled room temperature, 59° to 86°F (15° to 30°C).
U.S. Pharmaceuticals
Pfizer Inc, NY, NY 10017
Printed in U.S.A.
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
David Orloff
4/1/02 05:14:48 PM
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:27.863453
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20329s2lbl.pdf', 'application_number': 20329, 'submission_type': 'SUPPL ', 'submission_number': 2}
|
12,450
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GLUCOTROL XL®
(glipizide)
Extended Release Tablets
For Oral Use
DESCRIPTION
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5
methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea. The molecular formula is
C21H27N5O4S; the molecular weight is 445.55; the structural formula is shown below:
st
ru
ctur
al formula
Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols,
but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. GLUCOTROL XL® is a
registered trademark for glipizide GITS. Glipizide GITS (Gastrointestinal Therapeutic System)
is formulated as a once-a-day controlled release tablet for oral use and is designed to deliver 2.5,
5, or 10 mg of glipizide.
Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: polyethylene oxide,
hypromellose, magnesium stearate, sodium chloride, red ferric oxide, cellulose acetate,
polyethylene glycol, Opadry® blue (OY-LS-20921)(2.5 mg tablets), Opadry® white
(YS-2-7063)(5 mg and 10 mg tablet) and black ink (S-1-8106).
System Components and Performance
GLUCOTROL XL Extended Release Tablet is similar in appearance to a conventional tablet. It
consists, however, of an osmotically active drug core surrounded by a semipermeable membrane.
The core itself is divided into two layers: an “active” layer containing the drug, and a “push”
layer containing pharmacologically inert (but osmotically active) components. The membrane
surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from
the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes”
against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the
membrane on the drug side of the tablet.
Reference ID: 2900397
1
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The GLUCOTROL XL Extended Release Tablet is designed to provide a controlled rate of
delivery of glipizide into the gastrointestinal lumen which is independent of pH or
gastrointestinal motility. The function of the GLUCOTROL XL Extended Release Tablet
depends upon the existence of an osmotic gradient between the contents of the bi-layer core and
fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains
constant, and then gradually falls to zero. The biologically inert components of the tablet remain
intact during GI transit and are eliminated in the feces as an insoluble shell.
CLINICAL PHARMACOLOGY
Mechanism of Action: Glipizide appears to lower blood glucose acutely by stimulating the
release of insulin from the pancreas, an effect dependent upon functioning beta cells in the
pancreatic islets. Extrapancreatic effects also may play a part in the mechanism of action of oral
sulfonylurea hypoglycemic drugs. Two extrapancreatic effects shown to be important in the
action of glipizide are an increase in insulin sensitivity and a decrease in hepatic glucose
production. However, the mechanism by which glipizide lowers blood glucose during long-term
administration has not been clearly established. Stimulation of insulin secretion by glipizide in
response to a meal is of major importance. The insulinotropic response to a meal is enhanced
with GLUCOTROL XL administration in diabetic patients. The postprandial insulin and
C-peptide responses continue to be enhanced after at least 6 months of treatment. In
2 randomized, double-blind, dose-response studies comprising a total of 347 patients, there was
no significant increase in fasting insulin in all GLUCOTROL XL-treated patients combined
compared to placebo, although minor elevations were observed at some doses. There was no
increase in fasting insulin over the long term.
Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea
drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have
not responded or have ceased to respond to other sulfonylureas.
Effects on Blood Glucose: The effectiveness of GLUCOTROL XL Extended Release Tablets in
type 2 diabetes at doses from 5–60 mg once daily has been evaluated in 4 therapeutic clinical
trials each with long-term open extensions involving a total of 598 patients. Once daily
administration of 5, 10 and 20 mg produced statistically significant reductions from placebo in
hemoglobin A1C, fasting plasma glucose and postprandial glucose in patients with mild to severe
type 2 diabetes. In a pooled analysis of the patients treated with 5 mg and 20 mg, the relationship
between dose and GLUCOTROL XL’s effect of reducing hemoglobin A1C was not established.
However, in the case of fasting plasma glucose, patients treated with 20 mg had a statistically
significant reduction of fasting plasma glucose compared to the 5 mg-treated group.
The reductions in hemoglobin A1C and fasting plasma glucose were similar in younger and older
patients. Efficacy of GLUCOTROL XL was not affected by gender, race or weight (as assessed
by body mass index). In long-term extension trials, efficacy of GLUCOTROL XL was
maintained in 81% of patients for up to 12 months.
In an open, two-way crossover study, 132 patients were randomly assigned to either
GLUCOTROL XL or Glucotrol® for 8 weeks and then crossed over to the other drug for an
Reference ID: 2900397
2
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additional 8 weeks. GLUCOTROL XL administration resulted in significantly lower fasting
plasma glucose levels and equivalent hemoglobin A1C levels, as compared to Glucotrol.
In 12 week, well-controlled studies, there was a maximal average net reduction in hemoglobin
A1C of 1.7% in absolute units between placebo-treated and GLUCOTROL XL-treated patients.
Other Effects: It has been shown that GLUCOTROL XL therapy is effective in controlling
blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated
for type 2 diabetes.
In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic
activity, and, in fact, led to a slight increase in free water clearance.
Pharmacokinetics and Metabolism: Glipizide is rapidly and completely absorbed following
oral administration in an immediate release dosage form. The absolute bioavailability of
glipizide was 100% after single oral doses in patients with type 2 diabetes. Beginning 2 to
3 hours after administration of GLUCOTROL XL Extended Release Tablets, plasma drug
concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after
dosing. With subsequent once daily dosing of GLUCOTROL XL Extended Release Tablets,
effective plasma glipizide concentrations are maintained throughout the 24 hour dosing interval
with less peak to trough fluctuation than that observed with twice daily dosing of immediate
release glipizide. The mean relative bioavailability of glipizide in 21 males with type 2 diabetes
after administration of 20 mg GLUCOTROL XL Extended Release Tablets, compared to
immediate release Glucotrol (10 mg given twice daily), was 90% at steady-state. Steady-state
plasma concentrations were achieved by at least the fifth day of dosing with GLUCOTROL XL
Extended Release Tablets in 21 males with type 2 diabetes and patients younger than 65 years.
Approximately 1 to 2 days longer were required to reach steady-state in 24 elderly (≥65 years)
males and females with type 2 diabetes. No accumulation of drug was observed in patients with
type 2 diabetes during chronic dosing with GLUCOTROL XL Extended Release Tablets.
Administration of GLUCOTROL XL with food has no effect on the 2 to 3 hour lag time in drug
absorption. In a single dose, food effect study in 21 healthy male subjects, the administration of
GLUCOTROL XL immediately before a high fat breakfast resulted in a 40% increase in the
glipizide mean Cmax value, which was significant, but the effect on the AUC was not
significant. There was no change in glucose response between the fed and fasting state.
Markedly reduced GI retention times of the GLUCOTROL XL tablets over prolonged periods
(e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and
potentially result in lower plasma concentrations. In a multiple dose study in 26 males with
type 2 diabetes, the pharmacokinetics of glipizide were linear over the dose range of 5 to 60 mg
of GLUCOTROL XL in that the plasma drug concentrations increased proportionately with
dose. In a single dose study in 24 healthy subjects, four 5-mg, two 10-mg, and one 20-mg
GLUCOTROL XL Extended Release Tablets were bioequivalent. In a separate single dose study
in 36 healthy subjects, four 2.5-mg GLUCOTROL XL Extended Release Tablets were
bioequivalent to one 10-mg GLUCOTROL XL Extended Release Tablet.
Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is
excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as
Reference ID: 2900397
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For current labeling information, please visit https://www.fda.gov/drugsatfda
biotransformation products in urine (80%) and feces (10%). The major metabolites of glipizide
are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite
which accounts for less than 2% of a dose, an acetylamino-ethyl benzene derivative, is reported
to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound. The mean total body
clearance of glipizide was approximately 3 liters per hour after single intravenous doses in
patients with type 2 diabetes. The mean apparent volume of distribution was approximately
10 liters. Glipizide is 98–99% bound to serum proteins, primarily to albumin. The mean terminal
elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in
patients with type 2 diabetes. There were no significant differences in the pharmacokinetics of
glipizide after single dose administration to older diabetic subjects compared to younger healthy
subjects. There is only limited information regarding the effects of renal impairment on the
disposition of glipizide, and no information regarding the effects of hepatic disease. However,
since glipizide is highly protein bound and hepatic biotransformation is the predominant route of
elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in
patients with renal or hepatic impairment.
In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal
cord of males or females, nor in the fetuses of pregnant females. In another study, however, very
small amounts of radioactivity were detected in the fetuses of rats given labelled drug.
INDICATIONS AND USAGE
GLUCOTROL XL is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus.
CONTRAINDICATIONS
Glipizide is contraindicated in patients with:
1. Known hypersensitivity to glipizide or any excipients in the GITS tablets.
2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition
should be treated with insulin.
WARNINGS
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY:
The administration of oral hypoglycemic drugs has been reported to be associated with
increased cardiovascular mortality as compared to treatment with diet alone or diet plus
insulin. This warning is based on the study conducted by the University Group Diabetes
Program (UGDP), a long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in
patients with type 2 diabetes. The study involved 823 patients who were randomly assigned
to one of four treatment groups (Diabetes, 19, SUPP. 2: 747–830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of
tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately
2½ times that of patients treated with diet alone. A significant increase in total mortality
Reference ID: 2900397
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For current labeling information, please visit https://www.fda.gov/drugsatfda
was not observed, but the use of tolbutamide was discontinued based on the increase in
cardiovascular mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these results, the
findings of the UGDP study provide an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of glipizide and of alternative modes of
therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study,
it is prudent from a safety standpoint to consider that this warning may also apply to other
oral hypoglycemic drugs in this class, in view of their close similarities in mode of action
and chemical structure.
As with any other non-deformable material, caution should be used when administering
GLUCOTROL XL Extended Release Tablets in patients with preexisting severe gastrointestinal
narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in
patients with known strictures in association with the ingestion of another drug in this non-
deformable sustained release formulation.
PRECAUTIONS
General
Macrovascular Outcomes: There have been no clinical studies establishing conclusive
evidence of macrovascular risk reduction with GLUCOTROL XL or any other anti-diabetic
drug.
Renal and Hepatic Disease: The pharmacokinetics and/or pharmacodynamics of glipizide may
be affected in patients with impaired renal or hepatic function. If hypoglycemia should occur in
such patients, it may be prolonged and appropriate management should be instituted.
GI Disease: Markedly reduced GI retention times of the GLUCOTROL XL Extended Release
Tablets may influence the pharmacokinetic profile and hence the clinical efficacy of the drug.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper
patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal
or hepatic insufficiency may affect the disposition of glipizide and the latter may also diminish
gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions.
Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency
are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking
beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is
deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one
glucose-lowering drug is used. Therapy with a combination of glucose-lowering agents may
increase the potential for hypoglycemia.
Reference ID: 2900397
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is
exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At
such times, it may be necessary to discontinue glipizide and administer insulin.
The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose
to a desired level decreases in many patients over a period of time, which may be due to
progression of the severity of the diabetes or to diminished responsiveness to the drug. This
phenomenon is known as secondary failure, to distinguish it from primary failure in which the
drug is ineffective in an individual patient when first given. Adequate adjustment of dose and
adherence to diet should be assessed before classifying a patient as a secondary failure.
Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD)
deficiency with sulfonylurea agents can lead to hemolytic anemia. Because GLUCOTROL XL
belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD
deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports,
hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
Laboratory Tests: Blood and urine glucose should be monitored periodically. Measurement of
hemoglobin A1C may be useful.
Information for Patients: Patients should be informed that GLUCOTROL XL Extended
Release Tablets should be swallowed whole. Patients should not chew, divide or crush tablets.
Patients should not be concerned if they occasionally notice in their stool something that looks
like a tablet. In the GLUCOTROL XL Extended Release Tablet, the medication is contained
within a nonabsorbable shell that has been specially designed to slowly release the drug so the
body can absorb it. When this process is completed, the empty tablet is eliminated from the
body.
Patients should be informed of the potential risks and advantages of GLUCOTROL XL and of
alternative modes of therapy. They should also be informed about the importance of adhering to
dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood
glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its
development should be explained to patients and responsible family members. Primary and
secondary failure also should be explained.
Physician Counseling Information for Patients:
In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of
treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper
dietary management alone may be effective in controlling the blood glucose and symptoms of
hyperglycemia. The importance of regular physical activity should also be stressed, and
cardiovascular risk factors should be identified and corrective measures taken where possible.
Use of GLUCOTROL XL or other antidiabetic medications must be viewed by both the
physician and patient as a treatment in addition to diet and not as a substitution or as a
convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control
Reference ID: 2900397
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
on diet alone may be transient, thus requiring only short-term administration of GLUCOTROL
XL or other antidiabetic medications. Maintenance or discontinuation of GLUCOTROL XL or
other antidiabetic medications should be based on clinical judgment using regular clinical and
laboratory evaluations.
Drug Interactions: The hypoglycemic action of sulfonylureas may be potentiated by certain
drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein
bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase
inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient
receiving glipizide, the patient should be observed closely for hypoglycemia. When such drugs
are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss
of control. In vitro binding studies with human serum proteins indicate that glipizide binds
differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution
must be exercised in extrapolating these findings to the clinical situation and in the use of
glipizide with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,
estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel
blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide,
the patient should be closely observed for loss of control. When such drugs are withdrawn from a
patient receiving glipizide, the patient should be observed closely for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with the intravenous,
topical, or vaginal preparations of miconazole is not known. The effect of concomitant
administration of Diflucan® (fluconazole) and Glucotrol has been demonstrated in a
placebo-controlled crossover study in normal volunteers. All subjects received Glucotrol alone
and following treatment with 100 mg of Diflucan® as a single daily oral dose for 7 days. The
mean percentage increase in the Glucotrol AUC after fluconazole administration was 56.9%
(range: 35 to 81%).
Carcinogenesis, Mutagenesis, Impairment of Fertility: A twenty month study in rats and an
eighteen month study in mice at doses up to 75 times the maximum human dose revealed no
evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly
negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects
on fertility.
Pregnancy: Pregnancy Category C: Glipizide was found to be mildly fetotoxic in rat
reproductive studies at all dose levels (5–50 mg/kg). This fetotoxicity has been similarly noted
with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and
believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In
studies in rats and rabbits no teratogenic effects were found. There are no adequate and well
controlled studies in pregnant women. Glipizide should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Reference ID: 2900397
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Because recent information suggests that abnormal blood-glucose levels during pregnancy are
associated with a higher incidence of congenital abnormalities, many experts recommend that
insulin be used during pregnancy to maintain blood-glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives. If glipizide is
used during pregnancy, it should be discontinued at least one month before the expected delivery
date.
Nursing Mothers: Although it is not known whether glipizide is excreted in human milk, some
sulfonylurea drugs are known to be excreted in human milk. Because the potential for
hypoglycemia in nursing infants may exist, 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.
If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin
therapy should be considered.
Pediatric Use: Safety and effectiveness in children have not been established.
Geriatric Use: Of the total number of patients in clinical studies of GLUCOTROL XL,
33 percent were 65 and over. Approximately 1–2 days longer were required to reach steady-state
in the elderly. (See CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION.) There were no overall differences in effectiveness or safety between
younger and older patients, but greater sensitivity of some individuals cannot be ruled out. As
such, it should be noted that elderly, debilitated or malnourished patients, and those with adrenal
or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-
lowering drugs. Hypoglycemia may be difficult to recognize in the elderly. In addition, in
elderly, debilitated or malnourished patients, and patients with impaired renal or hepatic
function, the initial and maintenance dosing should be conservative to avoid hypoglycemic
reactions.
ADVERSE REACTIONS
In U.S. controlled studies the frequency of serious adverse experiences reported was very low
and causal relationship has not been established.
The 580 patients from 31 to 87 years of age who received GLUCOTROL XL Extended Release
Tablets in doses from 5 mg to 60 mg in both controlled and open trials were included in the
evaluation of adverse experiences. All adverse experiences reported were tabulated
independently of their possible causal relation to medication.
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.
Only 3.4% of patients receiving GLUCOTROL XL Extended Release Tablets had hypoglycemia
documented by a blood-glucose measurement <60 mg/dL and/or symptoms believed to be
Reference ID: 2900397
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
associated with hypoglycemia. In a comparative efficacy study of GLUCOTROL XL and
Glucotrol, hypoglycemia occurred rarely with an incidence of less than 1% with both drugs.
In double-blind, placebo-controlled studies the adverse experiences reported with an incidence
of 3% or more in GLUCOTROL XL-treated patients include:
GLUCOTROL XL (%)
Placebo (%)
(N=278)
(N=69)
Adverse Effect
Asthenia
10.1
13.0
Headache
8.6
8.7
Dizziness
6.8
5.8
Nervousness
3.6
2.9
Tremor
3.6
0.0
Diarrhea
5.4
0.0
Flatulence
3.2
1.4
The following adverse experiences occurred with an incidence of less than 3% in
GLUCOTROL XL-treated patients:
Body as a whole–pain
Nervous system–insomnia, paresthesia, anxiety, depression and hypesthesia
Gastrointestinal–nausea, dyspepsia, constipation and vomiting
Metabolic–hypoglycemia
Musculoskeletal–arthralgia, leg cramps and myalgia
Cardiovascular–syncope
Skin–sweating and pruritus
Respiratory–rhinitis
Special senses–blurred vision
Urogenital–polyuria
Other adverse experiences occurred with an incidence of less than 1% in
GLUCOTROL XL-treated patients:
Body as a whole–chills
Nervous system–hypertonia, confusion, vertigo, somnolence, gait abnormality and decreased
libido
Gastrointestinal–anorexia and trace blood in stool
Metabolic–thirst and edema
Cardiovascular–arrhythmia, migraine, flushing and hypertension
Skin–rash and urticaria
Respiratory–pharyngitis and dyspnea
Special senses–pain in the eye, conjunctivitis and retinal hemorrhage
Urogenital–dysuria
Reference ID: 2900397
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Although these adverse experiences occurred in patients treated with GLUCOTROL XL, a
causal relationship to the medication has not been established in all cases.
There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use
of another drug in this non-deformable sustained release formulation, although causal
relationship to the drug is uncertain.
Post-Marketing Experience
The following adverse events have been reported in post-marketing surveillance:
Gastrointestinal: abdominal pain
Hepatobiliary: Cholestatic and hepatocellular forms of liver injury accompanied by jaundice
have been reported rarely in association with glipizide; GLUCOTROL XL should be
discontinued if this occurs.
The following are adverse experiences reported with immediate release glipizide and other
sulfonylureas, but have not been observed with GLUCOTROL XL:
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see
PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas.
Metabolic: Hepatic porphyria and disulfiram-like reactions have been reported with
sulfonylureas. In the mouse, glipizide pretreatment did not cause an accumulation of
acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide
has an extremely low incidence of disulfiram-like alcohol reactions.
Endocrine Reactions: Cases of hyponatremia and the syndrome of inappropriate antidiuretic
hormone (SIADH) secretion have been reported with glipizide and other sulfonylureas.
Laboratory Tests: The pattern of laboratory test abnormalities observed with glipizide was
similar to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH,
alkaline phosphatase, BUN and creatinine were noted. One case of jaundice was reported. The
relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated
with clinical symptoms.
OVERDOSAGE
There is no well-documented experience with GLUCOTROL XL overdosage in humans. There
have been no known suicide attempts associated with purposeful overdosing with GLUCOTROL
XL. In nonclinical studies the acute oral toxicity of glipizide was extremely low in all species
tested (LD50 greater than 4 g/kg). Overdosage of sulfonylureas including glipizide can produce
hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic
findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or
meal patterns. Close monitoring should continue until the physician is assured that the patient is
10
Reference ID: 2900397
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For current labeling information, please visit https://www.fda.gov/drugsatfda
out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological
impairment occur infrequently, but constitute medical emergencies requiring immediate
hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given
rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a
continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood
glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24
to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of
glipizide from plasma may be prolonged in persons with liver disease. Because of the extensive
protein binding of glipizide, dialysis is unlikely to be of benefit.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with GLUCOTROL
XL Extended Release Tablet or any other hypoglycemic agent. Glycemic control should be
monitored with hemoglobin A1C and/or blood-glucose levels to determine the minimum effective
dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the
maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an
adequate blood-glucose-lowering response after an initial period of effectiveness. Home blood-
glucose monitoring may also provide useful information to the patient and physician. Short-term
administration of GLUCOTROL XL Extended Release Tablet may be sufficient during periods
of transient loss of control in patients usually controlled on diet.
In general, GLUCOTROL XL should be given with breakfast.
Recommended Dosing: The usual starting dose of GLUCOTROL XL as initial therapy is 5 mg
per day, given with breakfast. Those patients who may be more sensitive to hypoglycemic drugs
may be started at a lower dose.
Dosage adjustment should be based on laboratory measures of glycemic control. While fasting
blood-glucose levels generally reach steady-state following initiation or change in
GLUCOTROL XL dosage, a single fasting glucose determination may not accurately reflect the
response to therapy. In most cases, hemoglobin A1C level measured at three month intervals is
the preferred means of monitoring response to therapy.
Hemoglobin A1C should be measured as GLUCOTROL XL therapy is initiated and repeated
approximately three months later. If the result of this test suggests that glycemic control over the
preceding three months was inadequate, the GLUCOTROL XL dose may be increased.
Subsequent dosage adjustments should be made on the basis of hemoglobin A1C levels measured
at three month intervals. If no improvement is seen after three months of therapy with a higher
dose, the previous dose should be resumed. Decisions which utilize fasting blood glucose to
adjust GLUCOTROL XL therapy should be based on at least two or more similar, consecutive
values obtained seven days or more after the previous dose adjustment.
Most patients will be controlled with 5 mg to 10 mg taken once daily. However, some patients
may require up to the maximum recommended daily dose of 20 mg. While the glycemic control
of selected patients may improve with doses which exceed 10 mg, clinical studies conducted to
Reference ID: 2900397
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
date have not demonstrated an additional group average reduction of hemoglobin A1C beyond
what was achieved with the 10 mg dose.
Based on the results of a randomized crossover study, patients receiving immediate release
glipizide may be switched safely to GLUCOTROL XL Extended Release Tablets once-a-day at
the nearest equivalent total daily dose. Patients receiving immediate release Glucotrol also may
be titrated to the appropriate dose of GLUCOTROL XL starting with 5 mg once daily. The
decision to switch to the nearest equivalent dose or to titrate should be based on clinical
judgment.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or
hepatic function, the initial and maintenance dosing should be conservative to avoid
hypoglycemic reactions (see PRECAUTIONS section).
Combination Use: When adding other blood-glucose-lowering agents to GLUCOTROL XL for
combination therapy, the agent should be initiated at the lowest recommended dose, and patients
should be observed carefully for hypoglycemia. Refer to the product information supplied with
the oral agent for additional information.
When adding GLUCOTROL XL to other blood-glucose-lowering agents, GLUCOTROL XL can
be initiated at 5 mg. Those patients who may be more sensitive to hypoglycemic drugs may be
started at a lower dose. Titration should be based on clinical judgment.
Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many patients
with stable type 2 diabetes receiving insulin may be transferred safely to treatment with
GLUCOTROL XL Extended Release Tablets. When transferring patients from insulin to
GLUCOTROL XL, the following general guidelines should be considered:
For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and
GLUCOTROL XL therapy may begin at usual dosages. Several days should elapse between
titration steps.
For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be
reduced by 50% and GLUCOTROL XL therapy may begin at usual dosages. Subsequent
reductions in insulin dosage should depend on individual patient response. Several days should
elapse between titration steps.
During the insulin withdrawal period, the patient should test urine samples for sugar and ketone
bodies at least three times daily. Patients should be instructed to contact the prescriber
immediately if these tests are abnormal. In some cases, especially when the patient has been
receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization
during the transition period.
Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class
hypoglycemics, no transition period is necessary when transferring patients to
GLUCOTROL XL Extended Release Tablets. Patients should be observed carefully (1–2 weeks)
Reference ID: 2900397
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g.,
chlorpropamide) to GLUCOTROL XL due to potential overlapping of drug effect.
HOW SUPPLIED
GLUCOTROL XL (glipizide) Extended Release Tablets are supplied as 2.5 mg, 5 mg, and
10 mg round, biconvex tablets and imprinted with black ink as follows:
2.5 mg tablets are blue and imprinted with “GLUCOTROL XL 2.5” on one side.
Bottles of 30: NDC 0049-1620-30
5 mg tablets are white and imprinted with “GLUCOTROL XL 5” on one side.
Bottles of 100: NDC 0049-1550-66
Bottles of 500: NDC 0049-1550-73
10 mg tablets are white and imprinted with “GLUCOTROL XL 10” on one side.
Bottles of 100: NDC 0049-1560-66
Bottles of 500: NDC 0049-1560-73
Recommended Storage: The tablets should be protected from moisture and humidity and stored
at controlled room temperature, 59° to 86°F (15° to 30°C).
Rx only Pfizer
LAB-0113-7.0
Revised May 2010
PATIENT INFORMATION
GLUCOTROL XL
(glipizide) extended release tablets
Read this information carefully before you start taking this medicine. Read the information you
get with your medicine each time you refill your prescription. There may be new information.
This information does not take the place of your healthcare provider’s advice. Ask your
Reference ID: 2900397
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
healthcare provider or pharmacist if you do not understand some of this information or if you
want to know more about this medicine.
What is GLUCOTROL XL?
GLUCOTROL XL (glue-kuh-troll-ex-el) is a medicine you take by mouth. It is used to treat type
2 diabetes (also called non-insulin-dependant diabetes mellitus). Your healthcare provider has
prescribed GLUCOTROL XL because your current treatment, including diet and exercise, has
not been able to bring your blood sugar level under good control.
Your body makes insulin to keep the amount of sugar (glucose) in your blood at the right level.
With type 2 diabetes:
• your body may not be making enough insulin
• your body may not be using the insulin that you have already made
• the level of sugar in your blood is too high
If your blood sugar level is not under control, it can lead to serious medical problems, such as
kidney damage, nerve damage, blindness, problems with circulation (blood movement in your
body), loss of feet, legs or other limbs, high blood pressure, heart attack, or stroke.
GLUCOTROL XL works mainly by:
• helping the body release more of its own insulin
• helping the body respond better to its own insulin
• lowering the amount of sugar (glucose) made by the body
Even after you start taking GLUCOTROL XL, you must continue to follow your program of diet
and exercise.
Who Should Not Use GLUCOTROL XL?
Do not use GLUCOTROL XL if you:
• have a condition called diabetic ketoacidosis
• have ever had an allergic reaction to glipizide or any of the other ingredients in
GLUCOTROL XL. Ask your healthcare provider or pharmacist for a list of these ingredients.
Only your healthcare provider can decide if GLUCOTROL XL is right for you. Before you start
GLUCOTROL XL, tell the healthcare provider if you:
• are taking or using any prescription medicines or non-prescription medicines,
including natural or herbal remedies. Other medications can increase your chance of
getting low blood sugar or high blood sugar. Be sure to tell your healthcare provider
if you take the medicines miconazole or fluconazole, used to fight fungus infections.
• have ever had a condition called diabetic ketoacidosis
• have kidney or liver problems
• have had blockage or narrowing of your intestines due to illness or past surgery
• have chronic (continuing) diarrhea
Reference ID: 2900397
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• are pregnant or might be pregnant. Your healthcare provider may switch you to
insulin injections some time during your pregnancy. You should not take
GLUCOTROL XL during the last month of pregnancy.
• are breast- feeding. GLUCOTROL XL may pass to the baby through your milk and
cause harm.
• have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This condition usually
runs in families. People with G6PD deficiency who take GLUCOTROL XL may
develop hemolytic anemia (fast breakdown of red blood cells).
How Should I Take GLUCOTROL XL?
GLUCOTROL XL tablets come in three different strengths (2.5 mg, 5 mg and 10 mg). Your
healthcare provider will prescribe the dose that is right for you.
• Take GLUCOTROL XL once a day with breakfast. The tablet is designed to release
the medicine slowly over 24 hours. This is why you have to take it only once a day.
• Swallow the tablet whole. Never chew, crush or cut the tablet in half. This would
damage the tablet and release too much medicine into your body at one time.
• After all of the medicine has been released, the empty tablet shell will pass out of the
body normally in a bowel movement. Do not be concerned if you see the empty
tablet shell in your stool (bowel movement).
It is important to take GLUCOTROL XL every day to help keep your blood sugar level under
good control. Your healthcare provider may adjust your dose depending on your blood glucose
test results. If your blood sugar level is not under control, call your healthcare provider. Do not
change your dose without your healthcare provider’s approval.
In case of overdose, call the poison control center or your healthcare provider right away, or
have someone drive you to the nearest emergency room.
You must continue your diet and exercise program while taking GLUCOTROL XL. You must
also have your blood and urine tested regularly to be sure GLUCOTROL XL is working.
GLUCOTROL XL may not work for everyone. If it does work, you may find that GLUCOTROL
XL is not working as well for you after you have used it for a while. Tell your healthcare
provider if GLUCOTROL XL is not working well.
What Should I Avoid While Taking GLUCOTROL XL?
Some medicines can affect how well GLUCOTROL XL works or may affect your blood sugar
level. Check with your healthcare provider or pharmacist before you start or stop taking
prescription or over-the-counter medicines, including natural/herbal remedies, while on
GLUCOTROL XL.
What are the Possible Side Effects of GLUCOTROL XL?
Low blood sugar. GLUCOTROL XL may lower your blood sugar to low levels that are
dangerous (hypoglycemia). This can happen if you do not follow your diet, exercise too much,
Reference ID: 2900397
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For current labeling information, please visit https://www.fda.gov/drugsatfda
drink alcohol, are under stress, or get sick. This could also happen if your dose of GLUCOTROL
XL is higher than you need. Your healthcare provider may need to adjust it. Do not adjust the
dose on your own.
Be sure you know how to recognize your body’s signs that your blood sugar is too low. These
signs include:
• a cold clammy feeling
• hunger
• unusual sweating
• fast heartbeat
• dizziness
• headache
• weakness
• blurred vision
• trembling
• slurred speech
• shakiness
• tingling in the lips or hands
If you notice any of these signs, eat or drink something with sugar in it right away, such as a
regular (not diet) soft drink, orange juice, honey, sugar candy. You can also keep glucose tablets
on hand that are available from your pharmacy. If you do not feel better shortly or your blood
sugar level does not go up, call your healthcare provider. If you cannot reach your healthcare
provider in an emergency, call 911 or have someone drive you to the nearest emergency room.
Other side effects. GLUCOTROL XL may cause other side effects in some people. However,
the incidence of serious side effects with GLUCOTROL XL is very low. Other than the signs of
low blood sugar listed above, possible side effects include:
• feeling jittery
• diarrhea
• gas
GLUCOTROL XL may cause other less common side effects besides those listed here. For a list
of all side effects that have been reported, ask your healthcare provider or pharmacist.
While it has never been reported with GLUCOTROL XL, another similar type of diabetes
medicine has been linked to a higher risk of heart attacks. If you have risk factors for heart
disease and take GLUCOTROL XL, be sure to see your healthcare provider for regular
checkups.
How To Store GLUCOTROL XL
Keep GLUCOTROL XL and all medicines out of reach of children. Store GLUCOTROL XL in
a dry place, in its original container, and at room temperature (between 59°–-86°F or 15°–
30°C).
General Advice About Prescription Medicines
Medicines are sometimes prescribed for purposes other than those listed in a patient information
leaflet. If you have any concerns about GLUCOTROL XL, ask your healthcare provider. Your
healthcare provider or pharmacist can give you information about GLUCOTROL XL that was
written for healthcare professionals. Do not use GLUCOTROL XL for a condition for which it
Reference ID: 2900397
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For current labeling information, please visit https://www.fda.gov/drugsatfda
was not prescribed. Do not share GLUCOTROL XL with other people. For more information
about GLUCOTROL XL, you can visit the Pfizer internet site at www.pfizer.com. Pfizer
LAB-0115-3.0
Revised September 2009
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custom-source
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2025-02-12T13:47:27.976651
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020329s025lbl.pdf', 'application_number': 20329, 'submission_type': 'SUPPL ', 'submission_number': 25}
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GLUCOTROL XL®
(glipizide)
Extended Release Tablets
For Oral Use
DESCRIPTION
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5
methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea. The molecular formula is
C21H27N5O4S; the molecular weight is 445.55; the structural formula is shown below:
st
ru
ctur
al formula
Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols,
but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. GLUCOTROL XL® is a
registered trademark for glipizide GITS. Glipizide GITS (Gastrointestinal Therapeutic System) is
formulated as a once-a-day controlled release tablet for oral use and is designed to deliver 2.5, 5,
or 10 mg of glipizide.
Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: polyethylene oxide,
hypromellose, magnesium stearate, sodium chloride, red ferric oxide, cellulose acetate,
polyethylene glycol, Opadry® blue (OY-LS-20921)(2.5 mg tablets), Opadry® white
(YS-2-7063)(5 mg and 10 mg tablet) and black ink (S-1-8106).
System Components and Performance
GLUCOTROL XL Extended Release Tablet is similar in appearance to a conventional tablet. It
consists, however, of an osmotically active drug core surrounded by a semipermeable membrane.
The core itself is divided into two layers: an “active” layer containing the drug, and a “push”
layer containing pharmacologically inert (but osmotically active) components. The membrane
surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from
the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes”
against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the
membrane on the drug side of the tablet.
1
Reference ID: 3389345
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The GLUCOTROL XL Extended Release Tablet is designed to provide a controlled rate of
delivery of glipizide into the gastrointestinal lumen which is independent of pH or
gastrointestinal motility. The function of the GLUCOTROL XL Extended Release Tablet
depends upon the existence of an osmotic gradient between the contents of the bi-layer core and
fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains
constant, and then gradually falls to zero. The biologically inert components of the tablet remain
intact during GI transit and are eliminated in the feces as an insoluble shell.
CLINICAL PHARMACOLOGY
Mechanism of Action: Glipizide appears to lower blood glucose acutely by stimulating the
release of insulin from the pancreas, an effect dependent upon functioning beta cells in the
pancreatic islets. Extrapancreatic effects also may play a part in the mechanism of action of oral
sulfonylurea hypoglycemic drugs. Two extrapancreatic effects shown to be important in the
action of glipizide are an increase in insulin sensitivity and a decrease in hepatic glucose
production. However, the mechanism by which glipizide lowers blood glucose during long-term
administration has not been clearly established. Stimulation of insulin secretion by glipizide in
response to a meal is of major importance. The insulinotropic response to a meal is enhanced
with GLUCOTROL XL administration in diabetic patients. The postprandial insulin and
C-peptide responses continue to be enhanced after at least 6 months of treatment. In
2 randomized, double-blind, dose-response studies comprising a total of 347 patients, there was
no significant increase in fasting insulin in all GLUCOTROL XL-treated patients combined
compared to placebo, although minor elevations were observed at some doses. There was no
increase in fasting insulin over the long term.
Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea
drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have
not responded or have ceased to respond to other sulfonylureas.
Effects on Blood Glucose: The effectiveness of GLUCOTROL XL Extended Release Tablets in
type 2 diabetes at doses from 5–60 mg once daily has been evaluated in 4 therapeutic clinical
trials each with long-term open extensions involving a total of 598 patients. Once daily
administration of 5, 10 and 20 mg produced statistically significant reductions from placebo in
hemoglobin A1C, fasting plasma glucose and postprandial glucose in patients with mild to severe
type 2 diabetes. In a pooled analysis of the patients treated with 5 mg and 20 mg, the relationship
between dose and GLUCOTROL XL’s effect of reducing hemoglobin A1C was not established.
However, in the case of fasting plasma glucose, patients treated with 20 mg had a statistically
significant reduction of fasting plasma glucose compared to the 5 mg-treated group.
The reductions in hemoglobin A1C and fasting plasma glucose were similar in younger and older
patients. Efficacy of GLUCOTROL XL was not affected by gender, race or weight (as assessed
by body mass index). In long-term extension trials, efficacy of GLUCOTROL XL was
maintained in 81% of patients for up to 12 months.
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Reference ID: 3389345
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In an open, two-way crossover study, 132 patients were randomly assigned to either
GLUCOTROL XL or Glucotrol® for 8 weeks and then crossed over to the other drug for an
additional 8 weeks. GLUCOTROL XL administration resulted in significantly lower fasting
plasma glucose levels and equivalent hemoglobin A1C levels, as compared to Glucotrol.
In 12 week, well-controlled studies, there was a maximal average net reduction in hemoglobin
A1C of 1.7% in absolute units between placebo-treated and GLUCOTROL XL-treated patients.
Other Effects: It has been shown that GLUCOTROL XL therapy is effective in controlling
blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated
for type 2 diabetes.
In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic
activity, and, in fact, led to a slight increase in free water clearance.
Pharmacokinetics and Metabolism: Glipizide is rapidly and completely absorbed following
oral administration in an immediate release dosage form. The absolute bioavailability of glipizide
was 100% after single oral doses in patients with type 2 diabetes. Beginning 2 to 3 hours after
administration of GLUCOTROL XL Extended Release Tablets, plasma drug concentrations
gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With
subsequent once daily dosing of GLUCOTROL XL Extended Release Tablets, effective plasma
glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to
trough fluctuation than that observed with twice daily dosing of immediate release glipizide. The
mean relative bioavailability of glipizide in 21 males with type 2 diabetes after administration of
20 mg GLUCOTROL XL Extended Release Tablets, compared to immediate release Glucotrol
(10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were
achieved by at least the fifth day of dosing with GLUCOTROL XL Extended Release Tablets in
21 males with type 2 diabetes and patients younger than 65 years. Approximately 1 to 2 days
longer were required to reach steady-state in 24 elderly (≥65 years) males and females with
type 2 diabetes. No accumulation of drug was observed in patients with type 2 diabetes during
chronic dosing with GLUCOTROL XL Extended Release Tablets. Administration of
GLUCOTROL XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a
single dose, food effect study in 21 healthy male subjects, the administration of GLUCOTROL
XL immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean
Cmax value, which was significant, but the effect on the AUC was not significant. There was no
change in glucose response between the fed and fasting state. Markedly reduced GI retention
times of the GLUCOTROL XL tablets over prolonged periods (e.g., short bowel syndrome) may
influence the pharmacokinetic profile of the drug and potentially result in lower plasma
concentrations. In a multiple dose study in 26 males with type 2 diabetes, the pharmacokinetics
of glipizide were linear over the dose range of 5 to 60 mg of GLUCOTROL XL in that the
plasma drug concentrations increased proportionately with dose. In a single dose study in 24
healthy subjects, four 5-mg, two 10-mg, and one 20-mg GLUCOTROL XL Extended Release
Tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg
GLUCOTROL XL Extended Release Tablets were bioequivalent to one
10-mg GLUCOTROL XL Extended Release Tablet.
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Reference ID: 3389345
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Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is
excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as
biotransformation products in urine (80%) and feces (10%). The major metabolites of glipizide
are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite
which accounts for less than 2% of a dose, an acetylamino-ethyl benzene derivative, is reported
to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound. The mean total body
clearance of glipizide was approximately 3 liters per hour after single intravenous doses in
patients with type 2 diabetes. The mean apparent volume of distribution was approximately
10 liters. Glipizide is 98–99% bound to serum proteins, primarily to albumin. The mean terminal
elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in
patients with type 2 diabetes. There were no significant differences in the pharmacokinetics of
glipizide after single dose administration to older diabetic subjects compared to younger healthy
subjects. There is only limited information regarding the effects of renal impairment on the
disposition of glipizide, and no information regarding the effects of hepatic disease. However,
since glipizide is highly protein bound and hepatic biotransformation is the predominant route of
elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in
patients with renal or hepatic impairment.
In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal
cord of males or females, nor in the fetuses of pregnant females. In another study, however, very
small amounts of radioactivity were detected in the fetuses of rats given labelled drug.
INDICATIONS AND USAGE
GLUCOTROL XL is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus.
CONTRAINDICATIONS
Glipizide is contraindicated in patients with:
1. Known hypersensitivity to glipizide or any excipients in the GITS tablets.
2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition
should be treated with insulin.
WARNINGS
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY:
The administration of oral hypoglycemic drugs has been reported to be associated with
increased cardiovascular mortality as compared to treatment with diet alone or diet plus
insulin. This warning is based on the study conducted by the University Group Diabetes
Program (UGDP), a long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in
patients with type 2 diabetes. The study involved 823 patients who were randomly assigned
to one of four treatment groups (Diabetes, 19, SUPP. 2: 747–830, 1970).
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Reference ID: 3389345
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UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of
tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately
2½ times that of patients treated with diet alone. A significant increase in total mortality
was not observed, but the use of tolbutamide was discontinued based on the increase in
cardiovascular mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these results, the
findings of the UGDP study provide an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of glipizide and of alternative modes of
therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study,
it is prudent from a safety standpoint to consider that this warning may also apply to other
oral hypoglycemic drugs in this class, in view of their close similarities in mode of action
and chemical structure.
As with any other non-deformable material, caution should be used when administering
GLUCOTROL XL Extended Release Tablets in patients with preexisting severe gastrointestinal
narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in
patients with known strictures in association with the ingestion of another drug in this non
deformable sustained release formulation.
PRECAUTIONS
General
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence
of macrovascular risk reduction with GLUCOTROL XL or any other anti-diabetic drug.
Renal and Hepatic Disease: The pharmacokinetics and/or pharmacodynamics of glipizide may
be affected in patients with impaired renal or hepatic function. If hypoglycemia should occur in
such patients, it may be prolonged and appropriate management should be instituted.
GI Disease: Markedly reduced GI retention times of the GLUCOTROL XL Extended Release
Tablets may influence the pharmacokinetic profile and hence the clinical efficacy of the drug.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper
patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal
or hepatic insufficiency may affect the disposition of glipizide and the latter may also diminish
gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions.
Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are
particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia
may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic
blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after
severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering
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drug is used. Therapy with a combination of glucose-lowering agents may increase the potential
for hypoglycemia.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is
exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such
times, it may be necessary to discontinue glipizide and administer insulin.
The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose
to a desired level decreases in many patients over a period of time, which may be due to
progression of the severity of the diabetes or to diminished responsiveness to the drug. This
phenomenon is known as secondary failure, to distinguish it from primary failure in which the
drug is ineffective in an individual patient when first given. Adequate adjustment of dose and
adherence to diet should be assessed before classifying a patient as a secondary failure.
Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD)
deficiency with sulfonylurea agents can lead to hemolytic anemia. Because GLUCOTROL XL
belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD
deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports,
hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
Laboratory Tests: Blood and urine glucose should be monitored periodically. Measurement of
hemoglobin A1C may be useful.
Information for Patients: Patients should be informed that GLUCOTROL XL Extended
Release Tablets should be swallowed whole. Patients should not chew, divide or crush tablets.
Patients should not be concerned if they occasionally notice in their stool something that looks
like a tablet. In the GLUCOTROL XL Extended Release Tablet, the medication is contained
within a nonabsorbable shell that has been specially designed to slowly release the drug so the
body can absorb it. When this process is completed, the empty tablet is eliminated from the body.
Patients should be informed of the potential risks and advantages of GLUCOTROL XL and of
alternative modes of therapy. They should also be informed about the importance of adhering to
dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood
glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its
development should be explained to patients and responsible family members. Primary and
secondary failure also should be explained.
Physician Counseling Information for Patients:
In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of
treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper
dietary management alone may be effective in controlling the blood glucose and symptoms of
hyperglycemia. The importance of regular physical activity should also be stressed, and
cardiovascular risk factors should be identified and corrective measures taken where possible.
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Use of GLUCOTROL XL or other antidiabetic medications must be viewed by both the
physician and patient as a treatment in addition to diet and not as a substitution or as a convenient
mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet
alone may be transient, thus requiring only short-term administration of GLUCOTROL XL or
other antidiabetic medications. Maintenance or discontinuation of GLUCOTROL XL or other
antidiabetic medications should be based on clinical judgment using regular clinical and
laboratory evaluations.
Drug Interactions: The hypoglycemic action of sulfonylureas may be potentiated by certain
drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein
bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase
inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient
receiving glipizide, the patient should be observed closely for hypoglycemia. When such drugs
are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss
of control. In vitro binding studies with human serum proteins indicate that glipizide binds
differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution
must be exercised in extrapolating these findings to the clinical situation and in the use of
glipizide with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,
estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel
blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide,
the patient should be closely observed for loss of control. When such drugs are withdrawn from a
patient receiving glipizide, the patient should be observed closely for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with the intravenous,
topical, or vaginal preparations of miconazole is not known. The effect of concomitant
administration of Diflucan® (fluconazole) and Glucotrol has been demonstrated in a
placebo-controlled crossover study in normal volunteers. All subjects received Glucotrol alone
and following treatment with 100 mg of Diflucan® as a single daily oral dose for 7 days. The
mean percentage increase in the Glucotrol AUC after fluconazole administration was 56.9%
(range: 35 to 81%).
In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy
volunteers, reductions in glipizide AUC0-∞ and Cmax of 12% and 13%, respectively were
observed when colesevelam was coadministered with glipizide ER. When glipizide ER was
administered 4 hours prior to colesevelam, there was no significant change in glipizide AUC0-∞
or Cmax, -4% and 0%, respectively. Therefore, GLUCOTROL XL should be administered at least
4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of
glipizide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: A twenty month study in rats and an
eighteen month study in mice at doses up to 75 times the maximum human dose revealed no
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Reference ID: 3389345
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evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly
negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects
on fertility.
Pregnancy: Pregnancy Category C: Glipizide was found to be mildly fetotoxic in rat
reproductive studies at all dose levels (5–50 mg/kg). This fetotoxicity has been similarly noted
with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed
to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats
and rabbits no teratogenic effects were found. There are no adequate and well controlled studies
in pregnant women. Glipizide should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Because recent information suggests that abnormal blood-glucose levels during pregnancy are
associated with a higher incidence of congenital abnormalities, many experts recommend that
insulin be used during pregnancy to maintain blood-glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives. If glipizide is
used during pregnancy, it should be discontinued at least one month before the expected delivery
date.
Nursing Mothers: Although it is not known whether glipizide is excreted in human milk, some
sulfonylurea drugs are known to be excreted in human milk. Because the potential for
hypoglycemia in nursing infants may exist, 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.
If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin
therapy should be considered.
Pediatric Use: Safety and effectiveness in children have not been established.
Geriatric Use: Of the total number of patients in clinical studies of GLUCOTROL XL,
33 percent were 65 and over. Approximately 1–2 days longer were required to reach steady-state
in the elderly. (See CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION.) There were no overall differences in effectiveness or safety between
younger and older patients, but greater sensitivity of some individuals cannot be ruled out. As
such, it should be noted that elderly, debilitated or malnourished patients, and those with adrenal
or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-
lowering drugs. Hypoglycemia may be difficult to recognize in the elderly. In addition, in elderly,
debilitated or malnourished patients, and patients with impaired renal or hepatic function, the
initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.
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ADVERSE REACTIONS
In U.S. controlled studies the frequency of serious adverse experiences reported was very low
and causal relationship has not been established.
The 580 patients from 31 to 87 years of age who received GLUCOTROL XL Extended Release
Tablets in doses from 5 mg to 60 mg in both controlled and open trials were included in the
evaluation of adverse experiences. All adverse experiences reported were tabulated
independently of their possible causal relation to medication.
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.
Only 3.4% of patients receiving GLUCOTROL XL Extended Release Tablets had hypoglycemia
documented by a blood-glucose measurement <60 mg/dL and/or symptoms believed to be
associated with hypoglycemia. In a comparative efficacy study of GLUCOTROL XL and
Glucotrol, hypoglycemia occurred rarely with an incidence of less than 1% with both drugs.
In double-blind, placebo-controlled studies the adverse experiences reported with an incidence of
3% or more in GLUCOTROL XL-treated patients include:
GLUCOTROL XL (%)
Placebo (%)
(N=278)
(N=69)
Adverse Effect
Asthenia
10.1
13.0
Headache
8.6
8.7
Dizziness
6.8
5.8
Nervousness
3.6
2.9
Tremor
3.6
0.0
Diarrhea
5.4
0.0
Flatulence
3.2
1.4
The following adverse experiences occurred with an incidence of less than 3% in
GLUCOTROL XL-treated patients:
Body as a whole–pain
Nervous system–insomnia, paresthesia, anxiety, depression and hypesthesia
Gastrointestinal–nausea, dyspepsia, constipation and vomiting
Metabolic–hypoglycemia
Musculoskeletal–arthralgia, leg cramps and myalgia
Cardiovascular–syncope
Skin–sweating and pruritus
Respiratory–rhinitis
Special senses–blurred vision
Urogenital–polyuria
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Other adverse experiences occurred with an incidence of less than 1% in
GLUCOTROL XL-treated patients:
Body as a whole–chills
Nervous system–hypertonia, confusion, vertigo, somnolence, gait abnormality and decreased
libido
Gastrointestinal–anorexia and trace blood in stool
Metabolic–thirst and edema
Cardiovascular–arrhythmia, migraine, flushing and hypertension
Skin–rash and urticaria
Respiratory–pharyngitis and dyspnea
Special senses–pain in the eye, conjunctivitis and retinal hemorrhage
Urogenital–dysuria
Although these adverse experiences occurred in patients treated with GLUCOTROL XL, a causal
relationship to the medication has not been established in all cases.
There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of
another drug in this non-deformable sustained release formulation, although causal relationship
to the drug is uncertain.
Post-Marketing Experience
The following adverse events have been reported in post-marketing surveillance:
Gastrointestinal: abdominal pain
Hepatobiliary: Cholestatic and hepatocellular forms of liver injury accompanied by jaundice
have been reported rarely in association with glipizide; GLUCOTROL XL should be
discontinued if this occurs.
The following are adverse experiences reported with immediate release glipizide and other
sulfonylureas, but have not been observed with GLUCOTROL XL:
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see
PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas.
Metabolic: Hepatic porphyria and disulfiram-like reactions have been reported with
sulfonylureas. In the mouse, glipizide pretreatment did not cause an accumulation of
acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide
has an extremely low incidence of disulfiram-like alcohol reactions.
Endocrine Reactions: Cases of hyponatremia and the syndrome of inappropriate antidiuretic
hormone (SIADH) secretion have been reported with glipizide and other sulfonylureas.
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Laboratory Tests: The pattern of laboratory test abnormalities observed with glipizide was
similar to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH,
alkaline phosphatase, BUN and creatinine were noted. One case of jaundice was reported. The
relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated
with clinical symptoms.
OVERDOSAGE
There is no well-documented experience with GLUCOTROL XL overdosage in humans. There
have been no known suicide attempts associated with purposeful overdosing with GLUCOTROL
XL. In nonclinical studies the acute oral toxicity of glipizide was extremely low in all species
tested (LD50 greater than 4 g/kg). Overdosage of sulfonylureas including glipizide can produce
hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic
findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or
meal patterns. Close monitoring should continue until the physician is assured that the patient is
out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological
impairment occur infrequently, but constitute medical emergencies requiring immediate
hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given
rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a
continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood
glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to
48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide
from plasma may be prolonged in persons with liver disease. Because of the extensive protein
binding of glipizide, dialysis is unlikely to be of benefit.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with GLUCOTROL
XL Extended Release Tablet or any other hypoglycemic agent. Glycemic control should be
monitored with hemoglobin A1C and/or blood-glucose levels to determine the minimum effective
dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the
maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an
adequate blood-glucose-lowering response after an initial period of effectiveness. Home blood-
glucose monitoring may also provide useful information to the patient and physician. Short-term
administration of GLUCOTROL XL Extended Release Tablet may be sufficient during periods
of transient loss of control in patients usually controlled on diet.
In general, GLUCOTROL XL should be given with breakfast.
Recommended Dosing: The usual starting dose of GLUCOTROL XL as initial therapy is 5 mg
per day, given with breakfast. Those patients who may be more sensitive to hypoglycemic drugs
may be started at a lower dose.
Dosage adjustment should be based on laboratory measures of glycemic control. While fasting
blood-glucose levels generally reach steady-state following initiation or change in GLUCOTROL
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Reference ID: 3389345
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XL dosage, a single fasting glucose determination may not accurately reflect the response to
therapy. In most cases, hemoglobin A1C level measured at three month intervals is the preferred
means of monitoring response to therapy.
Hemoglobin A1C should be measured as GLUCOTROL XL therapy is initiated and repeated
approximately three months later. If the result of this test suggests that glycemic control over the
preceding three months was inadequate, the GLUCOTROL XL dose may be increased.
Subsequent dosage adjustments should be made on the basis of hemoglobin A1C levels measured
at three month intervals. If no improvement is seen after three months of therapy with a higher
dose, the previous dose should be resumed. Decisions which utilize fasting blood glucose to
adjust GLUCOTROL XL therapy should be based on at least two or more similar, consecutive
values obtained seven days or more after the previous dose adjustment.
Most patients will be controlled with 5 mg to 10 mg taken once daily. However, some patients
may require up to the maximum recommended daily dose of 20 mg. While the glycemic control
of selected patients may improve with doses which exceed 10 mg, clinical studies conducted to
date have not demonstrated an additional group average reduction of hemoglobin A1C beyond
what was achieved with the 10 mg dose.
Based on the results of a randomized crossover study, patients receiving immediate release
glipizide may be switched safely to GLUCOTROL XL Extended Release Tablets once-a-day at
the nearest equivalent total daily dose. Patients receiving immediate release Glucotrol also may
be titrated to the appropriate dose of GLUCOTROL XL starting with 5 mg once daily. The
decision to switch to the nearest equivalent dose or to titrate should be based on clinical
judgment.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or
hepatic function, the initial and maintenance dosing should be conservative to avoid
hypoglycemic reactions (see PRECAUTIONS section).
Combination Use: When adding other blood-glucose-lowering agents to GLUCOTROL XL for
combination therapy, the agent should be initiated at the lowest recommended dose, and patients
should be observed carefully for hypoglycemia. Refer to the product information supplied with
the oral agent for additional information.
When adding GLUCOTROL XL to other blood-glucose-lowering agents, GLUCOTROL XL can
be initiated at 5 mg. Those patients who may be more sensitive to hypoglycemic drugs may be
started at a lower dose. Titration should be based on clinical judgment.
When colesevelam is coadministered with glipizide ER, maximum plasma concentration and
total exposure to glipizide is reduced. Therefore, GLUCOTROL XL should be administered at
least 4 hours prior to colesevelam.
Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many patients with
stable type 2 diabetes receiving insulin may be transferred safely to treatment with
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GLUCOTROL XL Extended Release Tablets. When transferring patients from insulin to
GLUCOTROL XL, the following general guidelines should be considered:
For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and
GLUCOTROL XL therapy may begin at usual dosages. Several days should elapse between
titration steps.
For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be
reduced by 50% and GLUCOTROL XL therapy may begin at usual dosages. Subsequent
reductions in insulin dosage should depend on individual patient response. Several days should
elapse between titration steps.
During the insulin withdrawal period, the patient should test urine samples for sugar and ketone
bodies at least three times daily. Patients should be instructed to contact the prescriber
immediately if these tests are abnormal. In some cases, especially when the patient has been
receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization
during the transition period.
Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class
hypoglycemics, no transition period is necessary when transferring patients to GLUCOTROL XL
Extended Release Tablets. Patients should be observed carefully (1–2 weeks) for hypoglycemia
when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to
GLUCOTROL XL due to potential overlapping of drug effect.
HOW SUPPLIED
GLUCOTROL XL (glipizide) Extended Release Tablets are supplied as 2.5 mg, 5 mg, and 10 mg
round, biconvex tablets and imprinted with black ink as follows:
2.5 mg tablets are blue and imprinted with “GLUCOTROL XL 2.5” on one side.
Bottles of 30: NDC 0049-1620-30
5 mg tablets are white and imprinted with “GLUCOTROL XL 5” on one side.
Bottles of 100: NDC 0049-1550-66
Bottles of 500: NDC 0049-1550-73
10 mg tablets are white and imprinted with “GLUCOTROL XL 10” on one side.
Bottles of 100: NDC 0049-1560-66
Bottles of 500: NDC 0049-1560-73
Recommended Storage: The tablets should be protected from moisture and humidity and stored
at controlled room temperature, 59° to 86°F (15° to 30°C).
13
Reference ID: 3389345
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Rx only company logo
LAB-0113-7.1
Revised March 2013
14
Reference ID: 3389345
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
GLUCOTROL XL
(glipizide) extended release tablets
Read this information carefully before you start taking this medicine. Read the information you
get with your medicine each time you refill your prescription. There may be new information.
This information does not take the place of your healthcare provider’s advice. Ask your
healthcare provider or pharmacist if you do not understand some of this information or if you
want to know more about this medicine.
What is GLUCOTROL XL?
GLUCOTROL XL (glue-kuh-troll-ex-el) is a medicine you take by mouth. It is used to treat type
2 diabetes (also called non-insulin-dependant diabetes mellitus). Your healthcare provider has
prescribed GLUCOTROL XL because your current treatment, including diet and exercise, has
not been able to bring your blood sugar level under good control.
Your body makes insulin to keep the amount of sugar (glucose) in your blood at the right level.
With type 2 diabetes:
• your body may not be making enough insulin
• your body may not be using the insulin that you have already made
• the level of sugar in your blood is too high
If your blood sugar level is not under control, it can lead to serious medical problems, such as
kidney damage, nerve damage, blindness, problems with circulation (blood movement in your
body), loss of feet, legs or other limbs, high blood pressure, heart attack, or stroke.
GLUCOTROL XL works mainly by:
• helping the body release more of its own insulin
• helping the body respond better to its own insulin
• lowering the amount of sugar (glucose) made by the body
Even after you start taking GLUCOTROL XL, you must continue to follow your program of diet
and exercise.
Who Should Not Use GLUCOTROL XL?
Do not use GLUCOTROL XL if you:
• have a condition called diabetic ketoacidosis
• have ever had an allergic reaction to glipizide or any of the other ingredients in GLUCOTROL
XL. Ask your healthcare provider or pharmacist for a list of these ingredients.
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Only your healthcare provider can decide if GLUCOTROL XL is right for you. Before you start
GLUCOTROL XL, tell the healthcare provider if you:
• are taking or using any prescription medicines or non-prescription medicines,
including natural or herbal remedies. Other medications can increase your chance of
getting low blood sugar or high blood sugar. Be sure to tell your healthcare provider if
you take the medicines miconazole or fluconazole, used to fight fungus infections.
• have ever had a condition called diabetic ketoacidosis
• have kidney or liver problems
• have had blockage or narrowing of your intestines due to illness or past surgery
• have chronic (continuing) diarrhea
• are pregnant or might be pregnant. Your healthcare provider may switch you to
insulin injections some time during your pregnancy. You should not take
GLUCOTROL XL during the last month of pregnancy.
• are breast- feeding. GLUCOTROL XL may pass to the baby through your milk and
cause harm.
• have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This condition usually
runs in families. People with G6PD deficiency who take GLUCOTROL XL may
develop hemolytic anemia (fast breakdown of red blood cells).
How Should I Take GLUCOTROL XL?
GLUCOTROL XL tablets come in three different strengths (2.5 mg, 5 mg and 10 mg). Your
healthcare provider will prescribe the dose that is right for you.
• Take GLUCOTROL XL once a day with breakfast. The tablet is designed to release
the medicine slowly over 24 hours. This is why you have to take it only once a day.
• Swallow the tablet whole. Never chew, crush or cut the tablet in half. This would
damage the tablet and release too much medicine into your body at one time.
• After all of the medicine has been released, the empty tablet shell will pass out of the
body normally in a bowel movement. Do not be concerned if you see the empty tablet
shell in your stool (bowel movement).
It is important to take GLUCOTROL XL every day to help keep your blood sugar level under
good control. Your healthcare provider may adjust your dose depending on your blood glucose
test results. If your blood sugar level is not under control, call your healthcare provider. Do not
change your dose without your healthcare provider’s approval.
In case of overdose, call the poison control center or your healthcare provider right away, or have
someone drive you to the nearest emergency room.
You must continue your diet and exercise program while taking GLUCOTROL XL. You must
also have your blood and urine tested regularly to be sure GLUCOTROL XL is working.
16
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GLUCOTROL XL may not work for everyone. If it does work, you may find that GLUCOTROL
XL is not working as well for you after you have used it for a while. Tell your healthcare
provider if GLUCOTROL XL is not working well.
What Should I Avoid While Taking GLUCOTROL XL?
Some medicines can affect how well GLUCOTROL XL works or may affect your blood sugar
level. Check with your healthcare provider or pharmacist before you start or stop taking
prescription or over-the-counter medicines, including natural/herbal remedies, while on
GLUCOTROL XL.
What are the Possible Side Effects of GLUCOTROL XL?
Low blood sugar. GLUCOTROL XL may lower your blood sugar to low levels that are
dangerous (hypoglycemia). This can happen if you do not follow your diet, exercise too much,
drink alcohol, are under stress, or get sick. This could also happen if your dose of GLUCOTROL
XL is higher than you need. Your healthcare provider may need to adjust it. Do not adjust the
dose on your own.
Be sure you know how to recognize your body’s signs that your blood sugar is too low. These
signs include:
• a cold clammy feeling
• hunger
• unusual sweating
• fast heartbeat
• dizziness
• headache
• weakness
• blurred vision
• trembling
• slurred speech
• shakiness
• tingling in the lips or hands
If you notice any of these signs, eat or drink something with sugar in it right away, such as a
regular (not diet) soft drink, orange juice, honey, sugar candy. You can also keep glucose tablets
on hand that are available from your pharmacy. If you do not feel better shortly or your blood
sugar level does not go up, call your healthcare provider. If you cannot reach your healthcare
provider in an emergency, call 911 or have someone drive you to the nearest emergency room.
Other side effects. GLUCOTROL XL may cause other side effects in some people. However,
the incidence of serious side effects with GLUCOTROL XL is very low. Other than the signs of
low blood sugar listed above, possible side effects include:
• feeling jittery
• diarrhea
• gas
GLUCOTROL XL may cause other less common side effects besides those listed here. For a list
of all side effects that have been reported, ask your healthcare provider or pharmacist.
While it has never been reported with GLUCOTROL XL, another similar type of diabetes
medicine has been linked to a higher risk of heart attacks. If you have risk factors for heart
disease and take GLUCOTROL XL, be sure to see your healthcare provider for regular checkups.
17
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How To Store GLUCOTROL XL
Keep GLUCOTROL XL and all medicines out of reach of children. Store GLUCOTROL XL in a
dry place, in its original container, and at room temperature (between 59°–-86°F or 15°–-30°C).
General Advice About Prescription Medicines
Medicines are sometimes prescribed for purposes other than those listed in a patient information
leaflet. If you have any concerns about GLUCOTROL XL, ask your healthcare provider. Your
healthcare provider or pharmacist can give you information about GLUCOTROL XL that was
written for healthcare professionals. Do not use GLUCOTROL XL for a condition for which it
was not prescribed. Do not share GLUCOTROL XL with other people. For more information
about GLUCOTROL XL, you can visit the Pfizer internet site at www.pfizer.com. company logo
LAB-0115-3.0
Revised October 2013
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custom-source
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2025-02-12T13:47:28.228202
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020329s028lbl.pdf', 'application_number': 20329, 'submission_type': 'SUPPL ', 'submission_number': 28}
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NDA 20330/S-029
Page 4
TIMOPTIC-XE® 0.25% and 0.5%
(TIMOLOL MALEATE OPHTHALMIC GEL FORMING SOLUTION)
DESCRIPTION
TIMOPTIC-XE® (timolol maleate ophthalmic gel forming solution) is a non-selective
beta-adrenergic receptor blocking agent. Its chemical name is (-)-1-(tert-butylamino)-3
[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol
maleate possesses an asymmetric carbon atom in its structure and is provided as the
levo-isomer. The optical rotation of timolol maleate is:
25°
[α]
in 1.0N HCl (C = 5%) = -12.2° (-11.7° to -12.5°).
405 nm
Its molecular formula is C13H24N4O3S·C4H4O4 and its structural formula is: structural formula
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline
powder which is soluble in water, methanol, and alcohol.
TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is supplied as a sterile, isotonic,
buffered, aqueous solution of timolol maleate in two dosage strengths. The pH of the
solution is approximately 7.0, and the osmolarity is 260-330 mOsm. Each mL of
TIMOPTIC-XE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of
TIMOPTIC-XE 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive
ingredients: gellan gum, tromethamine, mannitol, and water for injection. Preservative:
benzododecinium bromide 0.012%.
The gel forming solution contains a purified anionic heteropolysaccharide derived from
gellan gum. An aqueous solution of gellan gum, in the presence of a cation, has the
ability to gel. Upon contact with the precorneal tear film, TIMOPTIC-XE forms a gel that
is subsequently removed by the flow of tears.
CLINICAL PHARMACOLOGY
Mechanism of Action
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent
that does not have significant intrinsic sympathomimetic, direct myocardial depressant,
or local anesthetic (membrane-stabilizing) activity.
TIMOPTIC-XE, when applied topically on the eye, has the action of reducing elevated,
as well as normal intraocular pressure, whether or not accompanied by glaucoma.
Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous
visual field loss and optic nerve damage.
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The precise mechanism of the ocular hypotensive action of TIMOPTIC-XE is not clearly
established at this time. Tonography and fluorophotometry studies of TIMOPTIC®
(timolol maleate ophthalmic solution) in man suggest that its predominant action may be
related to reduced aqueous formation. However, in some studies, a slight increase in
outflow facility was also observed.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and
patients with heart disease. In patients with severe impairment of myocardial function,
beta-adrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic
nervous system necessary to maintain adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased
airway resistance from unopposed parasympathetic activity. Such an effect in patients
with asthma or other bronchospastic conditions is potentially dangerous.
Pharmacokinetics
In a study of plasma drug concentration in six subjects, the systemic exposure to timolol
was determined following once daily administration of TIMOPTIC-XE 0.5% in the
morning. The mean peak plasma concentration following this morning dose was 0.28
ng/mL.
Clinical Studies
In controlled, double-masked, multicenter clinical studies, comparing TIMOPTIC-XE
0.25% to TIMOPTIC 0.25% and TIMOPTIC-XE 0.5% to TIMOPTIC 0.5%, TIMOPTIC
XE administered once a day was shown to be equally effective in lowering intraocular
pressure as the equivalent concentration of TIMOPTIC administered twice a day. The
effect of timolol in lowering intraocular pressure was evident for 24 hours with a single
dose of TIMOPTIC-XE. Repeated observations over a period of six months indicate that
the intraocular pressure-lowering effect of TIMOPTIC-XE was consistent. The results
from the largest U.S. and international clinical trials comparing TIMOPTIC-XE 0.5% to
TIMOPTIC 0.5% are shown in Figure 1.
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Figure 1
Mean IOP and Std Deviation
graph
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TIMOPTIC-XE administered once daily had a safety profile similar to that of an
equivalent concentration of TIMOPTIC administered twice daily. Due to the physical
characteristics of the formulation, there was a higher incidence of transient blurred
vision in patients administered TIMOPTIC-XE. A slight reduction in resting heart rate
was observed in some patients receiving TIMOPTIC-XE 0.5% (mean reduction 24 hours
post-dose 0.8 beats/minute, mean reduction 2 hours post-dose 3.8 beats/minute) [see
ADVERSE REACTIONS].
TIMOPTIC-XE has not been studied in patients wearing contact lenses.
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INDICATIONS AND USAGE
TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is indicated in the treatment of
elevated intraocular pressure in patients with ocular hypertension or open-angle
glaucoma.
CONTRAINDICATIONS
TIMOPTIC-XE is contraindicated in patients with (1) bronchial asthma; (2) a history of
bronchial asthma; (3) severe chronic obstructive pulmonary disease [see WARNINGS];
(4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac
failure [see WARNINGS)]; (7) cardiogenic shock; or (8) hypersensitivity to any
component of this product.
WARNINGS
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
The same adverse reactions found with systemic administration of beta
adrenergic blocking agents may occur with topical ophthalmic administration.
For example, severe respiratory reactions and cardiac reactions, including death
due to bronchospasm in patients with asthma, and rarely death in association
with cardiac failure, have been reported following systemic or ophthalmic
administration of timolol maleate [see CONTRAINDICATIONS].
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals
with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor
blockade may precipitate more severe failure.
In Patients Without a History of Cardiac Failure continued depression of the
myocardium with beta-blocking agents over a period of time can, in some cases, lead to
cardiac failure. At the first sign or symptom of cardiac failure, TIMOPTIC-XE should be
discontinued.
Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis,
emphysema) of mild or moderate severity, bronchospastic disease, or a history of
bronchospastic disease (other than bronchial asthma or a history of bronchial asthma,
in which TIMOPTIC-XE is contraindicated [see CONTRAINDICATIONS] should, in
general, not receive beta-blockers, including TIMOPTIC-XE.
Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to
major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of
the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment
the risk of general anesthesia in surgical procedures. Some patients receiving beta
adrenergic receptor blocking agents have experienced protracted, severe hypotension
during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been
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reported. For these reasons, in patients undergoing elective surgery, some authorities
recommend gradual withdrawal of beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be
reversed by sufficient doses of adrenergic agonists.
Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject
to spontaneous hypoglycemia or to diabetic patients (especially those with labile
diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic
receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed
carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might
precipitate a thyroid storm.
PRECAUTIONS
General
Because of potential effects of beta-adrenergic blocking agents on blood pressure and
pulse, these agents should be used with caution in patients with cerebrovascular
insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop
following initiation of therapy with TIMOPTIC-XE, alternative therapy should be
considered.
There have been reports of bacterial keratitis associated with the use of multiple-dose
containers of topical ophthalmic products. These containers had been inadvertently
contaminated by patients who, in most cases, had a concurrent corneal disease or a
disruption of the ocular epithelial surface [see PRECAUTIONS, Information for
Patients].
Choroidal detachment after filtration procedures has been reported with the
administration of aqueous suppressant therapy (e.g. timolol).
Angle-closure glaucoma
In patients with angle-closure glaucoma, the immediate objective of treatment is to
reopen the angle. This may require constricting the pupil. Timolol maleate has little or
no effect on the pupil. TIMOPTIC-XE should not be used alone in the treatment of
angle-closure glaucoma.
Anaphylaxis
While taking beta-blockers, patients with a history of atopy or a history of severe
anaphylactic reactions to a variety of allergens may be more reactive to repeated
accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may
be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.
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Muscle Weakness
Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent
with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).
Timolol has been reported rarely to increase muscle weakness in some patients with
myasthenia gravis or myasthenic symptoms.
Information for Patients
Patients should be instructed to avoid allowing the tip of the dispensing container to
contact the eye or surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly or if the tip
of the dispensing container contacts the eye or surrounding structures, can become
contaminated by common bacteria known to cause ocular infections. Serious damage to
the eye and subsequent loss of vision may result from using contaminated solutions
[see PRECAUTIONS, General].
Patients should also be advised that if they have ocular surgery or develop an
intercurrent ocular condition (e.g., trauma or infection), they should immediately seek
their physician's advice concerning the continued use of the present multidose
container.
Patients should be instructed to invert the closed container and shake once before each
use. It is not necessary to shake the container more than once.
Patients requiring concomitant topical ophthalmic medications should be instructed to
administer these at least 10 minutes before instilling TIMOPTIC-XE.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic
obstructive pulmonary disease, sinus bradycardia, second or third degree
atrioventricular block, or cardiac failure should be advised not to take this product [see
CONTRAINDICATIONS].
Transient blurred vision, generally lasting from 30 seconds to 5 minutes, following
instillation, and potential visual disturbances may impair the ability to perform hazardous
tasks such as operating machinery or driving a motor vehicle.
Drug Interactions
Beta-adrenergic blocking agents
Patients who are receiving a beta-adrenergic blocking agent orally and TIMOPTIC-XE
should be observed for potential additive effects of beta-blockade, both systemic and on
intraocular pressure. The concomitant use of two topical beta-adrenergic blocking
agents is not recommended.
Calcium antagonists
Caution should be used in the coadministration of beta-adrenergic blocking agents,
such as TIMOPTIC-XE, and oral or intravenous calcium antagonists because of
possible atrioventricular conduction disturbances, left ventricular failure, or hypotension.
In patients with impaired cardiac function, coadministration should be avoided.
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Catecholamine-depleting drugs
Close observation of the patient is recommended when a beta blocker is administered
to patients receiving catecholamine-depleting drugs such as reserpine, because of
possible additive effects and the production of hypotension and/or marked bradycardia,
which may result in vertigo, syncope, or postural hypotension.
Digitalis and calcium antagonists
The concomitant use of beta-adrenergic blocking agents with digitalis and calcium
antagonists may have additive effects in prolonging atrioventricular conduction time.
CYP2D6 inhibitors
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been
reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and
timolol.
Clonidine
Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which
can follow the withdrawal of clonidine. There have been no reports of exacerbation of
rebound hypertension with ophthalmic timolol maleate.
Injectable epinephrine
[See PRECAUTIONS, General, Anaphylaxis]
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year study of timolol maleate administered orally to rats, there was a
statistically significant increase in the incidence of adrenal pheochromocytomas in male
rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure
following the maximum recommended human ophthalmic dose). Similar differences
were not observed in rats administered oral doses equivalent to approximately 14,000
times the maximum recommended human ophthalmic dose.
In a lifetime oral study in mice, there were statistically significant increases in the
incidence of benign and malignant pulmonary tumors, benign uterine polyps, and
mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000
times the systemic exposure following the maximum recommended human ophthalmic
dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the
systemic exposure following the maximum recommended human ophthalmic dose). In a
subsequent study in female mice, in which post-mortem examinations were limited to
the uterus and the lungs, a statistically significant increase in the incidence of
pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with
elevations in serum prolactin, which occurred in female mice administered oral timolol at
500 mg/kg/day, but not at oral doses of 5 or 50 mg/kg/day. An increased incidence of
mammary adenocarcinomas in rodents has been associated with administration of
several other therapeutic agents that elevate serum prolactin, but no correlation
between serum prolactin levels and mammary tumors has been established in humans.
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Furthermore, in adult human female subjects who received oral dosages of up to 60 mg
of timolol maleate (the maximum recommended human oral dosage), there were no
clinically meaningful changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the
micronucleus test and cytogenetic assay (doses up to 800 mg) and in vitro in a
neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests, the highest
concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with
statistically significant elevations of revertants observed with tester strain TA 100 (in
seven replicate assays), but not in the remaining three strains. In the assays with tester
strain TA 100, no consistent dose response relationship was observed, and the ratio of
test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion
for a positive Ames test.
Reproduction and fertility studies in rats demonstrated no adverse effect on male or
female fertility at doses up to 21,000 times the systemic exposure following the
maximum recommended human ophthalmic dose.
Pregnancy
Teratogenic Effects
Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50
mg/kg/day (7,000 times the systemic exposure following the maximum recommended
human ophthalmic dose) demonstrated no evidence of fetal malformations. Although
delayed fetal ossification was observed at this dose in rats, there were no adverse
effects on postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times
the systemic exposure following the maximum recommended human ophthalmic dose)
were maternotoxic in mice and resulted in an increased number of fetal resorptions.
Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the
systemic exposure following the maximum recommended human ophthalmic dose, in
this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant women. TIMOPTIC-XE
should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus.
Nursing Mothers
Timolol maleate has been detected in human milk following oral and ophthalmic drug
administration. Because of the potential for serious adverse reactions from TIMOPTIC
XE in nursing infants, 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.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and
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younger patients.
ADVERSE REACTIONS
In clinical trials, transient blurred vision upon instillation of the drop was reported in
approximately one in three patients (lasting from 30 seconds to 5 minutes). Less than
1% of patients discontinued from the studies due to blurred vision.
The frequency of patients reporting burning and stinging upon instillation was
comparable between TIMOPTIC-XE and TIMOPTIC (approximately one in eight
patients).
Adverse experiences reported in 1-5% of patients were:
Ocular:
Pain, conjunctivitis, discharge (e.g., crusting), foreign body sensation,
itching and tearing;
Systemic:
Headache, dizziness, and upper respiratory infections.
The following additional adverse experiences have been reported with the ocular
administration of this or other timolol maleate formulations:
BODY AS A WHOLE
Asthenia/fatigue, and chest pain.
CARDIOVASCULAR
Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral
vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris,
palpitation, cardiac arrest, pulmonary edema, edema, claudication, Raynaud's
phenomenon, and cold hands and feet.
DIGESTIVE
Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.
IMMUNOLOGIC
Systemic lupus erythematosus.
NERVOUS SYSTEM/PSYCHIATRIC
Increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence,
insomnia, nightmares, behavioral changes and psychic disturbances including
depression, confusion, hallucinations, anxiety, disorientation, nervousness, and memory
loss.
SKIN
Alopecia and psoriasiform rash or exacerbation of psoriasis.
HYPERSENSITIVITY
Signs and symptoms of systemic allergic reactions including anaphylaxis, angioedema,
urticaria, localized and generalized rash.
RESPIRATORY
Bronchospasm (predominantly in patients with preexisting bronchospastic disease),
respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.
ENDOCRINE
Masked symptoms of hypoglycemia in diabetic patients [see WARNINGS].
SPECIAL SENSES
Signs and symptoms of ocular irritation including blepharitis, keratitis, and dry eyes;
ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances
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including refractive changes and diplopia; pseudopemphigoid; choroidal detachment
following filtration surgery [see PRECAUTIONS, General]; and tinnitus.
UROGENITAL
Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.
The following additional adverse effects have been reported in clinical experience with
ORAL timolol maleate or other ORAL beta-blocking agents and may be considered
potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever
combined with aching and sore throat, laryngospasm with respiratory distress; Body as
a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular:
Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain,
hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic:
Nonthrombocytopenic purpura, thrombocytopenic purpura, agranulocytosis; Endocrine:
Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation,
sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local
weakness, diminished concentration, reversible mental depression progressing to
catatonia, an acute reversible syndrome characterized by disorientation for time and
place, emotional lability, slightly clouded sensorium, and decreased performance on
neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination
difficulties.
OVERDOSAGE
No data are available in regard to human overdosage with or accidental oral ingestion of
TIMOPTIC-XE.
There have been reports of inadvertent overdosage with TIMOPTIC Ophthalmic
Solution resulting in systemic effects similar to those seen with systemic beta
adrenergic blocking agents such as dizziness, headache, shortness of breath,
bradycardia, bronchospasm, and cardiac arrest [see also ADVERSE REACTIONS].
Overdosage has been reported with timolol maleate tablets. A 30-year-old female
ingested 650 mg of timolol maleate tablets (maximum recommended oral daily dose is
60 mg) and experienced second and third degree heart block. She recovered without
treatment but approximately two months later developed irregular heartbeat,
hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first
degree heart block.
An in vitro hemodialysis study, using 14C timolol added to human plasma or whole
blood, showed that timolol was readily dialyzed from these fluids; however, a study of
patients with renal failure showed that timolol did not dialyze readily.
DOSAGE AND ADMINISTRATION
Patients should be instructed to invert the closed container and shake once before each
use. It is not necessary to shake the container more than once. Other topically applied
ophthalmic medications should be administered at least 10 minutes before TIMOPTIC
XE[see PRECAUTIONS, Information for Patients and accompanying INSTRUCTIONS
FOR USE].
TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is available in concentrations of
0.25% and 0.5%. The dose is one drop of TIMOPTIC-XE (either 0.25% or 0.5%) in the
affected eye(s) once a day.
Reference ID: 3830726
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20330/S-029
Page 15
Because in some patients the pressure-lowering response to TIMOPTIC-XE may
require a few weeks to stabilize, evaluation should include a determination of intraocular
pressure after approximately 4 weeks of treatment with TIMOPTIC-XE.
Dosages higher than one drop of 0.5% TIMOPTIC-XE once a day have not been
studied. If the patient's intraocular pressure is still not at a satisfactory level on this
regimen, concomitant therapy can be considered. The concomitant use of two topical
beta-adrenergic blocking agents is not recommended [see PRECAUTIONS, Drug
Interactions, Beta-adrenergic blocking agents].
When patients have been switched from therapy with TIMOPTIC administered twice
daily to TIMOPTIC-XE administered once daily, the ocular hypotensive effect has
remained consistent.
HOW SUPPLIED
TIMOPTIC-XE® (timolol maleate ophthalmic gel forming solution) is a colorless to nearly
colorless, slightly opalescent, and slightly viscous solution.
TIMOPTIC-XE® (timolol maleate ophthalmic gel forming solution), 0.25% timolol equivalent, is
supplied in a white low density polyethylene (LDPE) dispenser with a controlled drop tip and a
yellow polypropylene cap as follows:
NDC 24208-814-25, 5 mL in a 7.5 mL capacity bottle.
TIMOPTIC-XE® (timolol maleate ophthalmic gel forming solution), 0.5% timolol equivalent, is
supplied in a white low density polyethylene (LDPE) dispenser with a controlled drop tip and a
yellow polypropylene cap as follows:
NDC 24208-816-05, 5 mL in a 7.5 mL capacity bottle.
Storage:
Store at 15-25°C (59-77°F). Avoid Freezing. Protect from light.
Distributed by: Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLC,
Bridgewater, NJ 08807 USA
TIMOPTIC and TIMOPTIC-XE are trademarks of Valeant Pharmaceuticals International, Inc. or
its affiliates.
© Bausch & Lomb Incorporated.
Revised: Month Year
Part number
Reference ID: 3830726
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20330/S-029
Page 16
Instructions for Use
TIMOPTIC-XE® (tim-op´tik-XE)
(timolol maleate ophthalmic gel forming solution) 0.25% and 0.5%
Read this Instructions for Use that comes with TIMOPTIC-XE before you start using it
and each time you get a refill. There may be new information. This information does not
take the place of talking with your doctor about your medical condition or treatment.
Important information about TIMOPTIC-XE:
Use TIMOPTIC-XE exactly as your doctor tells you to use it. Your doctor will tell you
how much TIMOPTIC-XE to use and when to use it.
If you use other medicines in your eye, wait at least 10 minutes between using
TIMOPTIC-XE and your other eye medicines.
Do not touch your eye or areas around your eye with the tip of the TIMOPTIC
XE bottle. You may get bacteria on the tip of the bottle that can cause you to get an
eye infection that can lead to serious eye damage or vision loss.
How should I use TIMOPTIC-XE?
Step 1. Wash your hands.
Step 2. Turn your closed bottle of TIMOPTIC-XE upside down (invert) and shake once.
Step 3. Remove the TIMOPTIC-XE cap by turning the cap in the direction of the arrows
shown (See Figure A). Put the cap in a clean and dry area. Do not let the tip of the
bottle touch your fingers or other surfaces. usage illustration
Figure A
Step 4. Hold the bottle between your thumb and index finger with 1 hand. Use the index finger
of the other hand to pull down the lower eyelid to form a pocket for the eye drop (See Figure
B).Tilt your head backwards. usage illustration
Figure B
Step 5. Place the tip of the bottle close to your eye. Be careful not to touch your eye with the
tip of the bottle. Gently squeeze the bottle and let 1 drop fall into the space between your lower
eyelid and your eye (See Figure C). If a drop misses your eye, follow the instructions in steps 4
and 5 again.
Reference ID: 3830726
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20330/S-029
Page 17 usage illustration
Figure C
Step 6. If your doctor has told you to use TIMOPTIC-XE in both eyes, repeat steps 4 and 5 for
your other eye.
Step 7. Put the cap back on the bottle and close.
The TIMOPTIC-XE bottle tip is made to give 1 drop at a time. Do not try to make the hole in
the tip of your bottle bigger.
Do not wash the bottle tip.
After you have used all of your TIMOPTIC-XE doses, there will be some TIMOPTIC-XE left
in the bottle. Do not try to remove the extra TIMOPTIC-XE from the bottle. Throw it away.
How should I store TIMOPTIC-XE?
Store TIMOPTIC-XE at room temperature between 59⁰F to 77⁰F (20⁰C to 25⁰C) in an
upright position.
Do not freeze TIMOPTIC-XE.
Keep TIMOPTIC-XE out of light.
Keep TIMOPTIC-XE and all medicines out of the reach of children.
If you would like more information, talk with your doctor. You can ask your pharmacist or doctor
for more information about TIMOPTIC-XE that is written for health professionals.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed by: Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLC,
Bridgewater, NJ 08807 USA
TIMOPTIC and TIMOPTIC-XE are trademarks of Valeant Pharmaceuticals International, Inc. or
its affiliates.
© Bausch & Lomb Incorporated.
Revised: Month Year
Part number
Reference ID: 3830726
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020330s029lbl.pdf', 'application_number': 20330, 'submission_type': 'SUPPL ', 'submission_number': 29}
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STERILE OPHTHALMIC GEL FORMING SOLUTION
TIMOPTIC-XE®
0.25% AND 0.5%
(TIMOLOL MALEATE OPHTHALMIC GEL FORMING SOLUTION)
DESCRIPTION
TIMOPTIC-XE* (timolol maleate ophthalmic gel forming solution) is a non-selective beta-adrenergic receptor
blocking agent. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-
propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is
provided as the levo-isomer. The optical rotation of timolol maleate is:
25°
[α]
in 1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°).
405 nm
Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in
water, methanol, and alcohol.
TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is supplied as a sterile, isotonic, buffered, aqueous
solution of timolol maleate in two dosage strengths. The pH of the solution is approximately 7.0, and the
osmolarity is 260-330 mOsm. Each mL of TIMOPTIC-XE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol
maleate). Each mL of TIMOPTIC-XE 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive
ingredients: GELRITE gellan gum, tromethamine, mannitol, and water for injection. Preservative:
benzododecinium bromide 0.012%.
GELRITE is a purified anionic heteropolysaccharide derived from gellan gum. An aqueous solution of
GELRITE, in the presence of a cation, has the ability to gel. Upon contact with the precorneal tear film,
TIMOPTIC-XE forms a gel that is subsequently removed by the flow of tears.
CLINICAL PHARMACOLOGY
Mechanism of Action
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have
significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing)
activity.
TIMOPTIC-XE, when applied topically on the eye, has the action of reducing elevated, as well as normal
intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk
factor in the pathogenesis of glaucomatous visual field loss and optic nerve damage.
The precise mechanism of the ocular hypotensive action of TIMOPTIC-XE is not clearly established at this
time. Tonography and fluorophotometry studies of TIMOPTIC* (timolol maleate ophthalmic solution) in man
suggest that its predominant action may be related to reduced aqueous formation. However, in some studies, a
slight increase in outflow facility was also observed.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart
disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor blockade may
inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac
function.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1993, 2003
All rights reserved
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-330/S-018
NDA 20-330/S-019
Page 4
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from
unopposed parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions
is potentially dangerous.
Pharmacokinetics
In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined
following once daily administration of TIMOPTIC-XE 0.5% in the morning. The mean peak plasma concentration
following this morning dose was 0.28 ng/mL.
Clinical Studies
In controlled, double-masked, multicenter clinical studies, comparing TIMOPTIC-XE 0.25% to TIMOPTIC
0.25% and TIMOPTIC-XE 0.5% to TIMOPTIC 0.5%, TIMOPTIC-XE administered once a day was shown to be
equally effective in lowering intraocular pressure as the equivalent concentration of TIMOPTIC administered
twice a day. The effect of timolol in lowering intraocular pressure was evident for 24 hours with a single dose of
TIMOPTIC-XE. Repeated observations over a period of six months indicate that the intraocular pressure-
lowering effect of TIMOPTIC-XE was consistent. The results from the largest U.S. and international clinical trials
comparing TIMOPTIC-XE 0.5% to TIMOPTIC 0.5% are shown in Figure 1.
Figure 1
Mean IOP and Std Deviation
(mm Hg) by Treatment Group
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NDA 20-330/S-018
NDA 20-330/S-019
Page 5
TIMOPTIC-XE administered once daily had a safety profile similar to that of an equivalent concentration of
TIMOPTIC administered twice daily. Due to the physical characteristics of the formulation, there was a higher
incidence of transient blurred vision in patients administered TIMOPTIC-XE. A slight reduction in resting heart
rate was observed in some patients receiving TIMOPTIC-XE 0.5% (mean reduction 24 hours post-dose
0.8 beats/minute, mean reduction 2 hours post-dose 3.8 beats/minute). (See ADVERSE REACTIONS.)
TIMOPTIC-XE has not been studied in patients wearing contact lenses.
INDICATIONS AND USAGE
TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is indicated in the treatment of elevated intraocular
pressure in patients with ocular hypertension or open-angle glaucoma.
CONTRAINDICATIONS
TIMOPTIC-XE is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma;
(3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5) second or third
degree atrioventricular block; (6) overt cardiac failure (see WARNINGS); (7) cardiogenic shock; or
(8) hypersensitivity to any component of this product.
WARNINGS
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
The same adverse reactions found with systemic administration of beta-adrenergic blocking agents
may occur with topical ophthalmic administration. For example, severe respiratory reactions and
cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in
association with cardiac failure, have been reported following systemic or ophthalmic administration of
timolol maleate. (See CONTRAINDICATIONS.)
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished
myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe
failure.
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NDA 20-330/S-019
Page 6
In Patients Without a History of Cardiac Failure, continued depression of the myocardium with beta-blocking
agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac
failure, TIMOPTIC-XE should be discontinued.
Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or
moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma
or a history of bronchial asthma, in which TIMOPTIC-XE is contraindicated [see CONTRAINDICATIONS])
should, in general, not receive beta-blockers, including TIMOPTIC-XE.
Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is
controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-
adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures.
Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted, severe
hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For
these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of
beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient
doses of adrenergic agonists.
Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous
hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral
hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute
hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.
Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-
adrenergic blocking agents that might precipitate a thyroid storm.
PRECAUTIONS
General
Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents
should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting
reduced cerebral blood flow develop following initiation of therapy with TIMOPTIC-XE, alternative therapy
should be considered.
There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical
ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases,
had a concurrent corneal disease or a disruption of the ocular epithelial surface. (See PRECAUTIONS,
Information for Patients.)
Choroidal detachment after filtration procedures has been reported with the administration of aqueous
suppressant therapy (e.g. timolol).
Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to
reopen the angle. This may require constricting the pupil. Timolol maleate has little or no effect on the pupil.
TIMOPTIC-XE should not be used alone in the treatment of angle-closure glaucoma.
Anaphylaxis: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic
reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic
challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to
treat anaphylactic reactions.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent
with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported
rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.
Information for Patients
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or
surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing
container contacts the eye or surrounding structures, can become contaminated by common bacteria known to
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-330/S-018
NDA 20-330/S-019
Page 7
cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using
contaminated solutions. (See PRECAUTIONS, General.)
Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition
(e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use
of the present multidose container.
Patients should be instructed to invert the closed container and shake once before each use. It is not
necessary to shake the container more than once.
Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at
least 10 minutes before instilling TIMOPTIC-XE.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease,
sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take
this product. (See CONTRAINDICATIONS.)
Transient blurred vision, generally lasting from 30 seconds to 5 minutes, following instillation, and potential
visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a
motor vehicle.
Drug Interactions
Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and
TIMOPTIC-XE should be observed for potential additive effects of beta-blockade, both systemic and on
intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.
Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking agents,
such as TIMOPTIC-XE, and oral or intravenous calcium antagonists because of possible atrioventricular
conduction disturbances, left ventricular failure, or hypotension. In patients with impaired cardiac function,
coadministration should be avoided.
Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta blocker is
administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible
additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo,
syncope, or postural hypotension.
Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digitalis and
calcium antagonists may have additive effects in prolonging atrioventricular conduction time.
Quinidine: Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during
combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via
the P-450 enzyme, CYP2D6.
Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow
the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with
ophthalmic timolol maleate.
Injectable epinephrine: (See PRECAUTIONS, General, Anaphylaxis)
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase
in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately
42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar
differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the
maximum recommended human ophthalmic dose.
In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and
malignant pulmonary tumors, benign uterine polyps, and mammary adenocarcinomas in female mice at
500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended
human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the
systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in
female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically
significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin,
which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at oral doses of 5 or
50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with
administration of several other therapeutic agents that elevate serum prolactin, but no correlation between
serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human
female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended
human oral dosage), there were no clinically meaningful changes in serum prolactin.
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Page 8
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and
cytogenetic assay (doses up to 800 mg) and in vitro in a neoplastic cell transformation assay (up to
100 mcg/mL). In Ames tests, the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were
associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven
replicate assays), but not in the remaining three strains. In the assays with tester strain TA 100, no consistent
dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2
is usually considered the criterion for a positive Ames test.
Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses
up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.
Pregnancy:
Teratogenic Effects — Pregnancy Category C. Teratogenicity studies with timolol in mice, rats, and rabbits at
oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended
human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification
was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses
of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human
ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased
fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the
maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant women. TIMOPTIC-XE should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Timolol maleate has been detected in human milk following oral and ophthalmic drug administration.
Because of the potential for serious adverse reactions from TIMOPTIC-XE in nursing infants, 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.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
ADVERSE REACTIONS
In clinical trials, transient blurred vision upon instillation of the drop was reported in approximately one in
three patients (lasting from 30 seconds to 5 minutes). Less than 1% of patients discontinued from the studies
due to blurred vision. The frequency of patients reporting burning and stinging upon instillation was comparable
between TIMOPTIC-XE and TIMOPTIC (approximately one in eight patients).
Adverse experiences reported in 1-5% of patients were:
Ocular:
Pain, conjunctivitis, discharge
(e.g., crusting), foreign body sensation,
itching and tearing;
Systemic:
Headache, dizziness, and upper respiratory
infections.
The following additional adverse experiences have been reported with the ocular administration of this or
other timolol maleate formulations:
BODY AS A WHOLE
Asthenia/fatigue, and chest pain.
CARDIOVASCULAR
Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident,
cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema,
edema, claudication, Raynaud's phenomenon, and cold hands and feet.
DIGESTIVE
Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.
IMMUNOLOGIC
Systemic lupus erythematosus.
NERVOUS SYSTEM/PSYCHIATRIC
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Increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares,
behavioral changes and psychic disturbances including depression, confusion, hallucinations, anxiety,
disorientation, nervousness, and memory loss.
SKIN
Alopecia and psoriasiform rash or exacerbation of psoriasis.
HYPERSENSITIVITY
Signs and symptoms of systemic allergic reactions including anaphylaxis, angioedema, urticaria, localized
and generalized rash.
RESPIRATORY
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure,
dyspnea, nasal congestion, and cough.
ENDOCRINE
Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS).
SPECIAL SENSES
Signs and symptoms of ocular irritation including blepharitis, keratitis, and dry eyes; ptosis; decreased
corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia;
pseudopemphigoid; choroidal detachment following filtration surgery (see PRECAUTIONS, General); and
tinnitus.
UROGENITAL
Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.
The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate
or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate:
Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory
distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular:
Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting,
mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura, thrombocytopenic
purpura, agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased
pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness,
diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome
characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased
performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.
OVERDOSAGE
No data are available in regard to human overdosage with or accidental oral ingestion of TIMOPTIC-XE.
There have been reports of inadvertent overdosage with TIMOPTIC Ophthalmic Solution resulting in
systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness,
headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see also ADVERSE
REACTIONS).
Overdosage has been reported with Tablets BLOCADREN* (timolol maleate tablets). A 30 year old female
ingested 650 mg of BLOCADREN (maximum recommended oral daily dose is 60 mg) and experienced second
and third degree heart block. She recovered without treatment but approximately two months later developed
irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree
heart block.
An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that timolol
was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not
dialyze readily.
DOSAGE AND ADMINISTRATION
Patients should be instructed to invert the closed container and shake once before each use. It is not
necessary to shake the container more than once. Other topically applied ophthalmic medications should be
administered at least 10 minutes before TIMOPTIC-XE. (See PRECAUTIONS, Information for Patients and
accompanying INSTRUCTIONS FOR USE.)
TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is available in concentrations of 0.25% and 0.5%.
The dose is one drop of TIMOPTIC-XE (either 0.25% or 0.5%) in the affected eye(s) once a day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-330/S-018
NDA 20-330/S-019
Page 10
Because in some patients the pressure-lowering response to TIMOPTIC-XE may require a few weeks to
stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of
treatment with TIMOPTIC-XE.
Dosages higher than one drop of 0.5% TIMOPTIC-XE once a day have not been studied. If the patient's
intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy can be considered.
The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See
PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)
When patients have been switched from therapy with TIMOPTIC administered twice daily to TIMOPTIC-XE
administered once daily, the ocular hypotensive effect has remained consistent.
HOW SUPPLIED
TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is a colorless to nearly colorless, slightly opalescent,
and slightly viscous solution.
No. 3557 — TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution, 0.25% timolol equivalent, is supplied in
an OCUMETER®* PLUS container, a white, translucent, HDPE plastic ophthalmic dispenser with a controlled
drop tip and a white polystyrene cap with yellow label as follows:
NDC 0006-3557-35, 5 mL in a 7.5 mL bottle.
No. 3558 — TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution, 0.5% timolol equivalent, is supplied in
an OCUMETER PLUS container, a white, translucent, HDPE plastic ophthalmic dispenser with a controlled drop
tip and a white polystyrene cap with yellow label as follows:
NDC 0006-3558-35, 5 mL in a 7.5 mL bottle.
Storage
Store at 15-30°C (59-86°F). AVOID FREEZING. Protect from light.
By: Laboratories Merck Sharp & Dohme-Chibret
63963 Clermont-Ferrand Cedex 9, France
Issued September 2002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-330/S-018
NDA 20-330/S-019
Page 11
INSTRUCTIONS FOR USE
Please follow these instructions carefully when using TIMOPTIC-XE*. Use TIMOPTIC-XE as prescribed by
your doctor.
1. If you use other topically applied ophthalmic medications, they should be administered at least 10
minutes before TIMOPTIC-XE.
2. Wash hands before each use.
3. Before using the medication for the first time, be sure the Safety Strip on the front of the bottle is
unbroken. A gap between the bottle and the cap is normal for an unopened bottle.
4. Tear off the safety strip to break the seal.
5. Invert the closed bottle and shake ONCE before each use. (It is not necessary to shake the bottle
more than once.)
6. To open the bottle, unscrew the cap by turning as indicated by the arrows.
Opening Arrows 4
Safety Strip4
Gap4
Finger Push Area4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-330/S-018
NDA 20-330/S-019
Page 12
7. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid
and your eye.
8. Invert the bottle, and press lightly with the thumb or index finger over the “Finger Push Area” (as
shown) until a single drop is dispensed into the eye as directed by your doctor.
DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.
Ophthalmic medications, if handled improperly, can become contaminated by common bacteria
known to cause eye infections. Serious damage to the eye and subsequent loss of vision may result
from using contaminated ophthalmic medications. If you think your medication may be
contaminated, or you develop an eye infection, contact your doctor immediately concerning
continued use of this bottle.
9. Repeat steps 7 & 8 with the other eye if instructed to do so by your doctor.
10. Replace the cap by turning until it is firmly touching the bottle. Do not overtighten the cap.
w Finger Push Area
Finger Push Area4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-330/S-018
NDA 20-330/S-019
Page 13
11. The dispenser tip is designed to provide a pre-measured drop; therefore, do NOT
enlarge the hole of the dispenser tip.
12. After you have used all doses, there will be some TIMOPTIC-XE left in the bottle. You should not
be concerned since an extra amount of TIMOPTIC-XE has been added and you will get the full
amount of TIMOPTIC-XE that your doctor prescribed. Do not attempt to remove excess medicine
from the bottle.
WARNING: Keep out of reach of children.
If you have any questions about the use of TIMOPTIC-XE, please consult your doctor.
* Registered trademark of MERCK & CO., Inc.
Issued September 2002
MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1995, 2003
Whitehouse Station, NJ 08889, USA
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 20-330/S-018
NDA 20-330/S-019
Page 14
Container Labeling
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-330/S-018
NDA 20-330/S-019
Page 15
Carton Labeling
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:28.402828
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20330s018,019lbl.pdf', 'application_number': 20330, 'submission_type': 'SUPPL ', 'submission_number': 19}
|
12,452
|
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
•
Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas:
These highlights do not include all the information needed to use
Inform patient of risks, benefits and treatment alternatives (5.3).
GLUCOTROL XL safely and effectively. See full prescribing information
•
Macrovascular Outcomes: No clinical studies have established conclusive
for GLUCOTROL XL.
evidence of macrovascular risk reduction with GLUCOTROL XL or any
other anti-diabetic drug (5.4).
GLUCOTROL XL® (glipizide) extended release tablets, for oral use
Initial U.S. Approval: 1994
----------------------------------ADVERSE REACTIONS-----------------------------------
Most common adverse reactions (incidence > 3%) are dizziness, diarrhea,
------------------------INDICATIONS AND USAGE------------------------
nervousness, tremor, hypoglycemia and flatulence (6.1).
GLUCOTROL XL is a sulfonylurea indicated as an adjunct to diet and
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at
exercise to improve glycemic control in adults with type 2 diabetes mellitus
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Limitations of Use: Not for treatment of type 1 diabetes or diabetic
ketoacidosis
-----------------------------------DRUG INTERACTIONS----------------------------------
-----------------------DOSAGE AND ADMINISTRATION----------------
•
Miconazole: Monitor patients closely. Severe hypoglycemia can occur
•
Recommended starting dose is 5 mg once daily. Dose adjustment can be
when GLUCOTROL and oral miconazole are used concomitantly (7.1,
made based on the patient’s glycemic control. Maximum recommended
12.3).
dose is 20 mg once daily (2.1).
•
Fluconazole: Monitor patients closely. An increase in GLUCOTROL
•
Administer with breakfast or the first meal of the day (2.1).
AUC was seen after fluconazole administration (7.2, 12.3).
•
For combination therapy with other blood-glucose-lowering agents,
•
Colesevelam: GLUCOTROL XL should be administered at least 4 hours
initiate the agent at the lowest recommended dose, and observe patients
prior to colesevelam (7.3, 12.3).
for hypoglycemia (2.2).
-------------------------------USE IN SPECIFIC POPULATIONS---------------------
•
Pregnancy: Based on animal data, may cause fetal harm (8.1).
----------------------------DOSAGE FORMS AND STRENGTHS---------------------
•
Nursing Mothers: Discontinue GLUCOTROL XL or nursing taking into
Tablets: 2.5 mg, 5 mg, 10 mg (3).
consideration the importance of GLUCOTROL XL to the mother (8.2).
•
Geriatric, Hepatically Impaired Patients: At risk for hypoglycemia with
------------------------------------CONTRAINDICATIONS--------------------------------
GLUCOTROL XL. Use caution in dose selection and titration, and
•
Known hypersensitivity to glipizide or any of the product’s ingredients
monitor closely (8.5, 8.6).
(4)
•
Hypersensitivity to sulfonamide derivatives (4)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
------------------------------WARNINGS AND PRECAUTIONS----------------
•
Hypoglycemia: May be severe. Ensure proper patient selection, dosing,
Revised: [10/2015]
and instructions, particularly in at-risk populations (e.g., elderly, renally
impaired) and when used with other anti-diabetic medications (5.1).
•
Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase
(G6PD) deficient. Consider a non-sulfonylurea alternative (5.2).
FULL PRESCRIBING INFORMATION: CONTENTS*
7.3 Colesevelam
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
1
INDICATIONS AND USAGE
8.3 Nursing Mothers
1.1 Limitations of Use
8.4 Pediatric Use
2
DOSAGE AND ADMINISTRATION
8.5 Geriatric Use
2.1 Recommended Dosing
8.6 Hepatic Impairment
2.2 Use with Other Glucose Lowering Agents
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 Hypoglycemia
12.2 Pharmacodynamics
5.2 Hemolytic Anemia
12.3 Pharmacokinetics
5.3 Increased Risk of Cardiovascular Mortality with Sulfonylureas
13 NONCLINICAL TOXICOLOGY
5.4 Macrovascular Outcomes
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.5 Gastrointestinal Obstruction
15
REFERENCES
6
ADVERSE REACTIONS
16
HOW SUPPLIED/STORAGE AND HANDLING
6.1 Clinical Trials Experience
17
PATIENT COUNSELING INFORMATION
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
*Sections or subsections omitted from the full prescribing information are not
7.1 Miconazole
listed.
7.2 Fluconazole
Reference ID: 3828936
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
GLUCOTROL XL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
mellitus.
1.1 Limitations of Use
GLUCOTROL XL is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
GLUCOTROL XL should be administered orally with breakfast or the first main meal of the day.
The recommended starting dose of GLUCOTROL XL is 5 mg once daily. Start patients at increased risk for hypoglycemia (e.g.
the elderly or patients with hepatic insufficiency) at 2.5 mg [see Use in Specific Population (8.5, 8.6)].
Dosage adjustment can be made based on the patient’s glycemic control. The maximum recommended dose is 20 mg once daily.
Patients receiving immediate release glipizide may be switched to GLUCOTROL XL once daily at the nearest equivalent total
daily dose.
2.2 Use with Other Glucose Lowering Agents
When adding GLUCOTROL XL to other anti-diabetic drugs, initiate GLUCOTROL XL at 5 mg once daily. Start patients at
increased risk for hypoglycemia at a lower dose.
When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is
reduced. Therefore, GLUCOTROL XL should be administered at least 4 hours prior to colesevelam.
3
DOSAGE FORMS AND STRENGTHS
GLUCOTROL XL (glipizide) Extended Release tablets:
2.5 mg, blue and imprinted with “GLUCOTROL XL 2.5” or “GXL 2.5” on one side
5 mg, white and imprinted with “GLUCOTROL XL 5” or “GXL 5” on one side
10 mg, white and imprinted with “GLUCOTROL XL 10” or “GXL 10” on one side
4
CONTRAINDICATIONS
Glipizide is contraindicated in patients with:
•
Known hypersensitivity to glipizide or any of the product’s ingredients.
•
Hypersensitivity to sulfonamide derivatives.
5
WARNINGS AND PRECAUTIONS
5.1 Hypoglycemia
All sulfonylurea drugs, including GLUCOTROL XL, are capable of producing severe hypoglycemia [see Adverse Reactions (6)].
Concomitant use of GLUCOTROL XL with other anti-diabetic medication can increase the risk of hypoglycemia. A lower dose
of GLUCOTROL XL may be required to minimize the risk of hypoglycemia when combining it with other anti-diabetic
medications.
Educate patients to recognize and manage hypoglycemia. When initiating and increasing GLUCOTROL XL in patients who may
be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications)
start at 2.5 mg. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly
susceptible to the hypoglycemic action of anti-diabetic medications. Hypoglycemia is also more likely to occur when caloric
intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.
The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. Early warning symptoms of
hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are
taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia
before the patient is aware of the hypoglycemia.
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
These impairments may present a risk in situations where these abilities are especially important, such as driving or operating
other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent
impairment of brain function or death.
5.2 Hemolytic Anemia
Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including
GLUCOTROL XL, can lead to hemolytic anemia. Avoid use of GLUCOTROL XL in patients with G6PD deficiency. In post
marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
5.3 Increased Risk of Cardiovascular Mortality with Sulfonylureas
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as
compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group
Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs
in preventing or delaying vascular complications in patients with type 2 diabetes mellitus. The study involved 823 patients who
were randomly assigned to one of four treatment groups.
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of
cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality
was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the
opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these
results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the
potential risks and advantages of glipizide and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to
consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in
mode of action and chemical structure.
5.4 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOTROL XL or
any other anti-diabetic drug.
5.5 Gastrointestinal Obstruction
There have been reports of obstructive symptoms in patients with known strictures in association with the ingestion of another
drug with this non-dissolvable extended release formulation. Avoid use of GLUCOTROL XL in patients with preexisting severe
gastrointestinal narrowing (pathologic or iatrogenic).
ADVERSE REACTIONS
The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:
•
Hypoglycemia [see Warnings and Precautions (5.1)]
•
Hemolytic anemia [see Warnings and Precautions (5.2)]
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.
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In clinical trials, 580 patients from 31 to 87 years of age received GLUCOTROL XL in doses from 5 mg to 60 mg in both
controlled and open trials. The dosages above 20 mg are not recommended dosages. In these trials, approximately 180 patients
were treated with GLUCOTROL XL for at least 6 months.
Table 1 summarizes the incidence of adverse reactions, other than hypoglycemia, that were reported in pooled double-blind,
placebo-controlled trials in ≥3% of GLUCOTROL XL-treated patients and more commonly than in patients who received
placebo.
Table 1: Incidence (%) of Adverse Reactions Reported in ≥3% of Patients Treated
in Placebo-Controlled Clinical Trials and More Commonly in Patients Treated
with GLUCOTROL XL (Excluding Hypoglycemia)
GLUCOTROL XL (%)
Placebo (%)
(N=278)
(N=69)
Adverse Effect
Dizziness
6.8
5.8
Diarrhea
5.4
0.0
Nervousness
3.6
2.9
Tremor
3.6
0.0
Flatulence
3.2
1.4
Hypoglycemia:
Of the 580 patients that received GLUCOTROL XL in clinical trials, 3.4% had hypoglycemia documented by a blood-glucose
measurement <60 mg/dL and/or symptoms believed to be associated with hypoglycemia and 2.6% of patients discontinued for this
reason. Hypoglycemia was not reported for any placebo patients.
Gastrointestinal Reactions
In clinical trials, the incidence of gastrointestinal (GI) side effects (nausea, vomiting, constipation, dyspepsia), occurred in less than
3% of GLUCOTROL XL-treated patients and were more common in GLUCOTROL XL-treated patients than those receiving
placebo.
Dermatologic Reactions
In clinical trials, allergic skin reactions, i.e., urticaria occurred in less than 1.5% of treated patients and were more common in
GLUCOTROL XL treated patients than those receiving placebo. These may be transient and may disappear despite continued use
of glipizide XL; if skin reactions persist, the drug should be discontinued.
Laboratory Tests: Mild to moderate elevations of ALT, LDH, alkaline phosphatase, BUN and creatinine have been noted. The
relationship of these abnormalities to glipizide is uncertain.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of GLUCOTROL XL. 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.
•
Abdominal pain
•
Cholestatic and hepatocellular forms of liver injury accompanied by jaundice
•
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia [see Warnings and Precautions (5.2)], aplastic
anemia, pancytopenia
•
Hepatic porphyria and disulfiram-like reactions
•
Hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion
•
Rash
•
There have been reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug with this non-
dissolvable extended release formulation.
Reference ID: 3828936
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 Miconazole
Monitor patients closely for hypoglycemia when Glucotrol XL is co-administered with miconazole. A potential interaction
between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported [see Clinical
Phamacology (12.3)].
7.2 Fluconazole
Monitor patients closely for hypoglycemia when Glucotrol XL is co-administered with fluconazole. Concomitant treatment with
fluconazole increases plasma concentrations of glipizide, which may lead to hypoglycemia [see Clinical Pharmacology (12.3)].
7.3 Colesevelam
GLUCOTROL XL should be administered at least 4 hours prior to the administration of colesevelam. Colesevelam can reduce the
maximum plasma concentration and total exposure of glipizide when the two are coadministered [see Clinical Pharmacology
(12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1. Pregnancy
Pregnancy Category C: Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5–50 mg/kg). This
fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and
believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. There are no adequate and well controlled
studies in pregnant women. GLUCOTROL XL should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were
receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with
prolonged half-lives. If glipizide is used during pregnancy, it should be discontinued at least one month before the expected
delivery date.
8.3. Nursing Mothers
It is not known whether GLUCOTROL XL is excreted in human milk. Because the potential for hypoglycemia in nursing infants
may exist, 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.
8.4. Pediatric Use
Safety and effectiveness in children have not been established.
8.5 Geriatric Use
There were no overall differences in effectiveness or safety between younger and older patients, but greater sensitivity of some
individuals cannot be ruled out. Elderly patients are particularly susceptible to the hypoglycemic action of anti-diabetic agents.
Hypoglycemia may be difficult to recognize in these patients. Therefore, dosing should be conservative to avoid hypoglycemia.
[see Dosage and Administration (2.1), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]
8.6 Hepatic Impairment
There is no information regarding the effects of hepatic impairment on the disposition of glipizide. However, since glipizide is
highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or
pharmacodynamics of glipizide may be altered in patients with hepatic impairment. If hypoglycemia occurs in such patients, it
may be prolonged and appropriate management should be instituted. [see Dosage and Administration (2.1), Warnings and
Precautions (5.1) and Clinical Pharmacology (12.3)]
10 OVERDOSAGE
Overdosage of sulfonylureas including glipizide can produce severe hypoglycemia. Mild hypoglycemic symptoms without loss of
consciousness or neurologic findings should be treated with oral glucose. Severe hypoglycemic reactions with coma, seizure, or
other neurological impairment are medical emergencies requiring immediate treatment. The patient should be treated with
glucagon or intravenous glucose. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may
recur after apparent clinical recovery. Clearance of glipizide from plasma may be prolonged in persons with liver disease.
Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11 DESCRIPTION
GLUCOTROL XL (glipizide) is an oral sulfonylurea.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea.
The molecular formula is C 21 H27N5O4S; the molecular weight is 445.55; the structural formula is shown below: structural formula
Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is
freely soluble in dimethylformamide.
Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: polyethylene oxide, hypromellose, magnesium stearate, sodium
chloride, red ferric oxide, cellulose acetate, polyethylene glycol, Opadry® blue (OY-LS-20921)(2.5 mg tablets), Opadry® white
(YS-2-7063)(5 mg and 10 mg tablet) and Opacode® Black Ink (S-1-17823).
System Components and Performance
GLUCOTROL XL Extended Release Tablet is similar in appearance to a conventional tablet. It consists, however, of an
osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an “active”
layer containing the drug, and a “push” layer containing pharmacologically inert (but osmotically active) components. The
membrane surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal
tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, resulting in the release of drug
through a small, laser-drilled orifice in the membrane on the drug side of the tablet.
The function of the GLUCOTROL XL Extended Release Tablet depends upon the existence of an osmotic gradient between the
contents of the bi-layer core and fluid in the GI tract. The biologically inert components of the tablet remain intact during GI
transit and are eliminated in the feces as an insoluble shell.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Glipizide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon
functioning beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma
membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
12.2 Pharmacodynamics
The insulinotropic response to a meal is enhanced with GLUCOTROL XL administration in diabetic patients. The postprandial
insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In two randomized, double-blind,
dose-response studies comprising a total of 347 patients, there was no significant increase in fasting insulin in all GLUCOTROL
XL-treated patients combined compared to placebo, although minor elevations were observed at some doses.
In studies of GLUCOTROL XL in subjects with type 2 diabete mellitus, once daily administration produced reductions in
hemoglobin A1c, fasting plasma glucose and postprandial glucose. The relationship between dose and reduction in hemoglobin
A1c was not established, however subjects treated with 20 mg had a greater reduction in fasting plasma glucose compared to
subjects treated with 5 mg.
12.3 Pharmacokinetics
Absorption
The absolute bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes mellitus. Beginning 2 to
3 hours after administration of GLUCOTROL XL, plasma drug concentrations gradually rise reaching maximum concentrations
within 6 to 12 hours after dosing. With subsequent once daily dosing of GLUCOTROL XL, plasma glipizide concentrations are
maintained throughout the 24 hour dosing interval with less peak to trough fluctuation than that observed with twice daily dosing
of immediate release glipizide.
The mean relative bioavailability of glipizide in 21 males with type 2 diabetes mellitus after administration of 20 mg
GLUCOTROL XL, compared to immediate release Glucotrol (10 mg given twice daily), was 90% at steady-state. Steady-state
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
plasma concentrations were achieved by at least the fifth day of dosing with GLUCOTROL XL in 21 males with type 2 diabetes
mellitus and patients younger than 65 years. No accumulation of drug was observed in patients with type 2 diabetes mellitus
during chronic dosing with GLUCOTROL XL.
Administration of GLUCOTROL XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food
effect study in 21 healthy male subjects, the administration of GLUCOTROL XL immediately before a high fat breakfast resulted
in a 40% increase in the glipizide mean C max value, which was significant, but the effect on the AUC was not significant. There
was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the GLUCOTROL
XL tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and
potentially result in lower plasma concentrations.
In a multiple dose study in 26 males with type 2 diabetes mellitus, the pharmacokinetics of glipizide were linear with
GLUCOTROL XL in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24
healthy subjects, four 5-mg, two 10-mg, and one 20-mg GLUCOTROL XL tablets were bioequivalent. In a separate single dose
study in 36 healthy subjects, four 2.5-mg GLUCOTROL XL tablets were bioequivalent to one 10-mg GLUCOTROL XL tablet.
Distribution
The mean volume of distribution was approximately 10 liters after single intravenous doses in patients with type 2 diabetes
mellitus. Glipizide is 98–99% bound to serum proteins, primarily to albumin.
Metabolism
The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor
metabolite, an acetylamino-ethyl benzene derivative, which accounts for less than 2% of a dose, is reported to have 1/10 to 1/3 as
much hypoglycemic activity as the parent compound.
Elimination
Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and
feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%).
The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in patients with type
2 diabetes mellitus. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in
patients with type 2 diabetes mellitus.
Specific Populations
Pediatric:
Studies characterizing the pharmacokinetics of glipizide in pediatric patients have not been performed.
Geriatric:
There were no differences in the pharmacokinetics of glipizide after single dose administration to older diabetic subjects
compared to younger healthy subjects. [see Use in Specific Populations (8.5)]
Renal Impairment:
The pharmacokinetics of glipizide has not been evaluated in patients with varying degree of renal impairment. Limited data
indicates that glipizide biotransformation products may remain in circulation for a longer time in subjects with renal impairment
than that seen in subjects with normal renal function.
Hepatic Impairment:
The pharmacokinetics of glipizide has not been evaluated in patients with hepatic impairment.
Drug-drug Interactions
Miconazole
A potential interaction between oral miconazole and oral glipizide leading to severe hypoglycemia has been reported. Whether
this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. [see Drug
Interactions (7.1)]
Fluconazole
Concomitant treatment with fluconazole increases plasma concentrations of glipizide. The effect of concomitant administration
of Diflucan® (fluconazole) and Glucotrol has been demonstrated in a placebo controlled crossover study in healthy volunteers. All
subjects received Glucotrol alone and following treatment with 100 mg of Diflucan® as a single daily oral dose for 7 days. The
mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%). [see Drug
Interactions (7.2)]
Colesevelam
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Colesevelam can reduce the maximum plasma concentration and total exposure of glipizide when the two are coadministered. In
studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy volunteers, reductions in glipizide
AUC 0-∞ and C max of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide ER. When
glipizide ER was administered 4 hours prior to colesevelam, there was no significant change in glipizide AUC 0-∞ or Cmax , -4%
and 0%, respectively. [see Drug Interactions (7.3)]
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility
A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum human dose revealed no
evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both
sexes at doses up to 75 times the human dose showed no effects on fertility.
15 REFERENCES
1. Diabetes, 19, SUPP. 2: 747–830, 1970
16 HOW SUPPLIED/STORAGE AND HANDLING
GLUCOTROL XL (glipizide) Extended Release Tablets are supplied as 2.5 mg, 5 mg, and 10 mg round, biconvex tablets and
imprinted with black ink as follows:
Table ##. GLUCOTROL XL Tablet Presentations
Tablet
Strength
Tablet
Color/
Shape
Tablet Markings
Package
Size
NDC Code
2.5 mg
Blue
Round
imprinted with “GLUCOTROL XL 2.5” on
one side
Bottles of
30
NDC 0049
1620-30
Biconvex
imprinted with “GXL 2.5” on one side
Bottles of
30
NDC 0049
0170-01
5 mg
White
Round
Biconvex
imprinted with “GLUCOTROL XL 5” on one
side
Bottles of
100
Bottles of
500
NDC 0049
1550-66 NDC
0049-1550-73
imprinted with “GXL 5” on one side
Bottles of
100
Bottles of
500
NDC 0049
0174-02 NDC
0049-0174-03
10 mg
White
Round
Biconvex
imprinted with “GLUCOTROL XL 10” on
one side
Bottles of
100
Bottles of
500
NDC 0049
1560-66 NDC
0049-1560-73
imprinted with “GXL 10” on one side
Bottles of
100
Bottles of
500
NDC 0049
0178-07 NDC
0049-0178-08
Recommended Storage: The tablets should be protected from moisture and humidity. Store at 68-77°F (20-25°C); excursions
permitted between 59°F and 86°F (15°C and 30°C) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients of the potential adverse reactions of GLUCOTROL XL including hypoglycemia. Explain the risks of
hypoglycemia, its symptoms and treatment, and conditions that predispose to its development to patients and responsible family
members. Also inform patients about the importance of adhering to dietary instructions, of a regular exercise program, and of
regular testing of glycemic control.
Inform patients that GLUCOTROL XL should be swallowed whole. Inform patients that they should not chew, divide or crush
tablets and they may occasionally notice in their stool something that looks like a tablet. In the GLUCOTROL XL tablet, the
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
medication is contained within a non-dissolvable shell that has been specially designed to slowly release the drug so the body can
absorb it.
Advise patients with diabetes to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or
contemplating breastfeeding.
This product’s label may have been updated. For full prescribing information, please visit www.pfizer.com. company logo
LAB-0113-9.x
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
GLUCOTROL XL (GLˈUːKˌOTROL)
(glipizide)
extended release tablets
What is GLUCOTROL XL?
• GLUCOTROL XL is a prescription medicine you take by mouth used along with diet and exercise to lower
blood sugar in adults with type 2 diabetes mellitus.
• GLUCOTROL XL is not for people with type 1 diabetes or people with diabetic ketoacidosis.
It is not known if GLUCOTROL XL is safe and effective in children under 18 years of age.
Who Should Not Take GLUCOTROL XL?
Do not use GLUCOTROL XL if you:
• have a condition called diabetic ketoacidosis
• have ever had an allergic reaction to glipizide or any of the other ingredients in GLUCOTROL XL. See the
end of this Patient Information for a complete list of ingredients in GLUCOTROL XL.
What should I tell my doctor before taking GLUCOTROL XL?
Before you take GLUCOTROL XL, tell your healthcare provider if you:
• Have ever had a condition called diabetic ketoacidosis
• Have kidney or liver problems
• Have had a blockage or narrowing of your intestines due to illness or past surgery
• Have chronic (continuing) diarrhea
• Have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This condition usually runs in families.
People with G6PD deficiency who take GLUCOTROL XL may develop hemolytic anemia (fast breakdown
of red blood cells).
• Are pregnant or might be pregnant. It is not known if GLUCOTROL XL will harm your unborn baby. If
you are pregnant, talk to you healthcare provider about the best way to control your blood sugar while you
are pregnant. You should not take GLUCOTROL XL during the last month of pregnancy.
• Are breastfeeding or plan to breastfeed. It is not known if GLUCOTROL XL passes into your breast milk.
You and your healthcare provider should decide if you will take GLUCOTROL XL or breastfeed. You
should not do both.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements.
GLUCOTROL XL may affect the way other medicines work, and other medicines may affect how
GLUCOTROL XL works.
Some medicines can affect how well GLUCOTROL XL works or may affect you blood sugar level.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when
you get a new medicine.
How should I take GLUCOTROL XL?
• Take GLUCOTROL XL exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much GLUCOTROL XL to take and when to take it.
• Take GLUCOTROL XL by mouth, 1 time each day with breakfast or your first meal of the day.
• Each GLUCOTROL XL tablet will release the medicine slowly over 24 hours. This is why you take it only
1 time each day.
• Swallow the GLUCOTROL XL whole. Do not break, crush, dissolve, chew, or cut the tablet in half.
This will damage the tablet and release too much medicine into your body at one time.
• When you take GLUCOTROL XL you may see something in your stool that looks like a tablet. This is the
empty shell from the tablet. It is normal for the empty shell to pass with your bowel movement after
medicine has been absorbed by your body.
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• It is important to take GLUCOTROL XL every day to help keep your blood sugar level under good control.
Your healthcare provider may change your dose depending on your blood sugar test results. If your blood
sugar level is not under control, call your healthcare provider. Do not change your dose unless your
healthcare provider tells you to.
• If you take too much GLUCOTROL XL, call your healthcare provider or go to the nearest emergency room
right away.
Your healthcare provider may tell you to take GLUCOTROL XL with other diabetes medicines. Low blood
sugar can happen more often when GLUCOTROL XL is taken with other diabetes medicines. See “What
are the possible side effects of GLUCOTROL XL?”
• Check your blood sugar as your healthcare provider tells you to.
• Stay on your prescribed diet and exercise program while taking GLUCOTROL XL.
What should I avoid while taking GLUCOTROL XL?
• Do not drink alcohol while taking GLUCOTROL XL. It can increase your chances of getting serious side
effects.
• Do not drive, operate machinery, or do other dangerous activities until you know how GLUCOTROL XL
affects you.
What are the possible side effects of GLUCOTROL XL?
GLUCOTROL XL can cause serious side effects, including:
• Low blood sugar. GLUCOTROL XL may cause low blood sugar. Signs and symptoms of low blood sugar
may include:
• a cold clammy feeling
• hunger
• unusual sweating
• fast heartbeat
• dizziness
• headache
• weakness
• blurred vision
• trembling
• slurred speech
• shakiness
• tingling in the lips or hands
If you have signs or symptoms of low blood sugar, eat or drink something with sugar in it right away. If you do
not feel better or your blood sugar level does not go up, call your healthcare provider or go to the nearest
emergency room.
The most common side effects of GLUCOTROL XL include: dizziness, diarrhea, nervousness, tremor, and
gas.
These are not all the possible side effects of GLUCOTROL XL. For more information, ask your healthcare
provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How to store GLUCOTROL XL?
• Store GLUCOTROL XL at room temperature between 68oF to 77oF (20oC to 25oC).
• Store GLUCOTROL XL in a dry place, in its original container.
Keep GLUCOTROL XL and all medicines out of reach of children.
General information about the safe and effective use of GLUCOTROL XL.
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not
use GLUCOTROL XL for a condition for which it was not prescribed. Do not give GLUCOTROL XL to other
people, even if they have the same symptoms you have. It may harm them.
This Patient Information summarizes the most important information about GLUCOTROL XL. If you would
like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider
for information about GLUCOTROL XL that is written for healthcare professionals.
For more information about GLUCOTROL XL, you can visit the Pfizer internet site at www.pfizer.com.
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the ingredients in GLUCOTROL XL?
Active ingredient: glipizide
Inactive ingredients: polyethylene oxide, hypromellose, magnesium stearate, sodium chloride, red ferric oxide,
cellulose acetate, polyethylene glycol, Opadry® blue (OY-LS-20921), (2.5 mg tablets) Opadry® white (YS 2 7063), (5
mg and 10 mg tablet) Opacode® Black Ink (S-1-17823).
LAB-0115-5.x
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised 10/2015
Reference ID: 3828936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:28.669503
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020329s029lbl.pdf', 'application_number': 20329, 'submission_type': 'SUPPL ', 'submission_number': 29}
|
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NDA 20-333/S-002
Page 4
AGRYLIN77
(anagrelide hydrochloride)
Capsules
DESCRIPTION
Name: AGRYLIN77 (anagrelide hydrochloride)
Dosage Form: 0.5 mg and 1 mg capsules for oral administration
Active Ingredient: AGRYLIN77 Capsules contain either 0.5 mg or 1 mg of anagrelide base (as anagrelide
hydrochloride).
Inactive Ingredients: Povidone USP, Anhydrous Lactose NF, Lactose Monohydrate NF, Microcrystalline
Cellulose NF, Crospovidone NF, Magnesium Stearate NF.
Pharmacological Classification: Platelet-reducing agent.
Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride
monohydrate.
Molecular formula: C10H7Cl2N3OAHClAH2O
Molecular weight: 310.55
Structural formula:
Appearance: Off-white powder.
Solubility:
Water.............................Very slightly soluble
Dimethyl Sulfoxide.............Sparingly soluble
Dimethylformamide............Sparingly soluble
CLINICAL PHARMACOLOGY
The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in
patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in
megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a
disruption was found in the postmitotic phase of megakaryocyte development and a reduction in
megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-002
Page 5
white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red
cell parameters. Platelet aggregation is inhibited in people at doses higher than those required to reduce
platelet count. Anagrelide inhibits cyclic AMP phosphodiesterase, as well as ADP- and collagen-induced
platelet aggregation.
Following oral administration of 14C-anagrelide in people, more than 70% of radioactivity was recovered in
urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5 mg and
2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours. The available
plasma concentration time data at steady state in patients showed that anagrelide does not accumulate in
plasma after repeated administration. The drug is extensively metabolized; less than 1% is recovered in the
urine as anagrelide.
When a 0.5 mg dose of anagrelide was taken after food, its bioavailability (based on AUC values) was
modestly reduced by an average of 13.8% and its plasma half-life slightly increased (to 1.8 hours), when
compared with drug administered to the same subjects in the fasted state. The peak plasma level was lowered
by an average of 45% and delayed by 2 hours.
CLINICAL STUDIES
A total of 942 patients with myeloproliferative disorders including 551 patients with Essential
Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous
Leukemia (CML), and 96 patients with other myeloproliferative disorders (OMPD), were treated with
anagrelide in three clinical trials. Patients with OMPD included 87 patients who had Myeloid Metaplasia with
Myelofibrosis (MMM), and 9 patients who had unknown myeloproliferative disorders.
Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:
ET
$
Platelet count $900,000/FL on two
determinations
$
Profound megakaryocytic hyperplasia
in bone marrow
$
Absence of Philadelphia chromosome
$
Normal red cell mass
$
Normal serum iron and ferritin and
normal marrow iron stores.
CML
$ Persistent granulocyte count $ 50,000/FL
without evidence of infection
$ Absolute basophil count $ 100/FL
$ Evidence for hyperplasia of the
granulocytic line in the bone marrow
$ Philadelphia chromosome present
$ Leucocyte alkaline phosphatase # lower
limit of the laboratory normal range
PVH
$ A1
Increased red cell mass
$ A2
Normal arterial oxygen saturation
$ A3
Splenomegaly
$ B1
Platelet count $ 400,000/FL, in
absence of iron deficiency or
bleeding
$ B2
Leucocytosis ($ 12,000/FL, in the
absence of infection)
$ B3
Elevated leucocyte alkaline
phosphatase
$ B4
Elevated serum B12
H
Diagnosis positive if A1, A2, and A3
present; or, if no splenomegaly,
diagnosis is positive if A1 and A2 are
present with any two of B1, B2, or B3.
MMM
C
Myelofibrotic (hypocellular, fibrotic)
bone marrow
C
Prominent megakaryocytic metaplasia in
bone marrow
C
Splenomegaly
C
Moderate to severe normochromic
normocytic anemia
C
White cell count may be variable;
(80,000-100,000 per/FL)
C
Increased platelet count
C
Variable red cell mass; teardrop
poikilocytes
C
Normal to high leucocyte alkaline
phosphatase
C
Absence of Philadelphia chromosome
Patients were enrolled in clinical trials if their platelet count was $ 900,000/FL on two occasions or $
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-002
Page 6
650,000/FL on two occasions with documentation of symptoms associate with thrombocythemia. The
mean duration of anagrelide therapy for ET, PV, CML, and OMPD patients was 65, 67, 40, and 44
weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with
anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count
was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to
or near physiologic levels (150,000-400,000/FL). The criteria for defining subjects as "responders" were
reduction in platelets for at least 4 weeks to #600,000/FL, or by at least 50% from baseline value.
Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted
graphically below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-002
Page 7
Time on Treatment
Weeks
Years
Baseline
4
12
24
48
2
3
4
Mean*
N
1131
923H
683
868
575
814
526
662
484
530
460
407
437
207
457
55
*x 103/FL
H Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled
in three research studies. Of these, 923 had platelet counts over the duration
of the studies.
Agrylin was effective in phlebotomized patients as well as in patients treated with other concomitant
therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.
INDICATIONS AND USAGE
AGRYLIN7 Capsules are indicated for the treatment of patients with thrombocythemia, secondary to
myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to
ameliorate associated symptoms including thrombo-hemorrhagic events (see CLINICAL STUDIES,
DOSAGE and ADMINISTRATION).
WARNINGS
Cardiovascular
Anagrelide should be used with caution in patients with known or suspected heart disease, and only if the
potential benefits of therapy outweigh the potential risks. Because of the positive inotropic effects and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-002
Page 8
side-effects of anagrelide, a pre-treatment cardiovascular examination is recommended along with careful
monitoring during treatment. In humans, therapeutic doses of anagrelide may cause cardiovascular
effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.
Renal
It is recommended that patients with renal insufficiency (creatinine $ 2 mg/dL) receive anagrelide when,
in the physician's judgment, the potential benefits of therapy outweigh the potential risks. These patients
should be monitored closely for signs of renal toxicity while receiving anagrelide (see ADVERSE
REACTIONS, Urogenital System).
Hepatic
It is recommended that patients with evidence of hepatic dysfunction (bilirubin, SGOT, or measures of
liver function >1.5 times the upper limit of normal) receive anagrelide when, in the physician's judgment,
the potential benefits of therapy outweigh the potential risks. These patients should be monitored closely
for signs of hepatic toxicity while receiving anagrelide (see ADVERSE REACTIONS, Hepatic System).
PRECAUTIONS
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While the
platelet count is being lowered (usually during the first two weeks of treatment), blood counts
(hemoglobin, white blood cells), liver function (SGOT, SGPT) and renal function (serum creatinine,
BUN) should be monitored.
In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average of 22/15
mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were observed
following a dose of 2 mg.
Cessation of AGRYLIN77 Treatment: In general, interruption of anagrelide treatment is followed by an
increase in platelet count. After sudden stoppage of anagrelide therapy, the increase in platelet count can
be observed within four days.
Drug Interactions: Bioavailability studies evaluating possible interactions between anagrelide and other
drugs have not been conducted. The most common medications used concomitantly with anagrelide have
been aspirin, acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol. The most
frequently used concomitant cardiac medication has been digoxin. Although drug-to-drug interaction
studies have not been conducted, there is no clinical evidence to suggest that anagrelide interacts with any
of these compounds.
There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been
performed to evaluate carcinogenic potential of anagrelide hydrochloride. Anagrelide hydrochloride was
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-002
Page 9
not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test, the
human lymphocyte chromosome aberration test, or the mouse micronucleus test. Anagrelide
hydrochloride at oral doses up to 240 mg/kg/day (1,440 mg/m2/day, 195 times the recommended
maximum human dose based on body surface area) was found to have no effect on fertility and
reproductive performance of male rats. However, in female rats, at oral doses of 60 mg/kg/day (360
mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher, it
disrupted implantation when administered in early pregnancy and retarded or blocked parturition when
administered in late pregnancy.
Pregnancy: Pregnancy Category C.
(i) Teratogenic Effects
Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day
(5,400 mg/m2/day, 730 times the recommended maximum human dose based on body surface area) and in
pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the recommended maximum
human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to
the fetus due to anagrelide hydrochloride.
(ii) Nonteratogenic Effects
A fertility and reproductive performance study performed in female rats revealed that anagrelide
hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum
human dose based on body surface area) or higher disrupted implantation and exerted adverse effect on
embryo/fetal survival.
A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride at oral
doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body
surface area) or higher produced delay or blockage of parturition, deaths of nondelivering pregnant dams
and their fully developed fetuses, and increased mortality in the pups born.
Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day. Treatment was
stopped as soon as it was realized that they were pregnant. All delivered normal, healthy babies. There
are no adequate and well-controlled studies in pregnant women. Anagrelide hydrochloride should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the
potential harm to the fetus. Women of child-bearing potential should be instructed that they must not be
pregnant and that they should use contraception while taking anagrelide. Anagrelide may cause fetal
harm when administered to a pregnant woman.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reaction in nursing infants from
anagrelide hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-002
Page 10
Pediatric Use: The safety and efficacy of anagrelide in patients under the age of 16 years have not been
established. Myeloproliferative disorders are uncommon in pediatric patients. Anagrelide has been used
successfully in 12 pediatric patients (age range 6.8 to 17.4 years; 6 male and 6 female), including 8
patients with ET, 2 patients with CML, 1 patient with PV, and 1 patient with OMPD. Patients were
started on therapy with 0.5 mg qid to a maximum daily dose of 10 mg. The median duration of treatment
was 18.1 months with a range of 3.1 to 92 months. Three patients received treatment for greater than
three years.
ADVERSE REACTIONS
Analysis of the adverse events in a population consisting of 942 patients diagnosed with myelo-
proliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that all disease
groups have the same adverse event profile. While most reported adverse events during anagrelide
therapy have been mild in intensity and have decreased in frequency with continued therapy, serious
adverse events were reported in these patients. These include the following: congestive heart failure,
myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation,
cerebrovascular accident, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension,
pancreatitis, gastric/duodenal ulceration, and seizure.
Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161 (17%)
were discontinued from the study because of adverse events or abnormal laboratory test results. The
most common adverse events for treatment discontinuation were headache, diarrhea, edema, palpitation,
and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000 treatment
days. The occurrence rate of adverse events increased at higher dosages of anagrelide.
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with
myeloproliferative disease) in clinical trials were:
Headache
43.5%
Palpitations
26.1%
Diarrhea
25.7%
Asthenia
23.1%
Edema, other
20.6%
Nausea
17.1%
Abdominal Pain
16.4%
Dizziness
15.4%
Pain, other
15.0%
Dyspnea
11.9%
Flatulence
10.2%
Vomiting
9.7%
Fever
8.9%
Peripheral Edema
8.5%
Rash, including urticaria
8.3%
Chest Pain
7.8%
Anorexia
7.7%
Tachycardia
7.5%
Pharyngitis
6.8%
Malaise
6.4%
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NDA 20-333/S-002
Page 11
Cough
6.3%
Paresthesia
5.9%
Back Pain
5.9%
Pruritus
5.5%
Dyspepsia
5.2%
Adverse events with an incidence of 1% to < 5% included:
Body as a Whole System: Flu symptoms, chills, photosensitivity.
Cardiovascular System: Arrhythmia, hemorrhage, cardiovascular disease, angina pectoris, heart failure,
postural hypotension, thrombosis, vasodilatation, migraine, syncope.
Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous stomatitis,
eructation.
Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy.
Platelet counts below 100,000/FL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below
50,000/FL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy.
Thrombocytopenia promptly recovered upon discontinuation of anagrelide.
Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during anagrelide
therapy.
Musculoskeletal System: Arthralgia, myalgia, leg cramps.
Nervous System: Depression, somnolence, confusion, insomnia, hypertension, nervousness, amnesia.
Nutritional Disorders: Dehydration.
Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.
Skin and Appendages System: Skin disease, alopecia.
Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.
Urogenital System: Dysuria, Hematuria.
Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with OMPD
experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases, the renal failure
was considered to be possibly related to anagrelide treatment. The remaining 11 were found to have pre-
existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with exposure periods of 2 to 12 months.
No dose adjustment was required because of renal insufficiency.
The adverse event profile for patients in clinical trials on anagrelide therapy (in 5% or greater of 942
patients with myeloproliferative diseases) is shown in the following bar graph:
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NDA 20-333/S-002
Page 12
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Page 13
OVERDOSAGE
Acute Toxicity and Symptoms
Single oral doses of anagrelide hydrochloride at 2,500, 1,500 and 200 mg/kg in mice, rats and monkeys,
respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in mice and rats
and softened stools and decreased appetite in monkeys.
There are no reports of overdosage with anagrelide hydrochloride. Platelet reduction from anagrelide
therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected
from overdosage. Should overdosage occur, cardiac and central nervous system toxicity can also be
expected.
Management and Treatment
In case of overdosage, close clinical supervision of the patient is required; this especially includes
monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped, as
appropriate, until the platelet count returns to within the normal range.
DOSAGE AND ADMINISTRATION
Treatment with AGRYLIN77 Capsules should be initiated under close medical supervision. The
recommended starting dosage of AGRYLIN77 is 0.5 mg qid or 1 mg bid, which should be maintained for
at least one week. Dosage should then be adjusted to the lowest effective dosage required to reduce and
maintain platelet count below 600,000/FL, and ideally to the normal range. The dosage should be
increased by not more than 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or
2.5 mg in a single dose (see PRECAUTIONS). The decision to treat asymptomatic young adults with
thrombocythemia secondary to myeloproliferative disorders should be individualized.
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts
should be performed every two days during the first week of treatment and at least weekly thereafter until
the maintenance dosage is reached.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to
complete response, defined as platelet count # 600,000/FL, ranged from 4 to 12 weeks. Most patients
will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with known or suspected
heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.
HOW SUPPLIED
AGRYLIN77 is available as:
0.5 mg, opaque, white capsules imprinted "ROBERTS 063" in black ink: NDC 54092-063-01 = bottle of
100.
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NDA 20-333/S-002
Page 14
1 mg, opaque, gray capsules imprinted "ROBERTS 064" in black ink: NDC 54092-064-01 = bottle of
100.
Store from 15E to 25EC (59E to 77EF), in a light-resistant container.
Rx only
Manufactured for Roberts Laboratories Inc.
a subsidiary of
ROBERTS PHARMACEUTICAL CORP.
Eatontown, NJ 07724-2274, USA
by MALLINCKRODT INC.
Hobart, NY 13788
Copyright8 1997 Roberts Laboratories Inc.
12/97
063 0117 002
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
|
2025-02-12T13:47:28.734963
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20333S2lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 2}
|
12,456
|
NDA 20-333/S-008 & 009
Page 3
AGRYLIN®
(anagrelide hydrochloride)
Capsules
Rx only
DESCRIPTION
Name: AGRYLIN® (anagrelide hydrochloride)
Dosage Form: 0.5 mg and 1 mg capsules for oral administration
Active Ingredient: AGRYLIN® Capsules contain either 0.5 mg or 1 mg of anagrelide base (as
anagrelide hydrochloride).
Inactive Ingredients: Anhydrous Lactose NF, Crospovidone NF, Lactose Monohydrate NF,
Magnesium stearate NF, Microcrystalline cellulose NF, Povidone USP.
Pharmacological Classification: Platelet-reducing agent.
Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one
monohydrochloride monohydrate.
Molecular formula: C10H7Cl2N3O•HCl•H2O
Molecular weight: 310.55
Structural formula:
Cl
Cl
N
N
H
N
O•HCl•H2O
==
Appearance: Off-white powder.
Solubility:
Water
Very slightly soluble
Dimethyl Sulfoxide
Sparingly soluble
Dimethylformamide
Sparingly soluble
CLINICAL PHARMACOLOGY
The mechanism by which anagrelide reduces blood platelet count is still under investigation.
Studies in patients support a hypothesis of dose-related reduction in platelet production resulting
from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers
treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte
development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide
does not produce significant changes in white cell counts or coagulation parameters, and may
have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic
AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation.
However, significant inhibition of platelet aggregation is observed only at doses of
anagrelide higher than those required to reduce platelet count.
Following oral administration of 14C-anagrelide in people, more than 70% of radioactivity was
recovered in urine. Based on limited data, there appears to be a trend toward dose linearity
between doses of 0.5 mg and 2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma
half-life is 1.3 hours. The available plasma concentration time data at steady state in patients
showed that anagrelide does not accumulate in plasma after repeated administration.
Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).
There were no apparent differences between patient groups (pediatric versus adult patients) for
tmax and t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.
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When a 0.5 mg dose of anagrelide was taken after food, its bioavailability (based on AUC
values) was modestly reduced by an average of 13.8% and its plasma half-life slightly increased
(to 1.8 hours), when compared with drug administered to the same subjects in the fasted state.
The peak plasma level was lowered by an average of 45% and delayed by 2 hours.
Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86
years) patients with thrombocythemia secondary to a myeloproliferative disorder (MPD),
indicate that dose- and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were
lower in the pediatric patients compared to the adult patients (Cmax 48%, AUCτ 55%).
CLINICAL STUDIES
A total of 942 patients with myeloproliferative disorders including 551 patients with Essential
Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic
Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative disorders
(OMPD), were treated with anagrelide in three clinical trials. Patients with OMPD included 87
patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had
unknown myeloproliferative disorders.
Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:
ET
• Platelet count ≥ 900,000/µL on two determinations
• Profound megakaryocytic hyperplasia in bone marrow
• Absence of Philadelphia chromosome
• Normal red cell mass
• Normal serum iron and ferritin and normal marrow iron stores
CML
• Persistent granulocyte count ≥ 50,000/µL without evidence of infection
• Absolute basophil count ≥ 100/µL
• Evidence for hyperplasia of the granulocytic line in the bone marrow
• Philadelphia chromosome is present
• Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range
PV†
• A1 Increased red cell mass
• A2 Normal arterial oxygen saturation
• A3 Splenomegaly
• B1 Platelet count ≥ 400,000/µL, in absence of iron deficiency or bleeding
• B2 Leukocytosis (≥ 12,000/µL, in the absence of infection)
• B3 Elevated leukocyte alkaline phosphatase
• B4 Elevated serum B12
† Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if
A1 and A2 are present with any two of B1, B2, or B3.
MMM
• Myelofibrotic (hypocellular, fibrotic) bone marrow
• Prominent megakaryocytic metaplasia in bone marrow
• Splenomegaly
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Page 5
• Moderate to severe normo-chromic normocytic anemia
• White cell count may be variable; (80,000-100,000/µL)
• Increased platelet count
• Variable red cell mass; teardrop poikilocytes
• Normal to high leukocyte alkaline phosphatase
• Absence of Philadelphia chromosome
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions
or ≥ 650,000/µL on two occasions with documentation of symptoms associated with
thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPD
patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2
years. Patients were treated with anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The
dose was increased if the platelet count was still high, but to no more than 12 mg each day.
Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000-
400,000/µL). The criteria for defining subjects as “responders” were reduction in platelets for at
least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less
than 4 weeks were not considered evaluable. The results are depicted graphically below:
300
600
900
1200
0
12
24
36
48
104
156
208
Time of Treatment (Weeks)
Number of Subjects
in Assay
923 868 814 662 530 407 207 55
Mean Platelet Count (x 10 3/µL)
Patients with Thrombocytosis Secondary to Myeloproliferative Disorders:
Mean Platelet Count During Anagrelide Therapy
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Page 6
Time on Treatment
Weeks
Years
Baseline
4
12
24
48
2
3
4
Mean*
1131
683
575
526
484
460
437
457
N
923†
868
814
662
530
407
207
55
*x 103/µL
† Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three
research studies. Of these, 923 had platelet counts over the duration of the studies.
AGRYLIN® was effective in phlebotomized patients as well as in patients treated with other
concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and
alkylating agents.
INDICATIONS AND USAGE
AGRYLIN® Capsules are indicated for the treatment of patients with thrombocythemia,
secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of
thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events (see
CLINICAL STUDIES, DOSAGE and ADMINISTRATION).
WARNINGS
Cardiovascular
Anagrelide should be used with caution in patients with known or suspected heart disease, and
only if the potential benefits of therapy outweigh the potential risks. Because of the positive
inotropic effects and side-effects of anagrelide and metabolite 3-hydroxy anagrelide, a pre-
treatment cardiovascular examination is recommended along with careful monitoring during
treatment. In humans, therapeutic doses of anagrelide may cause cardiovascular effects,
including vasodilation, tachycardia, palpitations, and congestive heart failure.
Renal
It is recommended that patients with renal insufficiency (creatinine ≥ 2mg/dL) receive anagrelide
when, in the physician’s judgment, the potential benefits of therapy outweigh the potential risks.
These patients should be monitored closely for signs of renal toxicity while receiving anagrelide
(see ADVERSE REACTIONS, Urogenital System).
Hepatic
It is recommended that patients with evidence of hepatic dysfunction (bilirubin, SGOT, or
measures of liver function >1.5 times the upper limit of normal) receive anagrelide when, in the
physician’s judgment, the potential benefits of therapy outweigh the potential risks. These
patients should be monitored closely for signs of hepatic toxicity while receiving anagrelide (see
ADVERSE REACTIONS, Hepatic System).
PRECAUTIONS
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While
the platelet count is being lowered (usually during the first two weeks of treatment), blood counts
(hemoglobin, white blood cells), liver function (SGOT, SGPT) and renal function (serum
creatinine, BUN) should be monitored.
In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average
of 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure
were observed following a dose of 2 mg.
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Page 7
Cessation of AGRYLIN® Treatment: In general, interruption of anagrelide treatment is
followed by an increase in platelet count. After sudden stoppage of anagrelide therapy, the
increase in platelet count can be observed within four days.
Drug Interactions: Limited PK and/or PD studies investigating possible interactions between
anagrelide and other medicinal products have been conducted. In vivo interaction studies in
humans have demonstrated that digoxin and warfarin do not affect the PK properties of
anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.
Although additional drug interaction studies have not been conducted, the most common
medications used concomitantly with anagrelide in clinical trials were aspirin, acetaminophen,
furosemide, iron, ranitidine, hydroxyurea, and allopurinol. There is no clinical evidence to
suggest that anagrelide interacts with any of these compounds.
Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by
several medicinal products, including fluvoxamine, and such medicinal products could
theoretically adversely influence the clearance of anagrelide. Anagrelide demonstrates some
limited inhibitory activity towards CYP1A2 which may present a theoretical potential for
interaction with other co-administered medicinal products sharing that clearance mechanism e.g.
theophylline.
Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar
properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be
exacerbated by anagrelide.
There is a single case report which suggests that sucralfate may interfere with anagrelide
absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have
been performed to evaluate carcinogenic potential of anagrelide hydrochloride. Anagrelide
hydrochloride was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-)
forward mutation test, the human lymphocyte chromosome aberration test, or the mouse
micronucleus test. Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (1,440
mg/m2/day, 195 times the recommended maximum human dose based on body surface area) was
found to have no effect on fertility and reproductive performance of male rats. However, in
female rats, at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended
maximum human dose based on body surface area) or higher, it disrupted implantation when
administered in early pregnancy and retarded or blocked parturition when administered in late
pregnancy.
Pregnancy: Pregnancy Category C.
(i) Teratogenic Effects
Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day
(5,400 mg/m2/day, 730 times the recommended maximum human dose based on body surface
area) and in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the
recommended maximum human dose based on body surface area) and have revealed no evidence
of impaired fertility or harm to the fetus due to anagrelide hydrochloride.
(ii) Nonteratogenic Effects
A fertility and reproductive performance study performed in female rats revealed that anagrelide
hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended
maximum human dose based on body surface area) or higher disrupted implantation and exerted
adverse effect on embryo/fetal survival.
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A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride
at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human
dose based on body surface area) or higher produced delay or blockage of parturition, deaths of
nondelivering pregnant dams and their fully developed fetuses, and increased mortality in the
pups born.
Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day.
Treatment was stopped as soon as it was realized that they were pregnant. All delivered normal,
healthy babies. There are no adequate and well-controlled studies in pregnant women.
Anagrelide hydrochloride should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential harm to the fetus. Women of child-bearing potential should be instructed
that they must not be pregnant and that they should use contraception while taking anagrelide.
Anagrelide may cause fetal harm when administered to a pregnant woman.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious adverse reaction in
nursing infants from anagrelide hydrochloride, 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: Myeloproliferative disorders are uncommon in pediatric patients and limited data
are available in this population. An open label safety and PK/PD study (See Clinical
Pharmacology section) was conducted in 17 pediatric patients 7-14 years of age (8 patients 7-11
years of age and 9 patients 11-14 years of age, mean age of 11 years; 8 males and 9 females) with
thrombocythemia secondary to ET as compared to 18 adult patients (mean age of 63 years, 9
males and 9 females). Prior to entry on to the study, 16 of 17 pediatric patients and 13 of 18 adult
patients had received anagrelide treatment for an average of 2 years. The median starting total
daily dose, determined by retrospective chart review, for pediatric and adult ET patients who had
received anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 11-
14 year old patients and adults). The starting dose for 6 anagrelide-naive patients at study entry
was 0.5mg once daily. At study completion, the median total daily maintenance doses were
similar across age groups, median of 1.75mg for patients of 7-11 years of age, 2mg in patients
11-14 years of age, and 1.5mg for adults.
The study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anagrelide,
including platelet counts (See Clinical Pharmacology section).
The frequency of adverse events observed in pediatric patients was similar to adult patients. The
most common adverse events observed in pediatric patients were fever, epistaxis, headache, and
fatigue during a 3-months treatment of anagrelide in the study. Adverse events that had been
reported in these pediatric patients prior to the study and were considered to be related to
anagrelide treatment based on retrospective review were palpitation, headache, nausea, vomiting,
abdominal pain, back pain, anorexia, fatigue, and muscle cramps. Episodes of increased pulse
rate and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence
of clinical symptoms were observed in some patients. Reported AEs were consistent with the
known pharmacological profile of anagrelide and the underlying disease. There were no
apparent trends or differences in the types of adverse events observed between the pediatric
patients compared with those of the adult patients. No overall difference in dosing and safety
were observed between pediatric and adult patients.
In another open-label study, anagrelide had been used successfully in 12 pediatric patients (age
range 6.8 to 17.4 years; 6 male and 6 female), including 8 patients with ET, 2 patients with CML,
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Page 9
1 patient with PV, and 1 patient with OMPD. Patients were started on therapy with 0.5 mg qid up
to a maximum daily dose of 10 mg. The median duration of treatment was 18.1 months with a
range of 3.1 to 92 months. Three patients received treatment for greater than three years. Other
adverse events reported in spontaneous reports and literature reviews include anemia, cutaneous
photosensitivity and elevated leukocyte count.
Geriatric Use: Of the total number of subjects in clinical studies of AGRYLIN®, 42.1% were
65 years and over, while 14.9% were 75 years 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 response between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies
diagnosed with myeloproliferataive diseases of varying etiology (ET: 551; PV: 117; OMPD:
274) has shown that all disease groups have the same adverse event profile. While most reported
adverse events during anagrelide therapy have been mild in intensity and have decreased in
frequency with continued therapy, serious adverse events were reported in these patients. These
include the following: congestive heart failure, myocardial infarction, cardiomyopathy,
cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis,
pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary
hypertension, pancreatitis, gastric/duodenal ulceration, and seizure.
Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161
(17%) were discontinued from the study because of adverse events or abnormal laboratory test
results. The most common adverse events for treatment discontinuation were headache, diarrhea,
edema, palpitation, and abdominal pain. Overall, the occurrence rate of all adverse events was
17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages
of anagrelide.
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients
with myeloproliferative disease) in clinical trials were:
Headache.............................. 43.5%
Palpitations........................... 26.1%
Diarrhea ............................... 25.7%
Asthenia ............................... 23.1%
Edema, other ........................ 20.6%
Nausea.................................. 17.1%
Abdominal Pain.................... 16.4%
Dizziness.............................. 15.4%
Pain, other ............................ 15.0%
Dyspnea ............................... 11.9%
Flatulence............................. 10.2%
Vomiting .............................. 9.7%
Fever .................................... 8.9%
Peripheral Edema ................. 8.5%
Rash, including urticaria....... 8.3%
Chest Pain ............................ 7.8%
Anorexia............................... 7.7%
Tachycardia.......................... 7.5%
Pharyngitis ........................... 6.8%
Malaise................................. 6.4%
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Page 10
Cough................................... 6.3%
Paresthesia............................ 5.9%
Back Pain ............................. 5.9%
Pruritus................................. 5.5%
Dyspepsia............................. 5.2%
Adverse events with an incidence of 1% to < 5% included:
Body as a Whole System: Flu symptoms, chills, photosensitivity.
Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina
pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.
Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous
stomatitis, eructation.
Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy.
Platelet counts below 100,000/µL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction
below 50,000/µL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy.
Thrombocytopenia promptly recovered upon discontinuation of anagrelide.
Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during
anagrelide therapy.
Musculoskeletal System: Arthralgia, myalgia, leg cramps.
Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.
Nutritional Disorders: Dehydration.
Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis,
asthma.
Skin and Appendages System: Skin disease, alopecia.
Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.
Urogenital System: Dysuria, hematuria.
Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with
OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases,
the renal failure was considered to be possibly related to anagrelide treatment. The remaining 11
were found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with
exposure periods of 2 to 12 months. No dose adjustment was required because of renal
insufficiency.
The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or
greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-008 & 009
Page 11
All Patients with
Myeloproliferative Disease (N=942)
Pain (chest)
Pain (back)
Pain (Abd)
Pain
Malaise
Headache
Fever
Asthenia
Body
as a
Whole
Tachycardia
Palpitations
Cardiovascular
Edema (per)
Edema
Metabolic
Paresthesia
Dizziness
Nervous
Pharyngitis
Dyspnea
Cough
Respiratory
Vomiting
Nausea
Flatulence
Dyspepsia
Diarrhea
Anorexia
Gastro-
Intestinal
Rash
Pruritus
Skin &
Appendages
Percent of Subjects with Adverse Event
0
10
20
30
40
50
OVERDOSAGE
Acute Toxicity and Symptoms
Single oral doses of anagrelide hydrochloride at 2,500, 1,500 and 200 mg/kg in mice, rats and
monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor
activity in mice and rats and softened stools and decreased appetite in monkeys.
There are no reports of overdosage with anagrelide hydrochloride. Platelet reduction from
anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause
bleeding, is expected from overdosage. Should overdosage occur, cardiac and central nervous
system toxicity can also be expected.
Management and Treatment
In case of overdosage, close clinical supervision of the patient is required; this especially
includes monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or
stopped, as appropriate, until the platelet count returns to within the normal range.
DOSAGE AND ADMINISTRATION
Treatment with AGRYLIN® Capsules should be initiated under close medical supervision. The
recommended starting dosage of AGRYLIN® for adult patients is 0.5 mg qid or 1 mg bid, which
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-008 & 009
Page 12
should be maintained for at least one week. Starting doses in pediatric patients have ranged from
0.5 mg per day to 0.5 mg qid. As there are limited data on the appropriate starting dose for
pediatric patients, an initial dose of 0.5 mg per day is recommended. In both adult and pediatric
patients, dosage should then be adjusted to the lowest effective dosage required to reduce and
maintain platelet count below 600,000/µL, and ideally to the normal range. The dosage should be
increased by not more than 0.5 mg/day in any one week. Maintenance dosing is not expected to
be different between adult and pediatric patients. Dosage should not exceed 10 mg/day or
2.5 mg in a single dose (see precautions).
There are no special requirements for dosing the geriatric population.
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet
counts should be performed every two days during the first week of treatment and at least weekly
thereafter until the maintenance dosage is reached.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to
complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. Most
patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with known
or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored
closely.
HOW SUPPLIED
AGRYLIN® is available as:
0.5 mg, opaque, white capsules imprinted “
063” in black ink:
NDC 54092-063-01 = bottle of 100
1 mg, opaque, gray capsules imprinted “
064” in black ink:
NDC 54092-064-01 = bottle of 100
Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room
Temperature]. Store in a light resistant container.
Manufactured for
Shire US Inc.
725 Chesterbrook Blvd.
Wayne, PA 19087-5637 USA
By MALLINCKRODT INC.
Hobart, NY 13788
© 2003 Shire US Inc.
Rev. 12/04
063 0117 013
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
|
2025-02-12T13:47:28.921143
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20333s008,009lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 9}
|
12,457
|
NDA 20-333/S-010
Page 3
AGRYLIN®
(anagrelide hydrochloride)
Capsules
Rx only
DESCRIPTION
Name: AGRYLIN® (anagrelide hydrochloride)
Dosage Form: 0.5 mg and 1 mg capsules for oral administration
Active Ingredient: AGRYLIN® Capsules contain either 0.5 mg or 1 mg of anagrelide base (as
anagrelide hydrochloride).
Inactive Ingredients: Anhydrous Lactose NF, Crospovidone NF, Lactose Monohydrate NF,
Magnesium stearate NF, Microcrystalline cellulose NF, Povidone USP.
Pharmacological Classification: Platelet-reducing agent.
Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride
monohydrate.
Molecular formula: C10H7Cl2N3O•HCl•H2O
Molecular weight: 310.55
Structural formula:
Cl
Cl
N
N
H
N
O•HCl•H2O
==
Appearance: Off-white powder.
Solubility:
Water
Very slightly soluble
Dimethyl Sulfoxide
Sparingly soluble
Dimethylformamide
Sparingly soluble
CLINICAL PHARMACOLOGY
The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in
patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease
in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with
anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a
reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce
significant changes in white cell counts or coagulation parameters, and may have a small, but clinically
insignificant effect on red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase III
(PDEIII). PDEIII inhibitors can also inhibit platelet aggregation. However, significant inhibition
of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce
platelet count.
Following oral administration of 14C-anagrelide in people, more than 70% of radioactivity was
recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between
doses of 0.5 mg and 2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3
hours. The available plasma concentration time data at steady state in patients showed that anagrelide
does not accumulate in plasma after repeated administration.
Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).
There were no apparent differences between patient groups (pediatric versus adult patients) for tmax and
t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.
Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide
in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food
decreased the Cmax by 14%, but increased the AUC by 20%.
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NDA 20-333/S-010
Page 4
Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86 years)
patients with thrombocythemia secondary to a myeloproliferative disorder (MPD), indicate that dose-
and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were lower in the pediatric
patients compared to the adult patients (Cmax 48%, AUCτ 55%).
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment
(creatinine clearance <30ml/min) showed no significant effects on the pharmacokinetics of anagrelide.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic
impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.
CLINICAL STUDIES
A total of 942 patients with myeloproliferative disorders including 551 patients with Essential
Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic
Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative disorders (OMPD),
were treated with anagrelide in three clinical trials. Patients with OMPD included 87 patients who had
Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unknown myeloproliferative
disorders.
Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:
ET
• Platelet count ≥ 900,000/µL on two determinations
• Profound megakaryocytic hyperplasia in bone marrow
• Absence of Philadelphia chromosome
• Normal red cell mass
• Normal serum iron and ferritin and normal marrow iron stores
CML
• Persistent granulocyte count ≥ 50,000/µL without evidence of infection
• Absolute basophil count ≥ 100/µL
• Evidence for hyperplasia of the granulocytic line in the bone marrow
• Philadelphia chromosome is present
• Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range
PV†
• A1 Increased red cell mass
• A2 Normal arterial oxygen saturation
• A3 Splenomegaly
• B1 Platelet count ≥ 400,000/µL, in absence of iron deficiency or bleeding
• B2 Leukocytosis (≥ 12,000/µL, in the absence of infection)
• B3 Elevated leukocyte alkaline phosphatase
• B4 Elevated serum B12
† Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1 and
A2 are present with any two of B1, B2, or B3.
MMM
• Myelofibrotic (hypocellular, fibrotic) bone marrow
• Prominent megakaryocytic metaplasia in bone marrow
• Splenomegaly
• Moderate to severe normo-chromic normocytic anemia
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NDA 20-333/S-010
Page 5
• White cell count may be variable; (80,000-100,000/µL)
• Increased platelet count
• Variable red cell mass; teardrop poikilocytes
• Normal to high leukocyte alkaline phosphatase
• Absence of Philadelphia chromosome
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions or ≥
650,000/µL on two occasions with documentation of symptoms associated with thrombocythemia. The
mean duration of anagrelide therapy for ET, PV, CML, and OMPD patients was 65, 67, 40, and 44
weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with
anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count
was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count
to or near physiologic levels (150,000-400,000/µL). The criteria for defining subjects as “responders”
were reduction in platelets for at least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value.
Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted
graphically below:
300
600
900
1200
0
12
24
36
48
104
156
208
Time of Treatment (Weeks)
Number of Subjects
in Assay
923 868 814 662 530 407 207 55
Mean Platelet Count (x 10 3/µL)
Patients with Thrombocytosis Secondary to Myeloproliferative Disorders:
Mean Platelet Count During Anagrelide Therapy
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NDA 20-333/S-010
Page 6
Time on Treatment
Weeks
Years
Baseline
4
12
24
48
2
3
4
Mean*
1131
683
575
526
484
460
437
457
N
923†
868
814
662
530
407
207
55
*x 103/µL
† Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three
research studies. Of these, 923 had platelet counts over the duration of the studies.
AGRYLIN® was effective in phlebotomized patients as well as in patients treated with other
concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and
alkylating agents.
INDICATIONS AND USAGE
AGRYLIN® Capsules are indicated for the treatment of patients with thrombocythemia, secondary to
myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to
ameliorate associated symptoms including thrombo-hemorrhagic events (see CLINICAL STUDIES,
DOSAGE and ADMINISTRATION).
CONTRAINDICATIONS
Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide is
increased 8-fold in patients with moderate hepatic impairment (See CLINICAL
PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has not been
studied. (See also WARNINGS: Hepatic Impairment).
WARNINGS
Cardiovascular
Anagrelide should be used with caution in patients with known or suspected heart disease, and only if
the potential benefits of therapy outweigh the potential risks. Because of the positive inotropic effects
and side-effects of anagrelide, a pre-treatment cardiovascular examination is recommended along with
careful monitoring during treatment. In humans, therapeutic doses of anagrelide may cause
cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.
Hepatic
Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (See
CLINICAL PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has
not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and
moderate impairment of hepatic function should be assessed before treatment is commenced. In
patients with moderate hepatic impairment, dose reduction is required and patients should be carefully
monitored for cardiovascular effects (See DOSAGE AND ADMINISTRATION for specific dosing
recommendations).
PRECAUTIONS
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While the
platelet count is being lowered (usually during the first two weeks of treatment), blood counts
(hemoglobin, white blood cells), liver function (SGOT, SGPT) and renal function (serum creatinine,
BUN) should be monitored.
In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average of
22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were
observed following a dose of 2 mg.
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NDA 20-333/S-010
Page 7
Cessation of AGRYLIN® Treatment: In general, interruption of anagrelide treatment is followed by
an increase in platelet count. After sudden stoppage of anagrelide therapy, the increase in platelet count
can be observed within four days.
Drug Interactions: Limited PK and/or PD studies investigating possible interactions between
anagrelide and other medicinal products have been conducted. In vivo interaction studies in humans
have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide, nor does
anagrelide affect the PK properties of digoxin or warfarin.
Although additional drug interaction studies have not been conducted, the most common medications
used concomitantly with anagrelide in clinical trials were aspirin, acetaminophen, furosemide, iron,
ranitidine, hydroxyurea, and allopurinol. There is no clinical evidence to suggest that anagrelide
interacts with any of these compounds.
An in vivo interaction study in humans demonstrated that a single 1mg dose of anagrelide administered
concomitantly with a single 900 mg dose of aspirin was generally well tolerated. There was no effect
on bleeding time, PT or aPTT. No clinically relevant pharmacokinetic interactions between anagrelide
and acetylsalicylic acid were observed. In that same study, aspirin alone produced a marked inhibition
in platelet aggregation ex vivo. Anagrelide alone had no effect on platelet aggregation, but did slightly
enhance the inhibition of platelet aggregation by aspirin.
Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by
several medicinal products, including fluvoxamine, and such medicinal products could theoretically
adversely influence the clearance of anagrelide. Anagrelide demonstrates some limited inhibitory
activity towards CYP1A2 which may present a theoretical potential for interaction with other co-
administered medicinal products sharing that clearance mechanism e.g. theophylline.
Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar
properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be
exacerbated by anagrelide.
There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been
performed to evaluate carcinogenic potential of anagrelide hydrochloride. Anagrelide hydrochloride
was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test,
the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Anagrelide
hydrochloride at oral doses up to 240 mg/kg/day (1,440 mg/m2/day, 195 times the recommended
maximum human dose based on body surface area) was found to have no effect on fertility and
reproductive performance of male rats. However, in female rats, at oral doses of 60 mg/kg/day (360
mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher,
it disrupted implantation when administered in early pregnancy and retarded or blocked parturition
when administered in late pregnancy.
Pregnancy: Pregnancy Category C.
(i) Teratogenic Effects
Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day (5,400
mg/m2/day, 730 times the recommended maximum human dose based on body surface area) and in
pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the recommended
maximum human dose based on body surface area) and have revealed no evidence of impaired fertility
or harm to the fetus due to anagrelide hydrochloride.
(ii) Nonteratogenic Effects
A fertility and reproductive performance study performed in female rats revealed that anagrelide
hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum
human dose based on body surface area) or higher disrupted implantation and exerted adverse effect on
embryo/fetal survival.
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NDA 20-333/S-010
Page 8
A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride at oral
doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on
body surface area) or higher produced delay or blockage of parturition, deaths of nondelivering
pregnant dams and their fully developed fetuses, and increased mortality in the pups born.
Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day. Treatment was
stopped as soon as it was realized that they were pregnant. All delivered normal, healthy babies. There
are no adequate and well-controlled studies in pregnant women. Anagrelide hydrochloride should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential harm to the fetus. Women of child-bearing potential should be instructed that
they must not be pregnant and that they should use contraception while taking anagrelide. Anagrelide
may cause fetal harm when administered to a pregnant woman.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk and because of the potential for serious adverse reaction in nursing infants
from anagrelide hydrochloride, 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: Myeloproliferative disorders are uncommon in pediatric patients and limited data are
available in this population. An open label safety and PK/PD study (See Clinical Pharmacology
section) was conducted in 17 pediatric patients 7-14 years of age (8 patients 7-11 years of age and 9
patients 11-14 years of age, mean age of 11 years; 8 males and 9 females) with thrombocythemia
secondary to ET as compared to 18 adult patients (mean age of 63 years, 9 males and 9 females). Prior
to entry on to the study, 16 of 17 pediatric patients and 13 of 18 adult patients had received anagrelide
treatment for an average of 2 years. The median starting total daily dose, determined by retrospective
chart review, for pediatric and adult ET patients who had received anagrelide prior to study entry was
1mg for each of the three age groups (7-11 and 11-14 year old patients and adults). The starting dose
for 6 anagrelide-naive patients at study entry was 0.5mg once daily. At study completion, the median
total daily maintenance doses were similar across age groups, median of 1.75mg for patients of 7-11
years of age, 2mg in patients 11-14 years of age, and 1.5mg for adults.
The study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anagrelide,
including platelet counts (See Clinical Pharmacology section).
The frequency of adverse events observed in pediatric patients was similar to adult patients. The most
common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue
during a 3-months treatment of anagrelide in the study. Adverse events that had been reported in these
pediatric patients prior to the study and were considered to be related to anagrelide treatment based on
retrospective review were palpitation, headache, nausea, vomiting, abdominal pain, back pain,
anorexia, fatigue, and muscle cramps. Episodes of increased pulse rate and decreased systolic or
diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed
in some patients. Reported AEs were consistent with the known pharmacological profile of anagrelide
and the underlying disease. There were no apparent trends or differences in the types of adverse events
observed between the pediatric patients compared with those of the adult patients. No overall
difference in dosing and safety were observed between pediatric and adult patients.
In another open-label study, anagrelide had been used successfully in 12 pediatric patients (age range
6.8 to 17.4 years; 6 male and 6 female), including 8 patients with ET, 2 patients with CML, 1 patient
with PV, and 1 patient with OMPD. Patients were started on therapy with 0.5 mg qid up to a maximum
daily dose of 10 mg. The median duration of treatment was 18.1 months with a range of 3.1 to 92
months. Three patients received treatment for greater than three years. Other adverse events reported in
spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated
leukocyte count.
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NDA 20-333/S-010
Page 9
Geriatric Use: Of the total number of subjects in clinical studies of AGRYLIN®, 42.1% were 65
years and over, while 14.9% were 75 years 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 response between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out.
ADVERSE REACTIONS
Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies diagnosed
with myeloproliferataive diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that
all disease groups have the same adverse event profile. While most reported adverse events during
anagrelide therapy have been mild in intensity and have decreased in frequency with continued
therapy, serious adverse events were reported in these patients. These include the following:
congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block,
atrial fibrillation, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion,
pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal
ulceration, and seizure.
Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161 (17%)
were discontinued from the study because of adverse events or abnormal laboratory test results. The
most common adverse events for treatment discontinuation were headache, diarrhea, edema,
palpitation, and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000
treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide.
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with
myeloproliferative disease) in clinical trials were:
Headache.............................. 43.5%
Palpitations........................... 26.1%
Diarrhea ............................... 25.7%
Asthenia ............................... 23.1%
Edema, other ........................ 20.6%
Nausea.................................. 17.1%
Abdominal Pain.................... 16.4%
Dizziness.............................. 15.4%
Pain, other ............................ 15.0%
Dyspnea ............................... 11.9%
Flatulence............................. 10.2%
Vomiting .............................. 9.7%
Fever .................................... 8.9%
Peripheral Edema ................. 8.5%
Rash, including urticaria....... 8.3%
Chest Pain ............................ 7.8%
Anorexia............................... 7.7%
Tachycardia.......................... 7.5%
Pharyngitis ........................... 6.8%
Malaise................................. 6.4%
Cough................................... 6.3%
Paresthesia............................ 5.9%
Back Pain ............................. 5.9%
Pruritus................................. 5.5%
Dyspepsia............................. 5.2%
Adverse events with an incidence of 1% to < 5% included:
Body as a Whole System: Flu symptoms, chills, photosensitivity.
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Page 10
Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina
pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.
Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous stomatitis,
eructation.
Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy.
Platelet counts below 100,000/µL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below
50,000/µL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy.
Thrombocytopenia promptly recovered upon discontinuation of anagrelide.
Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during
anagrelide therapy.
Musculoskeletal System: Arthralgia, myalgia, leg cramps.
Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.
Nutritional Disorders: Dehydration.
Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.
Skin and Appendages System: Skin disease, alopecia.
Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.
Urogenital System: Dysuria, hematuria.
Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with
OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases, the
renal failure was considered to be possibly related to anagrelide treatment. The remaining 11 were
found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with exposure
periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency.
The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or greater of
942 patients with myeloproliferative diseases) is shown in the following bar graph:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-010
Page 11
All Patients with
Myeloproliferative Disease (N=942)
Pain (chest)
Pain (back)
Pain (Abd)
Pain
Malaise
Headache
Fever
Asthenia
Body
as a
Whole
Tachycardia
Palpitations
Cardiovascular
Edema (per)
Edema
Metabolic
Paresthesia
Dizziness
Nervous
Pharyngitis
Dyspnea
Cough
Respiratory
Vomiting
Nausea
Flatulence
Dyspepsia
Diarrhea
Anorexia
Gastro-
Intestinal
Rash
Pruritus
Skin &
Appendages
Percent of Subjects with Adverse Event
0
10
20
30
40
50
OVERDOSAGE
Acute Toxicity and Symptoms
Single oral doses of anagrelide hydrochloride at 2,500, 1,500 and 200 mg/kg in mice, rats and
monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in
mice and rats and softened stools and decreased appetite in monkeys.
There are no reports of overdosage with anagrelide hydrochloride. Platelet reduction from anagrelide
therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected
from overdosage. Should overdosage occur, cardiac and central nervous system toxicity can also be
expected.
Management and Treatment
In case of overdosage, close clinical supervision of the patient is required; this especially includes
monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped, as
appropriate, until the platelet count returns to within the normal range.
DOSAGE AND ADMINISTRATION
Treatment with AGRYLIN® Capsules should be initiated under close medical supervision. The
recommended starting dosage of AGRYLIN® for adult patients is 0.5 mg qid or 1 mg bid, which
should be maintained for at least one week. Starting doses in pediatric patients have ranged from 0.5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-010
Page 12
mg per day to 0.5 mg qid. As there are limited data on the appropriate starting dose for pediatric
patients, an initial dose of 0.5 mg per day is recommended. In both adult and pediatric patients, dosage
should then be adjusted to the lowest effective dosage required to reduce and maintain platelet count
below 600,000/µL, and ideally to the normal range. The dosage should be increased by not more than
0.5 mg/day in any one week. Maintenance dosing is not expected to be different between adult and
pediatric patients. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose (see precautions).
There are no special requirements for dosing the geriatric population.
It is recommended that patients with moderate hepatic impairment start anagrelide therapy at a dose of
0.5mg/day and be maintained for a minimum of one week with careful monitoring of cardiovascular
effects. The dosage increment must not exceed more than 0.5mg/day in any one-week. The potential
risks and benefits of anagrelide therapy in a patient with mild and moderate impairment of hepatic
function should be assessed before treatment is commenced. Use of anagrelide in patients with severe
hepatic impairment has not been studied. Use of anagrelide in patients with severe hepatic impairment
is contraindicated (See CONTRAINDICATIONS).
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts
should be performed every two days during the first week of treatment and at least weekly thereafter
until the maintenance dosage is reached.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to
complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. Most patients
will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with known or suspected
heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.
HOW SUPPLIED
AGRYLIN® is available as:
0.5 mg, opaque, white capsules imprinted “
063” in black ink:
NDC 54092-063-01 = bottle of 100
1 mg, opaque, gray capsules imprinted “
064” in black ink:
NDC 54092-064-01 = bottle of 100
Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room
Temperature]. Store in a light resistant container.
Manufactured for
Shire US Inc.
725 Chesterbrook Blvd.
Wayne, PA 19087-5637 USA
By MALLINCKRODT INC.
Hobart, NY 13788
© 2003 Shire US Inc.
Rev. 12/04
063 0117 013
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
|
2025-02-12T13:47:29.043344
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20333s010lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 10}
|
12,459
|
s
tr
uc
tu
ral formula
NDA 20-333/S-017
Page 3
AGRYLIN®
(anagrelide hydrochloride)
Capsules
Rx only
DESCRIPTION
Name: AGRYLIN® (anagrelide hydrochloride)
Dosage Form: 0.5 mg capsules for oral administration
Active Ingredient: AGRYLIN® Capsules contain 0.5 mg of anagrelide base (as anagrelide
hydrochloride).
Inactive Ingredients: Anhydrous Lactose NF, Crospovidone NF, Lactose Monohydrate NF,
Magnesium stearate NF, Microcrystalline cellulose NF, Povidone USP.
Pharmacological Classification: Platelet-reducing agent.
Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one
monohydrochloride monohydrate.
Molecular formula: C10H7Cl2N3O•HCl•H2O
Molecular weight: 310.55
Structural formula:
Appearance: Off-white powder
Solubility:
Water……………………….. Very slightly soluble
Dimethyl Sulfoxide………… Sparingly soluble
Dimethylformamide………... Sparingly soluble
CLINICAL PHARMACOLOGY
The mechanism by which anagrelide reduces blood platelet count is still under investigation.
Studies in patients support a hypothesis of dose-related reduction in platelet production resulting
from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers
treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte
development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide
does not produce significant changes in white cell counts or coagulation parameters, and may
have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic
AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation.
However, significant inhibition of platelet aggregation is observed only at doses of
anagrelide higher than those required to reduce platelet count.
Following oral administration of 14C-anagrelide in people, more than 70% of radioactivity was
recovered in urine. Based on limited data, there appears to be a trend toward dose linearity
between doses of 0.5 mg and 2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma
half-life is 1.3 hours. The available plasma concentration time data at steady state in patients
showed that anagrelide does not accumulate in plasma after repeated administration.
Reference ID: 2898487
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Page 4
Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).
There were no apparent differences between patient groups (pediatric versus adult patients) for
tmax and t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.
Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of
anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide
with food decreased the Cmax by 14%, but increased the AUC by 20%.
Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86
years) patients with thrombocythemia secondary to a myeloproliferative disorder (MPD),
indicate that dose- and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were
lower in the pediatric patients compared to the adult patients (Cmax 48%, AUCτ 55%).
Pharmacokinetic data from fasting elderly patients with ET (age range 65-75 years) compared to
fasting adult patients (age range 22-50 years) indicate that the Cmax and AUC of anagrelide were
36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active
metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal
impairment (creatinine clearance <30ml/min) showed no significant effects on the
pharmacokinetics of anagrelide.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic
impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.
CLINICAL STUDIES
A total of 942 patients with myeloproliferative disorders including 551 patients with Essential
Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic
Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative disorders
(OMPD), were treated with anagrelide in three clinical trials. Patients with OMPD included 87
patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had
unknown myeloproliferative disorders.
Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:
ET:
• Platelet count ≥ 900,000/µL on two determinations
• Profound megakaryocytic hyperplasia in bone marrow
• Absence of Philadelphia chromosome
• Normal red cell mass
• Normal serum iron and ferritin and normal marrow iron stores
Reference ID: 2898487
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NDA 20-333/S-017
Page 5
CML:
• Persistent granulocyte count ≥ 50,000/µL without evidence of infection
• Absolute basophil count ≥ 100/µL
• Evidence for hyperplasia of the granulocytic line in the bone marrow
• Philadelphia chromosome is present
• Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range
PV†:
• A1 Increased red cell mass
• A2 Normal arterial oxygen saturation
• A3 Splenomegaly
• B1 Platelet count ≥ 400,000/µL, in absence of iron deficiency or bleeding
• B2 Leukocytosis (≥ 12,000/µL, in the absence of infection)
• B3 Elevated leukocyte alkaline phosphatase
• B4 Elevated serum B12
†Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1
and A2 are present with any two of B1, B2, or B3.
MMM:
• Myelofibrotic (hypocellular, fibrotic) bone marrow
• Prominent megakaryocytic metaplasia in bone marrow
• Splenomegaly
• Moderate to severe normo-chromic normocytic anemia
• White cell count may be variable; (80,000-100,000/µL)
• Increased platelet count
• Variable red cell mass; teardrop poikilocytes
• Normal to high leukocyte alkaline phosphatase
• Absence of Philadelphia chromosome
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions
or ≥ 650,000/µL on two occasions with documentation of symptoms associated with
thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPD
patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2
years. Patients were treated with anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The
dose was increased if the platelet count was still high, but to no more than 12 mg each day.
Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000
400,000/µL). The criteria for defining subjects as “responders” were reduction in platelets for at
least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less
than 4 weeks were not considered evaluable. The results are depicted graphically below:
Reference ID: 2898487
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NDA 20-333/S-017
Page 6
Patients with Thrombocytosis Secondary to Myeloproliferative Disorders:
Mean Platelet Count During Anagrelide Therapy
grap
h
0
Number of Subjects
in Assay
923 868
Baseline
Mean*
1131
N
923†
12
814
4
683
868
24
662
12
575
814
36
48
104
Time of Treatment (Weeks)
530
407
Time on Treatment
Weeks
24
48
2
526
484
460
662
530
407
156
207
Years
3
437
207
208
55
4
457
55
*x 103/µL
†Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three
research studies. Of these, 923 had platelet counts over the duration of the studies.
AGRYLIN® was effective in phlebotomized patients as well as in patients treated with other
concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and
alkylating agents.
INDICATIONS AND USAGE
AGRYLIN® Capsules are indicated for the treatment of patients with thrombocythemia,
secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of
Reference ID: 2898487
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NDA 20-333/S-017
Page 7
thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events (see
CLINICAL STUDIES, DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide
is increased 8-fold in patients with moderate hepatic impairment (see CLINICAL
PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has not
been studied (see also WARNINGS: Hepatic).
WARNINGS
Cardiovascular
Anagrelide should be used with caution in patients with known or suspected heart disease, and
only if the potential benefits of therapy outweigh the potential risks. Because of the positive
inotropic effects and side-effects of anagrelide, a pre-treatment cardiovascular examination is
recommended along with careful monitoring during treatment. In humans, therapeutic doses of
anagrelide may cause cardiovascular effects, including vasodilation, tachycardia, palpitations,
and congestive heart failure.
Hepatic
Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see
CLINICAL PHARMACOLOGY). Use of anagrelide in patients with severe hepatic
impairment has not been studied. The potential risks and benefits of anagrelide therapy in a
patient with mild and moderate impairment of hepatic function should be assessed before
treatment is commenced. In patients with moderate hepatic impairment, dose reduction is
required and patients should be carefully monitored for cardiovascular effects (see DOSAGE
AND ADMINISTRATION for specific dosing recommendations).
Interstitial Lung Diseases
Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial
pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing
reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset
ranged from 1 week to several years after initiating anagrelide. In most cases, the symptoms
improved after discontinuation of anagrelide (See ADVERSE REACTIONS).
PRECAUTIONS
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While
the platelet count is being lowered (usually during the first two weeks of treatment), blood counts
(hemoglobin, white blood cells), and renal function (serum creatinine, BUN) should be
monitored. Cases of clinically significant hepatotoxicity (including symptomatic ALT and AST
elevations and elevations greater than three times the ULN) have been reported in post-
marketing surveillance. Measure liver function tests (ALT, AST) before initiating anagrelide
treatment and during therapy.
Reference ID: 2898487
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NDA 20-333/S-017
Page 8
In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average
of 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure
were observed following a dose of 2 mg.
Cessation of AGRYLIN® Treatment: In general, interruption of anagrelide treatment is
followed by an increase in platelet count. After sudden stoppage of anagrelide therapy, the
increase in platelet count can be observed within four days.
Drug Interactions: Limited PK and/or PD studies investigating possible interactions between
anagrelide and other medicinal products have been conducted. In vivo interaction studies in
humans have demonstrated that digoxin and warfarin do not affect the PK properties of
anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.
In two clinical interaction studies in healthy subjects, co-administration of single-dose anagrelide
1mg and aspirin 900mg or repeat-dose anagrelide 1mg once daily and aspirin 75mg once daily
showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Co
administered anagrelide 1mg and aspirin 900mg single-doses had no effect on bleeding time,
prothrombin time (PT) or activated partial thromboplastin time (aPTT).
The potential risks and benefits of concomitant use of anagrelide with aspirin should be assessed,
particularly in patients with a high risk profile for haemorrhage, before treatment is commenced.
Drug interaction studies have not been conducted with the other common medications used
concomitantly with anagrelide in clinical trials which were acetaminophen, furosemide, iron,
ranitidine, hydroxyurea, and allopurinol.
Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by
several medicinal products, including fluvoxamine, and such medicinal products could
theoretically adversely influence the clearance of anagrelide. Anagrelide demonstrates some
limited inhibitory activity towards CYP1A2 which may present a theoretical potential for
interaction with other co-administered medicinal products sharing that clearance mechanism e.g.
theophylline.
Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with
similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol
may be exacerbated by anagrelide.
There is a single case report which suggests that sucralfate may interfere with anagrelide
absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In a two year rat carcinogenicity study
a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females
Reference ID: 2898487
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NDA 20-333/S-017
Page 9
receiving 30mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose).
Adrenal phaeochromocytomas were increased relative to controls in males receiving 3mg/kg/day
and above, and in females receiving 10mg/kg/day and above (at least 10 and 18 times
respectively human AUC exposure after a 1mg twice daily dose). Anagrelide hydrochloride was
not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test,
the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Anagrelide
hydrochloride at oral doses up to 240 mg/kg/day (1,440 mg/m2/day, 195 times the recommended
maximum human dose based on body surface area) was found to have no effect on fertility and
reproductive performance of male rats. However, in female rats, at oral doses of 60 mg/kg/day
(360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area)
or higher, it disrupted implantation when administered in early pregnancy and retarded or
blocked parturition when administered in late pregnancy.
Pregnancy: Pregnancy Category C.
(i) Teratogenic Effects
Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day
(5,400 mg/m2/day, 730 times the recommended maximum human dose based on body surface
area) and in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the
recommended maximum human dose based on body surface area) and have revealed no evidence
of impaired fertility or harm to the fetus due to anagrelide hydrochloride.
(ii) Nonteratogenic Effects
A fertility and reproductive performance study performed in female rats revealed that anagrelide
hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended
maximum human dose based on body surface area) or higher disrupted implantation and exerted
adverse effect on embryo/fetal survival.
A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride
at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human
dose based on body surface area) or higher produced delay or blockage of parturition, deaths of
nondelivering pregnant dams and their fully developed fetuses, and increased mortality in the
pups born.
There are however, no adequate and well controlled studies with anagrelide hydrochloride in
pregnant women. Because animal reproduction studies are not always predictive of human
response, anagrelide hydrochloride should be used during pregnancy only if clearly needed.
Nonclinical toxicology: In the 2-year rat study, a significant increase in non-neoplastic lesions
was observed in anagrelide treated males and females in the adrenal (medullary hyperplasia),
heart (myocardial hypertrophy and chamber distension), kidney (hydronephrosis, tubular dilation
and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed in tissues
of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney
(arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular
mineralization), and testes (tubular atrophy and vascular infarct) in anagrelide treated males.
Reference ID: 2898487
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Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day.
Treatment was stopped as soon as it was realized that they were pregnant. All delivered normal,
healthy babies. There are no adequate and well-controlled studies in pregnant women.
Anagrelide hydrochloride should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential harm to the fetus. Women of child-bearing potential should be
instructed that they must not be pregnant and that they should use contraception while taking
anagrelide. Anagrelide may cause fetal harm when administered to a pregnant woman.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious adverse reaction in
nursing infants from anagrelide hydrochloride, 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: Myeloproliferative disorders are uncommon in pediatric patients and limited data
are available in this population. An open label safety and PK/PD study (see CLINICAL
PHARMACOLOGY) was conducted in 17 pediatric patients 7-14 years of age (8 patients 7-11
years of age and 9 patients 11-14 years of age, mean age of 11 years; 8 males and 9 females)
with thrombocythemia secondary to ET as compared to 18 adult patients (mean age of 63 years,
9 males and 9 females). Prior to entry on to the study, 16 of 17 pediatric patients and 13 of 18
adult patients had received anagrelide treatment for an average of 2 years. The median starting
total daily dose, determined by retrospective chart review, for pediatric and adult ET patients
who had received anagrelide prior to study entry was 1mg for each of the three age groups (7-11
and 11-14 year old patients and adults). The starting dose for 6 anagrelide-naive patients at
study entry was 0.5 mg once daily. At study completion, the median total daily maintenance
doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age, 2 mg
in patients 11-14 years of age, and 1.5 mg for adults.
The study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anagrelide,
including platelet counts (see CLINICAL PHARMACOLOGY).
Reference ID: 2898487
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The frequency of adverse events observed in pediatric patients was similar to adult patients. The
most common adverse events observed in pediatric patients were fever, epistaxis, headache, and
fatigue during a 3-months treatment of anagrelide in the study. Adverse events that had been
reported in these pediatric patients prior to the study and were considered to be related to
anagrelide treatment based on retrospective review were palpitations, headache, nausea,
vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps. Episodes of
increased pulse rate and decreased systolic or diastolic blood pressure beyond the normal ranges
in the absence of clinical symptoms were observed in some patients. Reported AEs were
consistent with the known pharmacological profile of anagrelide and the underlying disease.
There were no apparent trends or differences in the types of adverse events observed between the
pediatric patients compared with those of the adult patients. No overall difference in dosing and
safety were observed between pediatric and adult patients.
In another open-label study, anagrelide had been used successfully in 12 pediatric patients (age
range 6.8 to 17.4 years; 6 male and 6 female), including 8 patients with ET, 2 patients with
CML, 1 patient with PV, and 1 patient with OMPD. Patients were started on therapy with 0.5 mg
qid up to a maximum daily dose of 10 mg. The median duration of treatment was 18.1 months
with a range of 3.1 to 92 months. Three patients received treatment for greater than three years.
Other adverse events reported in spontaneous reports and literature reviews include anemia,
cutaneous photosensitivity and elevated leukocyte count.
Geriatric Use: Of the total number of subjects in clinical studies of AGRYLIN®, 42.1% were
65 years and over, while 14.9% were 75 years 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 response between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies
diagnosed with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274)
has shown that all disease groups have the same adverse event profile. While most reported
adverse events during anagrelide therapy have been mild in intensity and have decreased in
frequency with continued therapy, serious adverse events were reported in these patients. These
include the following: congestive heart failure, myocardial infarction, cardiomyopathy,
cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis,
pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary
hypertension, pancreatitis, gastric/duodenal ulceration, and seizure.
Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161
(17%) were discontinued from the study because of adverse events or abnormal laboratory test
results. The most common adverse events for treatment discontinuation were headache, diarrhea,
edema, palpitations, and abdominal pain. Overall, the occurrence rate of all adverse events was
17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages
of anagrelide.
Reference ID: 2898487
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NDA 20-333/S-017
Page 12
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients
with myeloproliferative disease) in clinical trials were:
Headache................................43.5%
Palpitations.............................26.1%
Diarrhea..................................25.7%
Asthenia .................................23.1%
Edema, other ..........................20.6%
Nausea....................................17.1%
Abdominal Pain .....................16.4%
Dizziness................................15.4%
Pain, other ..............................15.0%
Dyspnea..................................11.9%
Flatulence...............................10.2%
Vomiting ................................9.7%
Fever ......................................8.9%
Peripheral Edema...................8.5%
Rash, including urticaria ........8.3%
Chest Pain ..............................7.8%
Anorexia.................................7.7%
Tachycardia............................7.5%
Pharyngitis .............................6.8%
Malaise...................................6.4%
Cough.....................................6.3%
Paresthesia..............................5.9%
Back Pain ...............................5.9%
Pruritus...................................5.5%
Dyspepsia...............................5.2%
Adverse events with an incidence of 1% to < 5% included:
Body as a Whole System: Flu symptoms, chills, photosensitivity.
Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina
pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.
Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous
stomatitis, eructation.
Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy.
Platelet counts below 100,000/µL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction
below 50,000/µL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy.
Thrombocytopenia promptly recovered upon discontinuation of anagrelide.
Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during
anagrelide therapy.
Musculoskeletal System: Arthralgia, myalgia, leg cramps.
Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.
Nutritional Disorders: Dehydration.
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NDA 20-333/S-017
Page 13
Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis,
asthma.
Skin and Appendages System: Skin disease, alopecia.
Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.
Urogenital System: Dysuria, hematuria.
Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with
OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases,
the renal failure was considered to be possibly related to anagrelide treatment. The remaining 11
were found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with
exposure periods of 2 to 12 months. No dose adjustment was required because of renal
insufficiency.
The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or
greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:
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graph
NDA 20-333/S-017
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All Patients with
Myeloproliferative Disease (N=942)
Percent of Subjects with Adverse Event
Postmarketing Reports
Cases of interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and
interstitial pneumonitis), tubulointerstitial nephritis and clinically significant hepatotoxicity have
been reported (See WARNINGS, Interstitial Lung Diseases and PRECAUTIONS, Laboratory
Tests).
OVERDOSAGE
Acute Toxicity and Symptoms
Single oral doses of anagrelide hydrochloride at 2,500, 1,500 and 200 mg/kg in mice, rats and
monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor
activity in mice and rats and softened stools and decreased appetite in monkeys.
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There have been postmarketing case reports of intentional overdose with anagrelide
hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved
with conservative management. Platelet reduction from anagrelide therapy is dose-related;
therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.
Should overdosage occur, cardiac and central nervous system toxicity can also be expected.
Management and Treatment
In case of overdosage, close clinical supervision of the patient is required; this especially
includes monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or
stopped, as appropriate, until the platelet count returns to within the normal range.
DOSAGE AND ADMINISTRATION
Treatment with AGRYLIN® Capsules should be initiated under close medical supervision. The
recommended starting dosage of AGRYLIN® for adult patients is 0.5 mg qid or 1 mg bid (2
capsules of 0.5 mg twice a day), which should be maintained for at least one week. Starting
doses in pediatric patients have ranged from 0.5 mg per day to 0.5 mg qid. As there are limited
data on the appropriate starting dose for pediatric patients, an initial dose of 0.5 mg per day is
recommended. In both adult and pediatric patients, dosage should then be adjusted to the lowest
effective dosage required to reduce and maintain platelet count below 600,000/µL, and ideally to
the normal range. The dosage should be increased by not more than 0.5 mg/day in any one week.
Maintenance dosing is not expected to be different between adult and pediatric patients. Dosage
should not exceed 10 mg/day or 2.5 mg in a single dose (see PRECAUTIONS).
There are no special requirements for dosing the geriatric population.
It is recommended that patients with moderate hepatic impairment start anagrelide therapy at a
dose of 0.5 mg/day and be maintained for a minimum of one week with careful monitoring of
cardiovascular effects. The dosage increment must not exceed more than 0.5 mg/day in any one-
week. The potential risks and benefits of anagrelide therapy in a patient with mild or moderate
impairment of hepatic function should be assessed before treatment is commenced. Use of
anagrelide in patients with severe hepatic impairment has not been studied. Use of anagrelide in
patients with severe hepatic impairment is contraindicated (see CONTRAINDICATIONS).
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet
counts should be performed every two days during the first week of treatment and at least weekly
thereafter until the maintenance dosage is reached.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to
complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. Most
patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with
known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be
monitored closely.
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HOW SUPPLIED
AGRYLIN® is available as:
0.5 mg, opaque, white capsules imprinted “
063” in black ink: NDC 54092-063-01 = bottle
of 100
Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room
Temperature]. Store in a light resistant container.
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA
1-800-828-2088
By MALLINCKRODT INC., Hobart, NY 13788
© 2010 Shire US Inc.
Rev. 08/10
063 0117 019
Printed in USA
Reference ID: 2898487
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|
custom-source
|
2025-02-12T13:47:29.244419
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020333s017lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 17}
|
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NDA 20-333/S-013
Page 3
AGRYLIN®
(anagrelide hydrochloride)
Capsules
Rx only
DESCRIPTION
Name: AGRYLIN® (anagrelide hydrochloride)
Dosage Form: 0.5 mg capsules for oral administration
Active Ingredient: AGRYLIN® Capsules contain 0.5 mg of anagrelide base (as anagrelide
hydrochloride).
Inactive Ingredients: Anhydrous Lactose NF, Crospovidone NF, Lactose Monohydrate NF,
Magnesium stearate NF, Microcrystalline cellulose NF, Povidone USP.
Pharmacological Classification: Platelet-reducing agent.
Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride
monohydrate.
Molecular formula: C10H7Cl2N3O•HCl•H2O
Molecular weight: 310.55
Structural formula:
H
Ch
em
ical Structure
==O•HCl•H2O
Cl
Cl
Appearance: Off-white powder.
Solubility:
Water
Very slightly soluble
Dimethyl Sulfoxide
Sparingly soluble
Dimethylformamide
Sparingly soluble
CLINICAL PHARMACOLOGY
The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in
patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease
in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with
anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a
reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce
significant changes in white cell counts or coagulation parameters, and may have a small, but clinically
insignificant effect on red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase III
(PDEIII). PDEIII inhibitors can also inhibit platelet aggregation. However, significant inhibition
of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce
platelet count.
Following oral administration of 14C-anagrelide in people, more than 70% of radioactivity was
recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between
doses of 0.5 mg and 2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3
hours. The available plasma concentration time data at steady state in patients showed that anagrelide
does not accumulate in plasma after repeated administration.
Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).
There were no apparent differences between patient groups (pediatric versus adult patients) for tmax and
t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.
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Page 4
Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide
in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food
decreased the Cmax by 14%, but increased the AUC by 20%.
Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86 years)
patients with thrombocythemia secondary to a myeloproliferative disorder (MPD), indicate that dose-
and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were lower in the pediatric
patients compared to the adult patients (Cmax 48%, AUCτ 55%).
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment
(creatinine clearance <30ml/min) showed no significant effects on the pharmacokinetics of anagrelide.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic
impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.
CLINICAL STUDIES
A total of 942 patients with myeloproliferative disorders including 551 patients with Essential
Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic
Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative disorders (OMPD),
were treated with anagrelide in three clinical trials. Patients with OMPD included 87 patients who had
Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unknown myeloproliferative
disorders.
Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:
ET
• Platelet count ≥ 900,000/µL on two determinations
• Profound megakaryocytic hyperplasia in bone marrow
• Absence of Philadelphia chromosome
• Normal red cell mass
• Normal serum iron and ferritin and normal marrow iron stores
CML
• Persistent granulocyte count ≥ 50,000/µL without evidence of infection
• Absolute basophil count ≥ 100/µL
• Evidence for hyperplasia of the granulocytic line in the bone marrow
• Philadelphia chromosome is present
• Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range
PV†
• A1 Increased red cell mass
• A2 Normal arterial oxygen saturation
• A3 Splenomegaly
• B1 Platelet count ≥ 400,000/µL, in absence of iron deficiency or bleeding
• B2 Leukocytosis (≥ 12,000/µL, in the absence of infection)
• B3 Elevated leukocyte alkaline phosphatase
• B4 Elevated serum B12
† Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1 and
A2 are present with any two of B1, B2, or B3.
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Page 5
MMM
• Myelofibrotic (hypocellular, fibrotic) bone marrow
• Prominent megakaryocytic metaplasia in bone marrow
• Splenomegaly
• Moderate to severe normo-chromic normocytic anemia
• White cell count may be variable; (80,000-100,000/µL)
• Increased platelet count
• Variable red cell mass; teardrop poikilocytes
• Normal to high leukocyte alkaline phosphatase
• Absence of Philadelphia chromosome
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions or ≥
650,000/µL on two occasions with documentation of symptoms associated with thrombocythemia. The
mean duration of anagrelide therapy for ET, PV, CML, and OMPD patients was 65, 67, 40, and 44
weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with
anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count
was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count
to or near physiologic levels (150,000-400,000/µL). The criteria for defining subjects as “responders”
were reduction in platelets for at least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value.
Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted
graphically below:
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Page 6
Patients with Thrombocytosis Secondary to Myeloproliferative Disorders:
Mean Platelet Count During Anagrelide Therapy
Grap
h
0
12
24
36
48
104
156
Time of Treatment (Weeks)
Number of Subjects
in Assay
923 868
814
662
530
407
207
Time on Treatment
Weeks
Years
Baseline
4
12
24
48
2
3
Mean*
1131
683
575
526
484
460
437
N
923†
868
814
662
530
407
207
208
55
4
457
55
*x 103/µL
† Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three
research studies. Of these, 923 had platelet counts over the duration of the studies.
AGRYLIN® was effective in phlebotomized patients as well as in patients treated with other
concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and
alkylating agents.
INDICATIONS AND USAGE
AGRYLIN® Capsules are indicated for the treatment of patients with thrombocythemia, secondary to
myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to
ameliorate associated symptoms including thrombo-hemorrhagic events (see CLINICAL STUDIES,
DOSAGE AND ADMINISTRATION).
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CONTRAINDICATIONS
Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide is
increased 8-fold in patients with moderate hepatic impairment (see CLINICAL
PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has not been
studied (see also WARNINGS: Hepatic).
WARNINGS
Cardiovascular
Anagrelide should be used with caution in patients with known or suspected heart disease, and only if
the potential benefits of therapy outweigh the potential risks. Because of the positive inotropic effects
and side-effects of anagrelide, a pre-treatment cardiovascular examination is recommended along with
careful monitoring during treatment. In humans, therapeutic doses of anagrelide may cause
cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.
Hepatic
Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see
CLINICAL PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has
not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and
moderate impairment of hepatic function should be assessed before treatment is commenced. In
patients with moderate hepatic impairment, dose reduction is required and patients should be carefully
monitored for cardiovascular effects (see DOSAGE AND ADMINISTRATION for specific dosing
recommendations).
Interstitial Lung Diseases
Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial
pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing reports.
Most cases presented with progressive dyspnea with lung infiltrations. The time of onset ranged from 1
week to several years after initiating anagrelide. In most cases, the symptoms improved after
discontinuation of anagrelide (See ADVERSE REACTIONS).
PRECAUTIONS
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While the
platelet count is being lowered (usually during the first two weeks of treatment), blood counts
(hemoglobin, white blood cells), liver function (SGOT, SGPT) and renal function (serum creatinine,
BUN) should be monitored.
In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average of
22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were
observed following a dose of 2 mg.
Cessation of AGRYLIN® Treatment: In general, interruption of anagrelide treatment is followed by
an increase in platelet count. After sudden stoppage of anagrelide therapy, the increase in platelet count
can be observed within four days.
Drug Interactions:
Limited PK and/or PD studies investigating possible interactions between
anagrelide and other medicinal products have been conducted. In vivo interaction studies in humans
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NDA 20-333/S-013
Page 8
have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide, nor does
anagrelide affect the PK properties of digoxin or warfarin.
Although additional drug interaction studies have not been conducted, the most common medications
used concomitantly with anagrelide in clinical trials were aspirin, acetaminophen, furosemide, iron,
ranitidine, hydroxyurea, and allopurinol. There is no clinical evidence to suggest that anagrelide
interacts with any of these compounds.
An in vivo interaction study in humans demonstrated that a single 1mg dose of anagrelide administered
concomitantly with a single 900 mg dose of aspirin was generally well tolerated. There was no effect
on bleeding time, PT or aPTT. No clinically relevant pharmacokinetic interactions between anagrelide
and acetylsalicylic acid were observed. In that same study, aspirin alone produced a marked inhibition
in platelet aggregation ex vivo. Anagrelide alone had no effect on platelet aggregation, but did slightly
enhance the inhibition of platelet aggregation by aspirin.
Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by
several medicinal products, including fluvoxamine, and such medicinal products could theoretically
adversely influence the clearance of anagrelide. Anagrelide demonstrates some limited inhibitory
activity towards CYP1A2 which may present a theoretical potential for interaction with other co
administered medicinal products sharing that clearance mechanism e.g. theophylline.
Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar
properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be
exacerbated by anagrelide.
There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In a two year rat carcinogenicity study a
higher incidence of uterine adenocarcinoma, relative to controls, was observed in females receiving
30mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal
phaeochromocytomas were increased relative to controls in males receiving 3mg/kg/day and above,
and in females receiving 10mg/kg/day and above (at least 10 and 18 times respectively human AUC
exposure after a 1mg twice daily dose). Anagrelide hydrochloride was not genotoxic in the Ames test,
the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome
aberration test, or the mouse micronucleus test. Anagrelide hydrochloride at oral doses up to 240
mg/kg/day (1,440 mg/m2/day, 195 times the recommended maximum human dose based on body
surface area) was found to have no effect on fertility and reproductive performance of male rats.
However, in female rats, at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended
maximum human dose based on body surface area) or higher, it disrupted implantation when
administered in early pregnancy and retarded or blocked parturition when administered in late
pregnancy.
Pregnancy: Pregnancy Category C.
(i) Teratogenic Effects
Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day (5,400
mg/m2/day, 730 times the recommended maximum human dose based on body surface area) and in
pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the recommended
maximum human dose based on body surface area) and have revealed no evidence of impaired fertility
or harm to the fetus due to anagrelide hydrochloride.
(ii) Nonteratogenic Effects
A fertility and reproductive performance study performed in female rats revealed that anagrelide
hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum
human dose based on body surface area) or higher disrupted implantation and exerted adverse effect on
embryo/fetal survival.
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Page 9
A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride at oral
doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on
body surface area) or higher produced delay or blockage of parturition, deaths of nondelivering
pregnant dams and their fully developed fetuses, and increased mortality in the pups born.
There are however, no adequate and well controlled studies with anagrelide hydrochloride in pregnant
women. Because animal reproduction studies are not always predictive of human response, anagrelide
hydrochloride should be used during pregnancy only if clearly needed.
Nonclinical toxicology:
In the 2-year rat study, a significant increase in non-neoplastic lesions were observed in anagrelide
treated males and females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and
chamber distension), kidney (hydronephrosis, tubular dilation and urothelial hyperplasia) and bone
(femur enostosis). Vascular effects were observed in tissues of the pancreas (arteritis/periarteritis,
intimal proliferation and medial hypertrophy), kidney (arteritis/periarteritis, intimal proliferation and
medial hypertrophy), sciatic nerve (vascular mineralization), and testes (tubular atrophy and vascular
infarct) in anagrelide treated males.
Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day. Treatment was
stopped as soon as it was realized that they were pregnant. All delivered normal, healthy babies. There
are no adequate and well-controlled studies in pregnant women. Anagrelide hydrochloride should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential harm to the fetus. Women of child-bearing potential should be instructed that
they must not be pregnant and that they should use contraception while taking anagrelide. Anagrelide
may cause fetal harm when administered to a pregnant woman.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk and because of the potential for serious adverse reaction in nursing infants
from anagrelide hydrochloride, 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: Myeloproliferative disorders are uncommon in pediatric patients and limited data are
available in this population. An open label safety and PK/PD study (see CLINICAL
PHARMACOLOGY) was conducted in 17 pediatric patients 7-14 years of age (8 patients 7-11 years
of age and 9 patients 11-14 years of age, mean age of 11 years; 8 males and 9 females) with
thrombocythemia secondary to ET as compared to 18 adult patients (mean age of 63 years, 9 males and
9 females). Prior to entry on to the study, 16 of 17 pediatric patients and 13 of 18 adult patients had
received anagrelide treatment for an average of 2 years. The median starting total daily dose,
determined by retrospective chart review, for pediatric and adult ET patients who had received
anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 11-14 year old
patients and adults). The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once
daily. At study completion, the median total daily maintenance doses were similar across age groups,
median of 1.75 mg for patients of 7-11 years of age, 2 mg in patients 11-14 years of age, and 1.5 mg
for adults.
The study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anagrelide,
including platelet counts (see CLINICAL PHARMACOLOGY).
The frequency of adverse events observed in pediatric patients was similar to adult patients. The most
common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue
during a 3-months treatment of anagrelide in the study. Adverse events that had been reported in these
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Page 10
pediatric patients prior to the study and were considered to be related to anagrelide treatment based on
retrospective review were palpitation, headache, nausea, vomiting, abdominal pain, back pain,
anorexia, fatigue, and muscle cramps. Episodes of increased pulse rate and decreased systolic or
diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed
in some patients. Reported AEs were consistent with the known pharmacological profile of anagrelide
and the underlying disease. There were no apparent trends or differences in the types of adverse events
observed between the pediatric patients compared with those of the adult patients. No overall
difference in dosing and safety were observed between pediatric and adult patients.
In another open-label study, anagrelide had been used successfully in 12 pediatric patients (age range
6.8 to 17.4 years; 6 male and 6 female), including 8 patients with ET, 2 patients with CML, 1 patient
with PV, and 1 patient with OMPD. Patients were started on therapy with 0.5 mg qid up to a maximum
daily dose of 10 mg. The median duration of treatment was 18.1 months with a range of 3.1 to 92
months. Three patients received treatment for greater than three years. Other adverse events reported in
spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated
leukocyte count.
Geriatric Use: Of the total number of subjects in clinical studies of AGRYLIN®, 42.1% were 65
years and over, while 14.9% were 75 years 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 response between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out.
ADVERSE REACTIONS
Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies diagnosed
with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that
all disease groups have the same adverse event profile. While most reported adverse events during
anagrelide therapy have been mild in intensity and have decreased in frequency with continued
therapy, serious adverse events were reported in these patients. These include the following:
congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block,
atrial fibrillation, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion,
pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal
ulceration, and seizure.
Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161 (17%)
were discontinued from the study because of adverse events or abnormal laboratory test results. The
most common adverse events for treatment discontinuation were headache, diarrhea, edema,
palpitations, and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000
treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide.
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with
myeloproliferative disease) in clinical trials were:
Headache................................43.5%
Palpitations ............................26.1%
Diarrhea .................................25.7%
Asthenia .................................23.1%
Edema, other..........................20.6%
Nausea....................................17.1%
Abdominal Pain .....................16.4%
Dizziness................................15.4%
Pain, other..............................15.0%
Dyspnea .................................11.9%
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NDA 20-333/S-013
Page 11
Flatulence...............................10.2%
Vomiting................................9.7%
Fever ......................................8.9%
Peripheral Edema...................8.5%
Rash, including urticaria........8.3%
Chest Pain ..............................7.8%
Anorexia ................................7.7%
Tachycardia............................7.5%
Pharyngitis .............................6.8%
Malaise...................................6.4%
Cough.....................................6.3%
Paresthesia .............................5.9%
Back Pain ...............................5.9%
Pruritus...................................5.5%
Dyspepsia...............................5.2%
Adverse events with an incidence of 1% to < 5% included:
Body as a Whole System: Flu symptoms, chills, photosensitivity.
Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina
pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.
Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous stomatitis,
eructation.
Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy.
Platelet counts below 100,000/µL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below
50,000/µL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy.
Thrombocytopenia promptly recovered upon discontinuation of anagrelide.
Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during
anagrelide therapy.
Musculoskeletal System: Arthralgia, myalgia, leg cramps.
Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.
Nutritional Disorders: Dehydration.
Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.
Skin and Appendages System: Skin disease, alopecia.
Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.
Urogenital System: Dysuria, hematuria.
Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with
OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases, the
renal failure was considered to be possibly related to anagrelide treatment. The remaining 11 were
found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with exposure
periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency.
The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or greater of
942 patients with myeloproliferative diseases) is shown in the following bar graph:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-013
Page 12
All Patients with
Myeloproliferative Disease (N=942)
Body
as a
Whole
Cardiovascular
Gastro-
Intestinal
Metabolic
Nervous
Respiratory
Skin &
Appendages
Asthenia
Fever
Headache
Malaise
Pain
Pain (Abd)
Pain (back)
Pain (chest)
Palpitations
Tachycardia
Anorexia
Diarrhea
Dyspepsia
Flatulence
Nausea
Vomiting
Edema
Edema (per)
Dizziness
Paresthesia
Cough
Dyspnea
Pharyngitis
Pruritus
Rash Graph
0
10
20
30
40
50
Percent of Subjects with Adverse Event
Postmarketing Reports
Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial
pneumonitis) have been reported in patients who have taken anagrelide treatment in post-marketing
reports (See WARNINGS, Interstitial Lung Diseases).
OVERDOSAGE
Acute Toxicity and Symptoms
Single oral doses of anagrelide hydrochloride at 2,500, 1,500 and 200 mg/kg in mice, rats and
monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in
mice and rats and softened stools and decreased appetite in monkeys.
There have been postmarketing case reports of intentional overdose with anagrelide hydrochloride.
Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative
management. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia,
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-013
Page 13
which can potentially cause bleeding, is expected from overdosage. Should overdosage occur, cardiac
and central nervous system toxicity can also be expected.
Management and Treatment
In case of overdosage, close clinical supervision of the patient is required; this especially includes
monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped, as
appropriate, until the platelet count returns to within the normal range.
DOSAGE AND ADMINISTRATION
Treatment with AGRYLIN® Capsules should be initiated under close medical supervision. The
recommended starting dosage of AGRYLIN® for adult patients is 0.5 mg qid or 1 mg bid (2 capsules
of 0.5 mg twice a day), which should be maintained for at least one week. Starting doses in pediatric
patients have ranged from 0.5 mg per day to 0.5 mg qid. As there are limited data on the appropriate
starting dose for pediatric patients, an initial dose of 0.5 mg per day is recommended. In both adult and
pediatric patients, dosage should then be adjusted to the lowest effective dosage required to reduce and
maintain platelet count below 600,000/µL, and ideally to the normal range. The dosage should be
increased by not more than 0.5 mg/day in any one week. Maintenance dosing is not expected to be
different between adult and pediatric patients. Dosage should not exceed 10 mg/day or 2.5 mg in a
single dose (see PRECAUTIONS).
There are no special requirements for dosing the geriatric population.
It is recommended that patients with moderate hepatic impairment start anagrelide therapy at a dose of
0.5 mg/day and be maintained for a minimum of one week with careful monitoring of cardiovascular
effects. The dosage increment must not exceed more than 0.5 mg/day in any one-week. The potential
risks and benefits of anagrelide therapy in a patient with mild or moderate impairment of hepatic
function should be assessed before treatment is commenced. Use of anagrelide in patients with severe
hepatic impairment has not been studied. Use of anagrelide in patients with severe hepatic impairment
is contraindicated (see CONTRAINDICATIONS).
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts
should be performed every two days during the first week of treatment and at least weekly thereafter
until the maintenance dosage is reached.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to
complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. Most patients
will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with known or suspected
heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.
HOW SUPPLIED
AGRYLIN® is available as:
0.5 mg, opaque, white capsules imprinted “Capital S encircled
063” in black ink:
NDC 54092-063-01 = bottle of 100
Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room
Temperature]. Store in a light resistant container.
Manufactured for
Shire US Inc.
725 Chesterbrook Blvd.
Wayne, PA 19087, USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-333/S-013
Page 14
1-800-828-2088
By MALLINCKRODT INC.
Hobart, NY 13788
© 2007 Shire US Inc.
Rev. 11/07
063 0117 016
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
|
2025-02-12T13:47:29.423920
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020333s013lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 13}
|
12,461
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AGRYLIN safely and effectively. See full prescribing information
for AGRYLIN.
AGRYLIN® (anagrelide hydrochloride) capsules, for oral use
Initial U.S. Approval: 1997
----------------------RECENT MAJOR CHANGES----------------
Dosage and Administration (2)
10/2014
Contraindications (4)
10/2014
Warnings and Precautions (5)
10/2014
---------------------INDICATIONS AND USAGE-----------------------
Anagrelide is a platelet reducing agent indicated for the treatment of
thrombocythemia, secondary to myeloproliferative neoplasms, to
reduce the elevated platelet count and the risk of thrombosis and to
ameliorate associated symptoms including thrombo-hemorrhagic
events. (1)
-------------------DOSAGE AND ADMINISTRATION------------------
• The starting dose for adults is 0.5 mg four times a day or 1 mg twice
a day (2.1)
• The starting dose for pediatric patients is 0.5 mg per day (2.1)
• Maintain the starting dose for at least one week and then titrate to
maintain target platelet counts (2.2)
• Do not exceed a dose increment of 0.5 mg/day in any one week. Do
not exceed 10 mg/day or 2.5 mg in a single dose. (2.2)
• Moderate hepatic impairment: Start with 0.5 mg per day (2.3)
------------------DOSAGE FORMS AND STRENGTHS---------------
Capsules: 0.5mg (3)
--------------------------CONTRAINDICATIONS-------------------------
None (4)
------------------------WARNINGS AND PRECAUTIONS-------------------
• Cardiovascular Toxicity: QT prolongation and ventricular tachycardia have
been reported with anagrelide. Obtain a pre-treatment cardiovascular
examination including an ECG in all patients. Monitor patients for
cardiovascular effects. (5.1)
• Bleeding Risk: Monitor patients for bleeding, including those receiving
concomitant therapy with other drugs known to cause bleeding (5.2)
----------------------------ADVERSE REACTIONS--------------------------
The most common adverse reactions (incidence ≥ 5%) are headache,
palpitations, diarrhea, asthenia, edema, nausea, abdominal pain, dizziness,
pain, dyspnea, cough, flatulence, vomiting, fever, peripheral edema, rash,
chest pain, anorexia, tachycardia, malaise, paresthesia, back pain, pruritus,
dyspepsia (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Shire US
Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or
www.fda.gov./medwatch
------------------------------DRUG INTERACTIONS---------------------------
• Other PDE 3 inhibitors: Exacerbation of inotropic effects (7.2)
• Aspirin and Drugs that Increase Bleeding Risk: Increased risk of bleeding
with concomitant use (7.3)
-------------------------USE IN SPECIFIC POPULATIONS------------------
• Nursing Mothers: Discontinue nursing or discontinue the drug (8.3).
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 10/2014
Reference ID: 3650727
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FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
8 USE IN SPECIFIC POPULATIONS
2 DOSAGE AND ADMINISTRATION
8.1 Pregnancy
2.1 Starting Dose
8.3 Nursing Mothers
2.2 Titration
8.4 Pediatric Use
2.3 Dose Modifications for Hepatic Impairment
8.5 Geriatric Use
2.4 Clinical Monitoring
8.6 Hepatic Impairment
3 DOSAGE FORMS AND STRENGTHS
10 OVERDOSAGE
4 CONTRAINDICATIONS
11 DESCRIPTION
5 WARNINGS AND PRECAUTIONS
12 CLINICAL PHARMACOLOGY
5.1 Cardiovascular Toxicity
12.1 Mechanism of Action
5.2 Bleeding Risk
12.2 Pharmacodynamics
5.3 Pulmonary Toxicity
12.3 Pharmacokinetics
6 ADVERSE REACTIONS
13 NONCLINICAL TOXICOLOGY
6.1 Clinical Trial Experience
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
6.2 Postmarketing Experience
13.2
Animal Toxicology and/or Pharmacology
7 DRUG INTERACTIONS
14 CLINICAL STUDIES
7.1 Drugs that prolong QT
16 HOW SUPPLIED/STORAGE AND HANDLING
7.2 PDE3 Inhibitors
17 PATIENT COUNSELING INFORMATION
7.3 Aspirin and Drugs that Increase Bleeding Risk
7.4 CYP450 Interactions
*Sections or subsections omitted from full prescribing
information are not listed.
Reference ID: 3650727
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
AGRYLIN Capsules are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative
neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms
including thrombo-hemorrhagic events [see Clinical Studies (14), Dosage and Administration (2)].
2
DOSAGE AND ADMINISTRATION
2.1
Starting Dose
Adults: The recommended starting dosage of AGRYLIN is 0.5 mg four times daily or 1 mg twice daily.
Pediatric Patients: The recommended starting dosage of AGRYLIN is 0.5 mg daily.
2.2
Titration
Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below
600,000/µL, and ideally between 150,000/µL and 400,000/µL. The dose increment should not exceed 0.5 mg/day in any
one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose [see Warnings and Precautions (5)]. Most
patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Monitor platelet counts weekly during
titration then monthly or as necessary.
2.3
Dose Modifications for Hepatic Impairment
In patients with moderate hepatic impairment (Child Pugh score 7-9) start AGRYLIN therapy at a dose of 0.5 mg/day and
monitor frequently for cardiovascular events [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and
Clinical Pharmacology (12.3)]. Patients with moderate hepatic impairment who have tolerated AGRYLIN therapy for one
week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid
use of AGRYLIN in patients with severe hepatic impairment.
2.4
Clinical Monitoring
AGRYLIN therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal
function, and electrolytes.
To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment
and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7
to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count ≤
600,000/µL, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in
platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to
two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.
Reference ID: 3650727
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3
DOSAGE FORMS AND STRENGTHS
White, opaque capsule, containing 0.5 mg anagrelide (as anagrelide hydrochloride), imprinted with “
063” in black
ink.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Cardiovascular Toxicity
Torsades de pointes and ventricular tachycardia have been reported with anagrelide. Obtain a pre-treatment cardiovascular
examination including an ECG in all patients. During treatment with AGRYLIN monitor patients for cardiovascular
effects and evaluate as necessary.
Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers [see
Clinical Pharmacology (12.2)].
Do not use AGRYLIN in patients with known risk factors for QT interval prolongation, such as congenital long QT
syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and
hypokalemia [see Drug Interactions (7.1)].
Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with
hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of
anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is
commenced. Reduce AGRYLIN dose in patients with moderate hepatic impairment. Use of AGRYLIN in patients with
severe hepatic impairment has not been studied [see Dosage and Administration (2.3), Use in Specific Populations (8.6)
and Clinical Pharmacology (12.2, 12.3)].
In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with
electrocardiograms [see Clinical Pharmacology (12.2)].
Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and
congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in
patients with Class III-IV congestive heart failure [see Drug Interactions (7.2)].
In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.
5.2
Bleeding Risk
Reference ID: 3650727
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Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a postmarketing study. Assess the
potential risks and benefits for concomitant use of anagrelide with aspirin, since bleeding risks may be increased. Monitor
patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g.,
anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors) [see Drug
Interactions (7.3), Clinical Pharmacology (12.3)].
5.3
Pulmonary Toxicity
Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been
reported to be associated with the use of anagrelide in post-marketing reports. Most cases presented with progressive
dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating anagrelide. If
suspected, discontinue AGRYLIN and evaluate. Symptoms may improve after discontinuation [see Adverse Reactions
(6)].
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
•
Cardiovascular Toxicity [see Warnings and Precautions (5.1)]
•
Bleeding Risk [see Warnings and Precautions (5.2)]
•
Pulmonary Toxicity [see Warnings and Precautions (5.3)]
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 practice.
Clinical Studies in Adult Patients
In three single-arm clinical studies, 942 patients [see Clinical Trials (14)] diagnosed with myeloproliferative neoplasms of
varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65
weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial
infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial
effusion [see Warnings and Precautions (5.1)], pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary
hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study
because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment
discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative
neoplasms) in clinical trials were listed in Table 1.
Reference ID: 3650727
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Table 1
Adverse Reactions Reported in Clinical Studies in at least 5% of Patients
Adverse reactions
AGRYLIN
(N=942)
(%)
Cardiac Disorder
Palpitations
26%
Tachycardia
8%
Chest Pain
8%
General disorders and administration site
conditions
Asthenia
23%
Edema
21%
Pain
15%
Fever
9%
Peripheral edema
9%
Malaise
6%
Gastrointestinal disorders
Diarrhea
26%
Nausea
17%
Abdominal Pain
16%
Vomiting
10%
Flatulence
10%
Anorexia
8%
Reference ID: 3650727
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Dyspepsia
5%
Respiratory, thoracic and mediastinal disorders
Dyspnea
12%
Cough
6%
Skin and subcutaneous tissue disorders
Rash
8%
Pruritus
6%
Musculoskeletal and connective tissue disorders
Back Pain
6%
Nervous system disorders
Headache
44%
Dizziness
15%
Paresthesia
6%
Adverse Reactions (frequency 1% to < 5%) included:
General disorders and administration site conditions: Flu symptoms, chills.
Cardiac Disorders: Arrhythmia, angina pectoris, heart failure, syncope.
Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.
Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.
Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.
Hepatobiliary disorders: Elevated liver enzymes.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
Psychiatric disorders: Depression, confusion, nervousness.
Reference ID: 3650727
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Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.
Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.
Skin and subcutaneous tissue disorders: Alopecia.
Eye disorders: Abnormal vision, diplopia.
Ear and labyrinth disorders: Tinnitus
Renal and urinary disorders: Hematuria, renal failure.
Clinical Study in Pediatric Patients
The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse
events observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month anagrelide treatment
in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in
the absence of clinical symptoms were observed. Adverse events that had been reported in these pediatric patients prior to
the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations,
headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-marketing use of AGRYLIN. 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. Cases of torsades de pointes, ventricular tachycardia, interstitial lung
diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) [see Warnings and
Precautions (5)], tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and
AST elevations and elevations greater than three times the ULN) have been reported.
Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia,
cutaneous photosensitivity and elevated leukocyte count.
7
DRUG INTERACTIONS
7.1
Drugs that prolong QT
Do not use AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to,
chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide and
pimozide) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
7.2
PDE3 inhibitors
Reference ID: 3650727
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Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor. The effects of drug products with similar properties such as
inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) should be avoided [see Warnings and Precautions (5.1)
and Clinical Pharmacology (12.2)].
7.3
Aspirin and Drugs that Increase Bleeding Risk
Co-administration of single-dose or repeat-dose anagrelide and aspirin showed greater ex vivo anti-platelet aggregation
effects than administration of aspirin alone [see Clinical Pharmacology (12.3)]. Results from an observational study in
patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with
anagrelide is higher than in those subjects treated with another cytoreductive treatment. The majority of the major
hemorrhagic events occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily,
aspirin). Therefore, the potential risks of the concomitant use of anagrelide with aspirin should be assessed, particularly in
patients with a high risk profile for hemorrhage, before treatment is initiated [see Warnings and Precautions (5.2)].
Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding
(e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).
7.4
CYP450 Interactions
CYP1A2 inhibitors: Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit
CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide. Monitor patients for cardiovascular
events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.
CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2
inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.
CYP1A2 substrates: Anagrelide demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the
exposure of concomitant CYP1A2 substrates (e.g. theophylline, fluvoxamine, ondansetron).
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies with AGRYLIN in pregnant women. In animal embryo-fetal studies,
delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered
anagrelide hydrochloride during organogenesis at doses substantially higher than the maximum clinical dose of 10
mg/day. AGRYLIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Reference ID: 3650727
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Anagrelide hydrochloride was administered orally to pregnant rats and rabbits during the period of organogenesis at doses
up to 900 mg/kg/day in rats and up to 20 mg/kg/day in rabbits (875 and 39 times, respectively, the maximum clinical dose
of 10 mg/day based on body surface area). In rats, developmental delays were observed including reductions in fetal
weight at 300 and 900 mg/kg/day and delays in skeletal ossification at doses of 100 mg/kg/day and higher. The dose of
100 mg/kg/day (600 mg/m2/day) in rats is approximately 97 times the maximum clinical dose based on body surface area.
No adverse embryo-fetal effects were detected in rabbits at the highest dose of 20 mg/kg/day (39 times the maximal
clinical dose based on body surface area).
In a pre- and post-natal study conducted in female rats, anagrelide hydrochloride at oral doses of 60 mg/kg/day (58 times
the maximum clinical dose based on body surface area) or higher produced delay or blockage of parturition, deaths of
non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born.
In a placental transfer study, a single oral dose of [14C]-anagrelide hydrochloride was administered to pregnant rats on
gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.
8.3
Nursing Mothers
Risk Summary
It is not known whether anagrelide is excreted in human milk. Anagrelide or its metabolites have been detected in the milk
of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse
reaction in nursing infants from anagrelide, 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.
Data
In a rat milk secretion study, a single oral dose of [14C]-anagrelide hydrochloride was administered to lactating female rats
on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.
8.4
Pediatric Use
Experience with AGRYLIN in pediatric patients was based on an open label safety and PK/PD study conducted in 18
pediatric patients aged 7-16 years with thrombocytopenia secondary to ET [see Dosage and Administration (2.1), Clinical
Pharmacology (12.3) and Clinical Studies (14)].
There were no apparent trends or differences in the types of adverse events observed between the pediatric patients
compared with those of the adult patients [see Adverse Reactions (6.1)].
8.5
Geriatric Use
Of the 942 subjects in clinical studies of AGRYLIN, 42.1% were 65 years and over, while 14.9% were 75 years and over.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other
Reference ID: 3650727
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reported clinical experience has not identified differences in response between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
8.6
Hepatic Impairment
Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8-fold in patients with
moderate hepatic impairment [see Clinical Pharmacology (12.3)] and dose reduction is required [see Dosage and
Administration (2.3)]. Use of AGRYLIN in patients with severe hepatic impairment has not been studied. The potential
risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before
treatment is commenced. Assess hepatic function before and during anagrelide treatment [see Warnings and Precautions
(5.1)].
10
OVERDOSAGE
At higher than recommended doses, this medicine has been shown to cause hypotension. There have been postmarketing
case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and
vomiting. Symptoms resolved with supportive management. Platelet reduction from anagrelide therapy is dose-related;
therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.
In case of overdosage, close clinical supervision of the patient is required; this especially includes monitoring of the
platelet count for thrombocytopenia. Dosage should be stopped, as appropriate, until the platelet count returns to within
the normal range.
11
DESCRIPTION
AGRYLIN (anagrelide hydrochloride) is a platelet-reducing agent. Its chemical name is 6,7-dichloro-1,5
dihydroimidazo[2,1-b]quinazolin-2(3H)-one
monohydrochloride
monohydrate.
The
molecular
formula
is
C10H7Cl2N3O•HCl•H2O which corresponds to a molecular weight of 310.55. The structural formula is: structural formula
Anagrelide hydrochloride is an off-white powder. It is very slightly soluble in water and sparingly soluble in dimethyl
sulfoxide and dimethylformamide.
AGRYLIN is supplied as capsules for oral administration, containing 0.5 mg of anagrelide base (as anagrelide
hydrochloride). The capsules also contain anhydrous lactose NF, crospovidone NF, lactose monohydrate NF, magnesium
stearate NF, microcrystalline cellulose NF, and povidone NF as inactive ingredients. The capsule shell contains gelatin,
titanium dioxide and black iron oxide.
Reference ID: 3650727
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide
suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis,
ultimately leading to reduced platelet production.
12.2
Pharmacodynamics
In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of
megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not
produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically
insignificant effect on red cell parameters. The active metabolite, 3-hydroxy anagrelide, has similar potency and efficacy
to that of anagrelide in the platelet lowering effect; however, exposure (measured by plasma AUC) to 3-hydroxy
anagrelide is approximately 2-fold higher compared to anagrelide. Anagrelide and 3-hydroxy anagrelide inhibit cyclic
AMP phosphodiesterase 3 (PDE3) and 3-hydroxy anagrelide is approximately forty times more potent than anagrelide
(IC50s = 0.9 and 36nM, respectively). PDE3 inhibition does not alter platelet production. PDE3 inhibitors, as a class can
inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of
anagrelide higher than those typically required to reduce platelet count. PDE3 inhibitors have cardiovascular (CV) effects
including vasodilation, positive inotropy and chronotropy.
Cardiac Electrophysiology
The effect of anagrelide dose (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval prolongation potential
was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in 60 healthy adult men and
women.
A dose-related increase in heart rate was observed, with the maximum increase occurring around the time of maximal
drug concentration (0.5 – 4 hours). The maximum change in mean heart rate occurred at 2 hours after administration and
was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.
Dose-related increase in mean QTc was observed. The maximum mean (95% upper confidence bound) change in QTcI
(individual subject correction) from placebo after baseline-correction was 7.0 (9.8) ms and 13.0 (15.7) ms following
anagrelide doses of 0.5 mg and 2.5 mg, respectively.
12.3
Pharmacokinetics
Dose proportionality has been found in the dose range 0.5 mg to 2.5 mg.
Absorption
Following oral administration of AGRYLIN, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects,
anagrelide peak plasma concentrations occur within about 1 hour after administration.
Reference ID: 3650727
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Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and
fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased
the AUC by 20%. Food decreased the Cmax of the active metabolite 3-hydroxy-anagrelide by 29%, although it had no
effect on the AUC.
Metabolism
Anagrelide is primarily metabolized by CYP1A2 to the active metabolite, 3-hydroxy-anagrelide, which is subsequently
metabolized by CYP1A2 to the inactive metabolite, RL603. Less than 1% of the administered dose is recovered in the
urine as anagrelide, and approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy-anagrelide and
RL603, respectively.
Elimination
Anagrelide and 3-hydroxy-anagrelide are eliminated with plasma half-lives of approximately 1.5 and 2.5 hours,
respectively. Anagrelide and 3-hydroxy-anagrelide do not accumulate in plasma when the clinical dose regimens are
administered.
Drug Interactions
Aspirin: In two pharmacodynamic interaction studies in healthy subjects, co-administration of single-dose anagrelide 1 mg
and aspirin 900 mg or repeat-dose anagrelide 1 mg once daily and aspirin 75 mg once daily showed greater ex vivo anti-
platelet aggregation effects than administration of aspirin alone. Co-administered anagrelide 1mg and aspirin 900mg
single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).
Digoxin or warfarin: In vivo interaction studies in humans have demonstrated that anagrelide does not affect the
pharmacokinetic properties of digoxin or warfarin, nor does digoxin or warfarin affect the pharmacokinetic properties of
anagrelide.
Specific Populations
Pediatric: Dose-normalized Cmax and AUC of anagrelide were higher in children and adolescents (age range 7-16 years)
with essential thrombocythemia, by 17% and 56%, respectively, than in adult patients (19-57 years).
Geriatric: Cmax and AUC of anagrelide were 36% and 61% higher, respectively, in elderly patients (age range 65-75
years), than in younger adults (age range 22-50 years), but Cmax and AUC of the active metabolite, 3-hydroxy anagrelide,
were 42% and 37% lower, respectively, in the elderly patients.
Renal Impairment: Pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment
(creatinine clearance <30 mL/min) showed no significant effects on the pharmacokinetics of anagrelide.
Reference ID: 3650727
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Hepatic Impairment: A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic
impairment (Child Pugh score 7-9) showed a 2-fold increase in mean anagrelide Cmax and an 8-fold increase in total
exposure (AUC) to anagrelide compared with healthy subjects. Additionally, subjects with moderate hepatic impairment
showed 24% lower mean 3-hydroxy-anagrelide Cmax and 77% higher mean 3-hydroxy-anagrelide AUC compared to
healthy subjects.
13.
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in
females receiving 30 mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal
phaeochromocytomas were increased relative to controls in males receiving 3 mg/kg/day and above, and in females
receiving 10 mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1 mg twice daily
dose).
Anagrelide hydrochloride was not mutagenic in the bacterial mutagenesis (Ames) assay or the mouse lymphoma cell
(L5178Y, TK+/-) forward mutation assay, and was not clastogenic in the in vitro chromosome aberration assay using
human lymphocytes or the in vivo mouse micronucleus test.
Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (233 times the recommended human dose of 10 mg/day
based on body surface area) had no effect on fertility and reproductive function of male rats. However, in fertility studies
in female rats, oral doses of 30 mg/kg/day (360 mg/m2/day, 29 times the recommended maximum human dose based on
body surface area) or higher resulted in increased pre- and post-implantation loss and a decrease in the number of live
embryos.
13.2
Animal Toxicology and/or Pharmacology
In the 2-year rat study, a significant increase in non-neoplastic lesions was observed in anagrelide treated males and
females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and chamber distension), kidney
(hydronephrosis, tubular dilation and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed
in tissues of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney
(arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular mineralization), and testes
(tubular atrophy and vascular infarct) in anagrelide treated males.
CLINICAL STUDIES
Clinical Studies in Adult Patients:
A total of 942 patients with myeloproliferative neoplasms including 551 patients with Essential Thrombocythemia (ET),
117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous Leukemia (CML), and 96 patients
with other myeloproliferative neoplasms (OMPN), were treated with AGRYLIN in three clinical trials. Patients with
Reference ID: 3650727
14
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For current labeling information, please visit https://www.fda.gov/drugsatfda
OMPN included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had
unclassified myeloproliferative neoplasms.
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions or ≥ 650,000/µL on two
occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy
for ET, PV, CML, and OMPN patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for
2 years. Patients were treated with AGRYLIN starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the
platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or
near physiologic levels (150,000-400,000/µL). The criteria for defining subjects as “responders” were reduction in
platelets for at least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less than 4
weeks were not considered evaluable. The results are depicted graphically below: graph
Time on Treatment
Weeks
Years
Baseline
4
12
24
48
2
3
4
Mean*
1131
683
575
526
484
460
437
457
N
923†
868
814
662
530
407
207
55
Reference ID: 3650727
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*x 103/µL
†Nine hundred and forty-two subjects with myeloproliferative neoplasms were enrolled in three research studies. Of these,
923 had platelet counts measured over the duration of the studies.
AGRYLIN was effective in phlebotomized patients as well as in patients treated with other concomitant therapies
including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.
Clinical Study in Pediatric Patients:
An open label safety and PK/PD study was conducted in 18 pediatric patients 7-16 years of age (8 patients 7-11 years of
age and 10 patients 12-16 years of age, mean age of 12 years; 8 males and 10 females) with thrombocythemia secondary
to ET as compared to 17 adult patients (mean age of 66 years, 9 males and 8 females). Prior to entry on to the study, 17 of
18 pediatric patients and 12 of 17 adult patients had received anagrelide treatment for an average of 2 years. The median
starting total daily dose, determined by retrospective chart review, for pediatric and adult patients with ET who had
received anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 12-16 year old patients and
adults). The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once daily. At study completion, the
median total daily maintenance doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age,
2.25 mg in patients 12-16 years of age, and 1.5 mg for adults.
16
HOW SUPPLIED/STORAGE AND HANDLING
AGRYLIN is available as:
0.5 mg, opaque, white capsules imprinted “
063” in black ink: NDC 54092-063-01 = bottle of 100
Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room Temperature]. Store in a
light resistant container.
17
PATIENT COUNSELING INFORMATION
• Dose: Tell the patient that their dose will be adjusted on a weekly basis until they are on a dose that lowers their
platelets to an appropriate level. This will also help the patient to adjust to common side effects. Tell the patient to
contact their doctor if they experience tolerability issues, so the dose or dosing frequency can be adjusted
[see Dosage and Administration (2)].
• Cardiovascular effects: Tell the patient to contact a doctor immediately if they experience chest pain,
palpitations, or feel their heartbeat is irregular [see Warnings and Precautions (5.1)].
Reference ID: 3650727
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Risk of bleeding: Warn the patient that concomitant aspirin (or other medicines that affect blood clotting) may
increase the risk of bleeding. Tell the patient to contact a doctor immediately if they experience signs or
symptoms of bleeding (e.g. vomit blood, pass bloody or black stools) or experience unexplained bruising/bruise
more easily than usual [see Warnings and Precautions (5.2), Drug Interactions (7.1)].
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA
1-800-828-2088
© 2014 Shire US Inc.
063 0117 020
Printed in USA
Reference ID: 3650727
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:29.504595
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020333s022lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
12,460
|
AGRYLIN®
(anagrelide hydrochloride)
Capsules
Rx only
DESCRIPTION
Name: AGRYLIN® (anagrelide hydrochloride)
Dosage Form: 0.5 mg capsules for oral administration
Active Ingredient: AGRYLIN® Capsules contain 0.5 mg of anagrelide base (as anagrelide
hydrochloride).
Inactive Ingredients: Anhydrous Lactose NF, Crospovidone NF, Lactose Monohydrate NF,
Magnesium stearate NF, Microcrystalline cellulose NF, Povidone USP.
Pharmacological Classification: Platelet-reducing agent.
Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one
monohydrochloride monohydrate.
Molecular formula: C10H7Cl2N3O•HCl•H2O
Molecular weight: 310.55
Structural formula:
H
st
ru
ctural formula
== O•HCl•H2O
Cl
Cl
Appearance: Off-white powder
Solubility:
Water……………………….. Very slightly soluble
Dimethyl Sulfoxide………… Sparingly soluble
Dimethylformamide………... Sparingly soluble
CLINICAL PHARMACOLOGY
The mechanism by which anagrelide reduces blood platelet count is still under investigation.
Studies in patients support a hypothesis of dose-related reduction in platelet production resulting
from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers
treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte
development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide
does not produce significant changes in white cell counts or coagulation parameters, and may
have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic
AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation.
However, significant inhibition of platelet aggregation is observed only at doses of
anagrelide higher than those required to reduce platelet count.
Following oral administration of 14C-anagrelide in people, more than 70% of radioactivity was
recovered in urine. Based on limited data, there appears to be a trend toward dose linearity
between doses of 0.5 mg and 2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma
half-life is 1.3 hours. The available plasma concentration time data at steady state in patients
showed that anagrelide does not accumulate in plasma after repeated administration.
1
Reference ID: 3048374
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Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).
There were no apparent differences between patient groups (pediatric versus adult patients) for
tmax and t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.
Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of
anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide
with food decreased the Cmax by 14%, but increased the AUC by 20%.
Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86
years) patients with thrombocythemia secondary to a myeloproliferative disorder (MPD),
indicate that dose- and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were
lower in the pediatric patients compared to the adult patients (Cmax 48%, AUCτ 55%).
Pharmacokinetic data from fasting elderly patients with ET (age range 65-75 years) compared to
fasting adult patients (age range 22-50 years) indicate that the Cmax and AUC of anagrelide were
36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active
metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal
impairment (creatinine clearance <30ml/min) showed no significant effects on the
pharmacokinetics of anagrelide.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic
impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.
CLINICAL STUDIES
A total of 942 patients with myeloproliferative disorders including 551 patients with Essential
Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic
Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative disorders
(OMPD), were treated with anagrelide in three clinical trials. Patients with OMPD included 87
patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had
unknown myeloproliferative disorders.
Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:
ET:
• Platelet count ≥ 900,000/µL on two determinations
• Profound megakaryocytic hyperplasia in bone marrow
• Absence of Philadelphia chromosome
• Normal red cell mass
• Normal serum iron and ferritin and normal marrow iron stores
CML:
• Persistent granulocyte count ≥ 50,000/µL without evidence of infection
2
Reference ID: 3048374
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• Absolute basophil count ≥ 100/µL
• Evidence for hyperplasia of the granulocytic line in the bone marrow
• Philadelphia chromosome is present
• Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range
PV†:
• A1 Increased red cell mass
• A2 Normal arterial oxygen saturation
• A3 Splenomegaly
• B1 Platelet count ≥ 400,000/µL, in absence of iron deficiency or bleeding
• B2 Leukocytosis (≥ 12,000/µL, in the absence of infection)
• B3 Elevated leukocyte alkaline phosphatase
• B4 Elevated serum B12
†Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1
and A2 are present with any two of B1, B2, or B3.
MMM:
• Myelofibrotic (hypocellular, fibrotic) bone marrow
• Prominent megakaryocytic metaplasia in bone marrow
• Splenomegaly
• Moderate to severe normo-chromic normocytic anemia
• White cell count may be variable; (80,000-100,000/µL)
• Increased platelet count
• Variable red cell mass; teardrop poikilocytes
• Normal to high leukocyte alkaline phosphatase
• Absence of Philadelphia chromosome
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions
or ≥ 650,000/µL on two occasions with documentation of symptoms associated with
thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPD
patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2
years. Patients were treated with anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The
dose was increased if the platelet count was still high, but to no more than 12 mg each day.
Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000
400,000/µL). The criteria for defining subjects as “responders” were reduction in platelets for at
least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less
than 4 weeks were not considered evaluable. The results are depicted graphically below:
3
Reference ID: 3048374
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Patients with Thrombocytosis Secondary to Myeloproliferative Disorders:
Mean Platelet Count During Anagrelide Therapy
grap
h
0
Number of Subjects
in Assay
923 868
Baseline
Mean*
1131
N
923†
12
814
4
683
868
24
662
12
575
814
36
48
104
Time of Treatment (Weeks)
530
407
Time on Treatment
Weeks
24
48
2
526
484
460
662
530
407
156
207
Years
3
437
207
208
55
4
457
55
*x 103/µL
†Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three
research studies. Of these, 923 had platelet counts over the duration of the studies.
AGRYLIN® was effective in phlebotomized patients as well as in patients treated with other
concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and
alkylating agents.
INDICATIONS AND USAGE
AGRYLIN® Capsules are indicated for the treatment of patients with thrombocythemia,
secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of
thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events (see
CLINICAL STUDIES, DOSAGE AND ADMINISTRATION).
4
Reference ID: 3048374
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CONTRAINDICATIONS
Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide
is increased 8-fold in patients with moderate hepatic impairment (see CLINICAL
PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has not
been studied (see also WARNINGS: Hepatic).
WARNINGS
Cardiovascular
Anagrelide should be used with caution in patients with known or suspected heart disease, and
only if the potential benefits of therapy outweigh the potential risks. Because of the positive
inotropic effects and side-effects of anagrelide, a pre-treatment cardiovascular examination is
recommended along with careful monitoring during treatment. In humans, therapeutic doses of
anagrelide may cause cardiovascular effects, including vasodilation, tachycardia, palpitations,
and congestive heart failure.
Hepatic
Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see
CLINICAL PHARMACOLOGY). Use of anagrelide in patients with severe hepatic
impairment has not been studied. The potential risks and benefits of anagrelide therapy in a
patient with mild and moderate impairment of hepatic function should be assessed before
treatment is commenced. In patients with moderate hepatic impairment, dose reduction is
required and patients should be carefully monitored for cardiovascular effects (see DOSAGE
AND ADMINISTRATION for specific dosing recommendations).
Interstitial Lung Diseases
Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial
pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing
reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset
ranged from 1 week to several years after initiating anagrelide. In most cases, the symptoms
improved after discontinuation of anagrelide (See ADVERSE REACTIONS).
PRECAUTIONS
Bleeding: Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a
postmarketing study. Assess the potential risks and benefits for concomitant use of anagrelide
with aspirin, particularly in patients with a high risk profile for hemorrhage.
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While
the platelet count is being lowered (usually during the first two weeks of treatment), blood counts
(hemoglobin, white blood cells), and renal function (serum creatinine, BUN) should be
monitored. Cases of clinically significant hepatotoxicity (including symptomatic ALT and AST
elevations and elevations greater than three times the ULN) have been reported in post
5
Reference ID: 3048374
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For current labeling information, please visit https://www.fda.gov/drugsatfda
marketing surveillance. Measure liver function tests (ALT, AST) before initiating anagrelide
treatment and during therapy.
In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average
of 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure
were observed following a dose of 2 mg.
Cessation of AGRYLIN® Treatment: In general, interruption of anagrelide treatment is
followed by an increase in platelet count. After sudden stoppage of anagrelide therapy, the
increase in platelet count can be observed within four days.
Drug Interactions: Limited PK and/or PD studies investigating possible interactions between
anagrelide and other medicinal products have been conducted. In vivo interaction studies in
humans have demonstrated that digoxin and warfarin do not affect the PK properties of
anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.
In two clinical interaction studies in healthy subjects, co-administration of single-dose anagrelide
1mg and aspirin 900mg or repeat-dose anagrelide 1mg once daily and aspirin 75mg once daily
showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Co
administered anagrelide 1mg and aspirin 900mg single-doses had no effect on bleeding time,
prothrombin time (PT) or activated partial thromboplastin time (aPTT).
Analyses of an ongoing observational study in patients with ET suggest the rate of major
hemorrhagic events (MHEs) in patients treated with anagrelide is higher than in those subjects
treated with another cytoreductive treatment. The majority of the major hemorrhagic events
occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily,
aspirin). Therefore, the potential risks of the concomitant use of anagrelide with aspirin should
be assessed, particularly in patients with a high risk profile for hemorrhage, before treatment is
initiated.
Drug interaction studies have not been conducted with the other common medications used
concomitantly with anagrelide in clinical trials which were acetaminophen, furosemide, iron,
ranitidine, hydroxyurea, and allopurinol.
Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by
several medicinal products, including fluvoxamine, and such medicinal products could
theoretically adversely influence the clearance of anagrelide. Anagrelide demonstrates some
limited inhibitory activity towards CYP1A2 which may present a theoretical potential for
interaction with other co-administered medicinal products sharing that clearance mechanism e.g.
theophylline.
Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with
similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol
may be exacerbated by anagrelide.
6
Reference ID: 3048374
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There is a single case report which suggests that sucralfate may interfere with anagrelide
absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In a two year rat carcinogenicity study
a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females
receiving 30mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose).
Adrenal phaeochromocytomas were increased relative to controls in males receiving 3mg/kg/day
and above, and in females receiving 10mg/kg/day and above (at least 10 and 18 times
respectively human AUC exposure after a 1mg twice daily dose). Anagrelide hydrochloride was
not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test,
the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Anagrelide
hydrochloride at oral doses up to 240 mg/kg/day (1,440 mg/m2/day, 195 times the recommended
maximum human dose based on body surface area) was found to have no effect on fertility and
reproductive performance of male rats. However, in female rats, at oral doses of 60 mg/kg/day
(360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area)
or higher, it disrupted implantation when administered in early pregnancy and retarded or
blocked parturition when administered in late pregnancy.
Pregnancy: Pregnancy Category C.
(i) Teratogenic Effects
Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day
(5,400 mg/m2/day, 730 times the recommended maximum human dose based on body surface
area) and in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the
recommended maximum human dose based on body surface area) and have revealed no evidence
of impaired fertility or harm to the fetus due to anagrelide hydrochloride.
(ii) Nonteratogenic Effects
A fertility and reproductive performance study performed in female rats revealed that anagrelide
hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended
maximum human dose based on body surface area) or higher disrupted implantation and exerted
adverse effect on embryo/fetal survival.
A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride
at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human
dose based on body surface area) or higher produced delay or blockage of parturition, deaths of
nondelivering pregnant dams and their fully developed fetuses, and increased mortality in the
pups born.
There are however, no adequate and well controlled studies with anagrelide hydrochloride in
pregnant women. Because animal reproduction studies are not always predictive of human
response, anagrelide hydrochloride should be used during pregnancy only if clearly needed.
7
Reference ID: 3048374
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Nonclinical toxicology: In the 2-year rat study, a significant increase in non-neoplastic lesions
was observed in anagrelide treated males and females in the adrenal (medullary hyperplasia),
heart (myocardial hypertrophy and chamber distension), kidney (hydronephrosis, tubular dilation
and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed in tissues
of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney
(arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular
mineralization), and testes (tubular atrophy and vascular infarct) in anagrelide treated males.
Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day.
Treatment was stopped as soon as it was realized that they were pregnant. All delivered normal,
healthy babies. There are no adequate and well-controlled studies in pregnant women.
Anagrelide hydrochloride should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential harm to the fetus. Women of child-bearing potential should be
instructed that they must not be pregnant and that they should use contraception while taking
anagrelide. Anagrelide may cause fetal harm when administered to a pregnant woman.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious adverse reaction in
nursing infants from anagrelide hydrochloride, 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: Myeloproliferative disorders are uncommon in pediatric patients and limited data
are available in this population. An open label safety and PK/PD study (see CLINICAL
PHARMACOLOGY) was conducted in 17 pediatric patients 7-14 years of age (8 patients 7-11
years of age and 9 patients 11-14 years of age, mean age of 11 years; 8 males and 9 females)
with thrombocythemia secondary to ET as compared to 18 adult patients (mean age of 63 years,
9 males and 9 females). Prior to entry on to the study, 16 of 17 pediatric patients and 13 of 18
adult patients had received anagrelide treatment for an average of 2 years. The median starting
total daily dose, determined by retrospective chart review, for pediatric and adult ET patients
who had received anagrelide prior to study entry was 1mg for each of the three age groups (7-11
and 11-14 year old patients and adults). The starting dose for 6 anagrelide-naive patients at
study entry was 0.5 mg once daily. At study completion, the median total daily maintenance
doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age, 2 mg
in patients 11-14 years of age, and 1.5 mg for adults.
The study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anagrelide,
including platelet counts (see CLINICAL PHARMACOLOGY).
The frequency of adverse events observed in pediatric patients was similar to adult patients. The
most common adverse events observed in pediatric patients were fever, epistaxis, headache, and
fatigue during a 3-months treatment of anagrelide in the study. Adverse events that had been
reported in these pediatric patients prior to the study and were considered to be related to
8
Reference ID: 3048374
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For current labeling information, please visit https://www.fda.gov/drugsatfda
anagrelide treatment based on retrospective review were palpitations, headache, nausea,
vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps. Episodes of
increased pulse rate and decreased systolic or diastolic blood pressure beyond the normal ranges
in the absence of clinical symptoms were observed in some patients. Reported AEs were
consistent with the known pharmacological profile of anagrelide and the underlying disease.
There were no apparent trends or differences in the types of adverse events observed between the
pediatric patients compared with those of the adult patients. No overall difference in dosing and
safety were observed between pediatric and adult patients.
In another open-label study, anagrelide had been used successfully in 12 pediatric patients (age
range 6.8 to 17.4 years; 6 male and 6 female), including 8 patients with ET, 2 patients with
CML, 1 patient with PV, and 1 patient with OMPD. Patients were started on therapy with 0.5 mg
qid up to a maximum daily dose of 10 mg. The median duration of treatment was 18.1 months
with a range of 3.1 to 92 months. Three patients received treatment for greater than three years.
Other adverse events reported in spontaneous reports and literature reviews include anemia,
cutaneous photosensitivity and elevated leukocyte count.
Geriatric Use: Of the total number of subjects in clinical studies of AGRYLIN®, 42.1% were
65 years and over, while 14.9% were 75 years 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 response between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies
diagnosed with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274)
has shown that all disease groups have the same adverse event profile. While most reported
adverse events during anagrelide therapy have been mild in intensity and have decreased in
frequency with continued therapy, serious adverse events were reported in these patients. These
include the following: congestive heart failure, myocardial infarction, cardiomyopathy,
cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis,
pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary
hypertension, pancreatitis, gastric/duodenal ulceration, and seizure.
Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161
(17%) were discontinued from the study because of adverse events or abnormal laboratory test
results. The most common adverse events for treatment discontinuation were headache, diarrhea,
edema, palpitations, and abdominal pain. Overall, the occurrence rate of all adverse events was
17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages
of anagrelide.
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients
with myeloproliferative disease) in clinical trials were:
Headache................................43.5%
9
Reference ID: 3048374
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Palpitations.............................26.1%
Diarrhea..................................25.7%
Asthenia .................................23.1%
Edema, other ..........................20.6%
Nausea....................................17.1%
Abdominal Pain .....................16.4%
Dizziness................................15.4%
Pain, other ..............................15.0%
Dyspnea..................................11.9%
Flatulence...............................10.2%
Vomiting ................................9.7%
Fever ......................................8.9%
Peripheral Edema...................8.5%
Rash, including urticaria ........8.3%
Chest Pain ..............................7.8%
Anorexia.................................7.7%
Tachycardia............................7.5%
Pharyngitis .............................6.8%
Malaise...................................6.4%
Cough.....................................6.3%
Paresthesia..............................5.9%
Back Pain ...............................5.9%
Pruritus...................................5.5%
Dyspepsia...............................5.2%
Adverse events with an incidence of 1% to < 5% included:
Body as a Whole System: Flu symptoms, chills, photosensitivity.
Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina
pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.
Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous
stomatitis, eructation.
Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy.
Platelet counts below 100,000/µL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction
below 50,000/µL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy.
Thrombocytopenia promptly recovered upon discontinuation of anagrelide.
Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during
anagrelide therapy.
Musculoskeletal System: Arthralgia, myalgia, leg cramps.
Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.
Nutritional Disorders: Dehydration.
Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis,
asthma.
Skin and Appendages System: Skin disease, alopecia.
Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.
Urogenital System: Dysuria, hematuria.
10
Reference ID: 3048374
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with
OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases,
the renal failure was considered to be possibly related to anagrelide treatment. The remaining 11
were found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with
exposure periods of 2 to 12 months. No dose adjustment was required because of renal
insufficiency.
The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or
greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:
All Patients with
Myeloproliferative Disease (N=942)
Body
as a
Whole
Cardiovascular
Gastro-
Intestinal
Metabolic
Nervous
Respiratory
Skin &
Appendages
Asthenia
Fever
Headache
Malaise
Pain
Pain (Abd)
Pain (back)
Pain (chest)
Palpitations
Tachycardia
Anorexia
Diarrhea
Dyspepsia
Flatulence
Nausea
Vomiting
Edema
Edema (per)
Dizziness
Paresthesia
Cough
Dyspnea
Pharyngitis
Pruritus
Rash graph
0
10
20
30
40
50
Percent of Subjects with Adverse Event
Postmarketing Reports
Cases of interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and
interstitial pneumonitis), tubulointerstitial nephritis and clinically significant hepatotoxicity have
11
Reference ID: 3048374
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been reported (See WARNINGS, Interstitial Lung Diseases and PRECAUTIONS, Laboratory
Tests).
OVERDOSAGE
Acute Toxicity and Symptoms
Single oral doses of anagrelide hydrochloride at 2,500, 1,500 and 200 mg/kg in mice, rats and
monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor
activity in mice and rats and softened stools and decreased appetite in monkeys.
There have been postmarketing case reports of intentional overdose with anagrelide
hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved
with conservative management. Platelet reduction from anagrelide therapy is dose-related;
therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.
Should overdosage occur, cardiac and central nervous system toxicity can also be expected.
Management and Treatment
In case of overdosage, close clinical supervision of the patient is required; this especially
includes monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or
stopped, as appropriate, until the platelet count returns to within the normal range.
DOSAGE AND ADMINISTRATION
Treatment with AGRYLIN® Capsules should be initiated under close medical supervision. The
recommended starting dosage of AGRYLIN® for adult patients is 0.5 mg qid or 1 mg bid (2
capsules of 0.5 mg twice a day), which should be maintained for at least one week. Starting
doses in pediatric patients have ranged from 0.5 mg per day to 0.5 mg qid. As there are limited
data on the appropriate starting dose for pediatric patients, an initial dose of 0.5 mg per day is
recommended. In both adult and pediatric patients, dosage should then be adjusted to the lowest
effective dosage required to reduce and maintain platelet count below 600,000/µL, and ideally to
the normal range. The dosage should be increased by not more than 0.5 mg/day in any one week.
Maintenance dosing is not expected to be different between adult and pediatric patients. Dosage
should not exceed 10 mg/day or 2.5 mg in a single dose (see PRECAUTIONS).
There are no special requirements for dosing the geriatric population.
It is recommended that patients with moderate hepatic impairment start anagrelide therapy at a
dose of 0.5 mg/day and be maintained for a minimum of one week with careful monitoring of
cardiovascular effects. The dosage increment must not exceed more than 0.5 mg/day in any one-
week. The potential risks and benefits of anagrelide therapy in a patient with mild or moderate
impairment of hepatic function should be assessed before treatment is commenced. Use of
anagrelide in patients with severe hepatic impairment has not been studied. Use of anagrelide in
patients with severe hepatic impairment is contraindicated (see CONTRAINDICATIONS).
12
Reference ID: 3048374
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For current labeling information, please visit https://www.fda.gov/drugsatfda
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet
counts should be performed every two days during the first week of treatment and at least weekly
thereafter until the maintenance dosage is reached.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to
complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. Most
patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with
known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be
monitored closely.
HOW SUPPLIED
AGRYLIN® is available as:
0.5 mg, opaque, white capsules imprinted “
063” in black ink: NDC 54092-063-01 = bottle
of 100
Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room
Temperature]. Store in a light resistant container.
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA
1-800-828-2088
© 2011 Shire US Inc.
Rev. 11/11
063 0117 020
Printed in USA
13
Reference ID: 3048374
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:29.572608
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020333s019lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 19}
|
12,462
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AGRYLIN safely and effectively. See full prescribing information
for AGRYLIN.
AGRYLIN® (anagrelide hydrochloride) capsules, for oral use
Initial U.S. Approval: 1997
----------------------RECENT MAJOR CHANGES----------------
Dosage and Administration (2)
10/2014
Contraindications (4)
10/2014
Warnings and Precautions (5)
10/2014
---------------------INDICATIONS AND USAGE-----------------------
Anagrelide is a platelet reducing agent indicated for the treatment of
thrombocythemia, secondary to myeloproliferative neoplasms, to
reduce the elevated platelet count and the risk of thrombosis and to
ameliorate associated symptoms including thrombo-hemorrhagic
events. (1)
-------------------DOSAGE AND ADMINISTRATION------------------
• The starting dose for adults is 0.5 mg four times a day or 1 mg twice
a day (2.1)
• The starting dose for pediatric patients is 0.5 mg per day (2.1)
• Maintain the starting dose for at least one week and then titrate to
maintain target platelet counts (2.2)
• Do not exceed a dose increment of 0.5 mg/day in any one week. Do
not exceed 10 mg/day or 2.5 mg in a single dose. (2.2)
• Moderate hepatic impairment: Start with 0.5 mg per day (2.3)
------------------DOSAGE FORMS AND STRENGTHS---------------
Capsules: 0.5mg (3)
--------------------------CONTRAINDICATIONS-------------------------
None (4)
------------------------WARNINGS AND PRECAUTIONS-------------------
• Cardiovascular Toxicity: QT prolongation and ventricular tachycardia have
been reported with anagrelide. Obtain a pre-treatment cardiovascular
examination including an ECG in all patients. Monitor patients for
cardiovascular effects. (5.1)
• Bleeding Risk: Monitor patients for bleeding, including those receiving
concomitant therapy with other drugs known to cause bleeding (5.2)
----------------------------ADVERSE REACTIONS--------------------------
The most common adverse reactions (incidence ≥ 5%) are headache,
palpitations, diarrhea, asthenia, edema, nausea, abdominal pain, dizziness,
pain, dyspnea, cough, flatulence, vomiting, fever, peripheral edema, rash,
chest pain, anorexia, tachycardia, malaise, paresthesia, back pain, pruritus,
dyspepsia (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Shire US
Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or
www.fda.gov./medwatch
------------------------------DRUG INTERACTIONS---------------------------
• Other PDE 3 inhibitors: Exacerbation of inotropic effects (7.2)
• Aspirin and Drugs that Increase Bleeding Risk: Increased risk of bleeding
with concomitant use (7.3)
-------------------------USE IN SPECIFIC POPULATIONS------------------
• Nursing Mothers: Discontinue nursing or discontinue the drug (8.3).
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 07/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Starting Dose
2.2 Titration
2.3 Dose Modifications for Hepatic Impairment
2.4 Clinical Monitoring
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Toxicity
5.2 Bleeding Risk
5.3 Pulmonary Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Drugs that prolong QT
7.2 PDE3 Inhibitors
7.3 Aspirin and Drugs that Increase Bleeding Risk
7.4 CYP450 Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action
12.2Pharmacodynamics
12.3Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment
of Fertility
13.2Animal Toxicology and/or Pharmacology
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: 3791349
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
AGRYLIN Capsules are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative
neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms
including thrombo-hemorrhagic events [see Clinical Studies (14), Dosage and Administration (2)].
2
DOSAGE AND ADMINISTRATION
2.1
Starting Dose
Adults: The recommended starting dosage of AGRYLIN is 0.5 mg four times daily or 1 mg twice daily.
Pediatric Patients: The recommended starting dosage of AGRYLIN is 0.5 mg daily.
2.2
Titration
Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below
600,000/µL, and ideally between 150,000/µL and 400,000/µL. The dose increment should not exceed 0.5 mg/day in any
one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose [see Warnings and Precautions (5)]. Most
patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Monitor platelet counts weekly during
titration then monthly or as necessary.
2.3
Dose Modifications for Hepatic Impairment
In patients with moderate hepatic impairment (Child Pugh score 7-9) start AGRYLIN therapy at a dose of 0.5 mg/day and
monitor frequently for cardiovascular events [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and
Clinical Pharmacology (12.3)]. Patients with moderate hepatic impairment who have tolerated AGRYLIN therapy for one
week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid
use of AGRYLIN in patients with severe hepatic impairment.
2.4
Clinical Monitoring
AGRYLIN therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal
function, and electrolytes.
To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment
and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7
to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count ≤
600,000/µL, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in
platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to
two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.
Reference ID: 3791349
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
DOSAGE FORMS AND STRENGTHS
White, opaque capsule, containing 0.5 mg anagrelide (as anagrelide hydrochloride), imprinted with “
063” in black
ink.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Cardiovascular Toxicity
Torsades de pointes and ventricular tachycardia have been reported with anagrelide. Obtain a pre-treatment cardiovascular
examination including an ECG in all patients. During treatment with AGRYLIN monitor patients for cardiovascular
effects and evaluate as necessary.
Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers [see
Clinical Pharmacology (12.2)].
Do not use AGRYLIN in patients with known risk factors for QT interval prolongation, such as congenital long QT
syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and
hypokalemia [see Drug Interactions (7.1)].
Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with
hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of
anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is
commenced. Reduce AGRYLIN dose in patients with moderate hepatic impairment. Use of AGRYLIN in patients with
severe hepatic impairment has not been studied [see Dosage and Administration (2.3), Use in Specific Populations (8.6)
and Clinical Pharmacology (12.2, 12.3)].
In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with
electrocardiograms [see Clinical Pharmacology (12.2)].
Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and
congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in
patients with Class III-IV congestive heart failure [see Drug Interactions (7.2)].
In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.
5.2
Bleeding Risk
Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a postmarketing study. Assess the
potential risks and benefits for concomitant use of anagrelide with aspirin, since bleeding risks may be increased. Monitor
Reference ID: 3791349
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For current labeling information, please visit https://www.fda.gov/drugsatfda
patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g.,
anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors) [see Drug
Interactions (7.3), Clinical Pharmacology (12.3)].
5.3
Pulmonary Toxicity
Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been
reported to be associated with the use of anagrelide in post-marketing reports. Most cases presented with progressive
dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating anagrelide. If
suspected, discontinue AGRYLIN and evaluate. Symptoms may improve after discontinuation [see Adverse Reactions
(6)].
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
•
Cardiovascular Toxicity [see Warnings and Precautions (5.1)]
•
Bleeding Risk [see Warnings and Precautions (5.2)]
•
Pulmonary Toxicity [see Warnings and Precautions (5.3)]
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 practice.
Clinical Studies in Adult Patients
In three single-arm clinical studies, 942 patients [see Clinical Trials (14)] diagnosed with myeloproliferative neoplasms of
varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65
weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial
infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial
effusion [see Warnings and Precautions (5.1)], pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary
hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study
because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment
discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.
The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative
neoplasms) in clinical trials were listed in Table 1.
Table 1
Adverse Reactions Reported in Clinical Studies in at least 5% of Patients
Reference ID: 3791349
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Adverse reactions
AGRYLIN
(N=942)
(%)
Cardiac disorders
Palpitations
26%
Tachycardia
8%
Chest pain
8%
General disorders and administration site
conditions
Asthenia
23%
Edema
21%
Pain
15%
Fever
9%
Peripheral edema
9%
Malaise
6%
Gastrointestinal disorders
Diarrhea
26%
Nausea
17%
Abdominal pain
16%
Vomiting
10%
Flatulence
10%
Anorexia
8%
Dyspepsia
5%
Reference ID: 3791349
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Respiratory, thoracic and mediastinal disorders
Dyspnea
12%
Cough
6%
Skin and subcutaneous tissue disorders
Rash
8%
Pruritus
6%
Musculoskeletal and connective tissue disorders
Back pain
6%
Nervous system disorders
Headache
44%
Dizziness
15%
Paresthesia
6%
Adverse Reactions (frequency 1% to < 5%) included:
General disorders and administration site conditions: Flu symptoms, chills.
Cardiac disorders: Arrhythmia, angina pectoris, heart failure, syncope.
Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.
Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.
Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.
Hepatobiliary disorders: Elevated liver enzymes.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
Psychiatric disorders: Depression, confusion, nervousness.
Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.
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Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.
Skin and subcutaneous tissue disorders: Alopecia.
Eye disorders: Abnormal vision, diplopia.
Ear and labyrinth disorders: Tinnitus
Renal and urinary disorders: Hematuria, renal failure.
Other less frequent adverse reactions (<1%) were:
Cardiac disorders: Ventricular tachycardia, supraventricular tachycardia.
Nervous system disorders: Hypoesthesia.
Clinical Study in Pediatric Patients
The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse
events observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month anagrelide treatment
in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in
the absence of clinical symptoms were observed. Adverse events that had been reported in these pediatric patients prior to
the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations,
headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-marketing use of AGRYLIN. 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. Cases of torsades de pointes, interstitial lung diseases (including
allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) [see Warnings and Precautions (5)],
tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and
elevations greater than three times the ULN) have been reported.
Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia,
cutaneous photosensitivity and elevated leukocyte count.
Reference ID: 3791349
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7
DRUG INTERACTIONS
7.1
Drugs that Prolong QT
Do not use AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to,
chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide and
pimozide) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
7.2
PDE3 Inhibitors
Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor. The effects of drug products with similar properties such as
inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) should be avoided [see Warnings and Precautions (5.1)
and Clinical Pharmacology (12.2)].
7.3
Aspirin and Drugs that Increase Bleeding Risk
Co-administration of single-dose or repeat-dose anagrelide and aspirin showed greater ex vivo anti-platelet aggregation
effects than administration of aspirin alone [see Clinical Pharmacology (12.3)]. Results from an observational study in
patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with
anagrelide is higher than in those subjects treated with another cytoreductive treatment. The majority of the major
hemorrhagic events occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily,
aspirin). Therefore, the potential risks of the concomitant use of anagrelide with aspirin should be assessed, particularly in
patients with a high risk profile for hemorrhage, before treatment is initiated [see Warnings and Precautions (5.2)].
Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding
(e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).
7.4
CYP450 Interactions
CYP1A2 inhibitors: Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit
CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide. Monitor patients for cardiovascular
events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.
CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2
inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.
CYP1A2 substrates: Anagrelide demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the
exposure of concomitant CYP1A2 substrates (e.g. theophylline, fluvoxamine, ondansetron).
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
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Risk Summary
There are no adequate and well-controlled studies with AGRYLIN in pregnant women. In animal embryo-fetal studies,
delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered
anagrelide hydrochloride during organogenesis at doses substantially higher than the maximum clinical dose of 10
mg/day. AGRYLIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Anagrelide hydrochloride was administered orally to pregnant rats and rabbits during the period of organogenesis at doses
up to 900 mg/kg/day in rats and up to 20 mg/kg/day in rabbits (875 and 39 times, respectively, the maximum clinical dose
of 10 mg/day based on body surface area). In rats, developmental delays were observed including reductions in fetal
weight at 300 and 900 mg/kg/day and delays in skeletal ossification at doses of 100 mg/kg/day and higher. The dose of
100 mg/kg/day (600 mg/m2/day) in rats is approximately 97 times the maximum clinical dose based on body surface area.
No adverse embryo-fetal effects were detected in rabbits at the highest dose of 20 mg/kg/day (39 times the maximal
clinical dose based on body surface area).
In a pre- and post-natal study conducted in female rats, anagrelide hydrochloride at oral doses of 60 mg/kg/day (58 times
the maximum clinical dose based on body surface area) or higher produced delay or blockage of parturition, deaths of
non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born.
In a placental transfer study, a single oral dose of [14C]-anagrelide hydrochloride was administered to pregnant rats on
gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.
8.3
Nursing Mothers
Risk Summary
It is not known whether anagrelide is excreted in human milk. Anagrelide or its metabolites have been detected in the milk
of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse
reaction in nursing infants from anagrelide, 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.
Data
In a rat milk secretion study, a single oral dose of [14C]-anagrelide hydrochloride was administered to lactating female rats
on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.
8.4
Pediatric Use
Experience with AGRYLIN in pediatric patients was based on an open label safety and PK/PD study conducted in 18
pediatric patients aged 7-16 years with thrombocythemia secondary to ET [see Dosage and Administration (2.1), Clinical
Pharmacology (12.3) and Clinical Studies (14)].
Reference ID: 3791349
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There were no apparent trends or differences in the types of adverse events observed between the pediatric patients
compared with those of the adult patients [see Adverse Reactions (6.1)].
8.5
Geriatric Use
Of the 942 subjects in clinical studies of AGRYLIN, 42.1% were 65 years and over, while 14.9% were 75 years 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 response between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
8.6
Hepatic Impairment
Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8-fold in patients with
moderate hepatic impairment [see Clinical Pharmacology (12.3)] and dose reduction is required [see Dosage and
Administration (2.3)]. Use of AGRYLIN in patients with severe hepatic impairment has not been studied. The potential
risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before
treatment is commenced. Assess hepatic function before and during anagrelide treatment [see Warnings and Precautions
(5.1)].
10
OVERDOSAGE
At higher than recommended doses, this medicine has been shown to cause hypotension. There have been postmarketing
case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and
vomiting. Symptoms resolved with supportive management. Platelet reduction from anagrelide therapy is dose-related;
therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.
In case of overdosage, close clinical supervision of the patient is required; this especially includes monitoring of the
platelet count for thrombocytopenia. Dosage should be stopped, as appropriate, until the platelet count returns to within
the normal range.
11
DESCRIPTION
AGRYLIN (anagrelide hydrochloride) is a platelet-reducing agent. Its chemical name is 6,7-dichloro-1,5
dihydroimidazo[2,1-b]quinazolin-2(3H)-one
monohydrochloride
monohydrate.
The
molecular
formula
is
C10H7Cl2N3O•HCl•H2O which corresponds to a molecular weight of 310.55. The structural formula is: structural formula
Reference ID: 3791349
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Anagrelide hydrochloride is an off-white powder. It is very slightly soluble in water and sparingly soluble in dimethyl
sulfoxide and dimethylformamide.
AGRYLIN is supplied as capsules for oral administration, containing 0.5 mg of anagrelide base (as anagrelide
hydrochloride). The capsules also contain anhydrous lactose NF, crospovidone NF, lactose monohydrate NF, magnesium
stearate NF, microcrystalline cellulose NF, and povidone NF as inactive ingredients. The capsule shell contains gelatin,
titanium dioxide and black iron oxide.
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide
suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis,
ultimately leading to reduced platelet production.
12.2
Pharmacodynamics
In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of
megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not
produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically
insignificant effect on red cell parameters. The active metabolite, 3-hydroxy anagrelide, has similar potency and efficacy
to that of anagrelide in the platelet lowering effect; however, exposure (measured by plasma AUC) to 3-hydroxy
anagrelide is approximately 2-fold higher compared to anagrelide. Anagrelide and 3-hydroxy anagrelide inhibit cyclic
AMP phosphodiesterase 3 (PDE3) and 3-hydroxy anagrelide is approximately forty times more potent than anagrelide
(IC50s = 0.9 and 36nM, respectively). PDE3 inhibition does not alter platelet production. PDE3 inhibitors, as a class can
inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of
anagrelide higher than those typically required to reduce platelet count. PDE3 inhibitors have cardiovascular (CV) effects
including vasodilation, positive inotropy and chronotropy.
Cardiac Electrophysiology
The effect of anagrelide dose (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval prolongation potential
was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in 60 healthy adult men and
women.
A dose-related increase in heart rate was observed, with the maximum increase occurring around the time of maximal
drug concentration (0.5 – 4 hours). The maximum change in mean heart rate occurred at 2 hours after administration and
was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.
Dose-related increase in mean QTc was observed. The maximum mean (95% upper confidence bound) change in QTcI
(individual subject correction) from placebo after baseline-correction was 7.0 (9.8) ms and 13.0 (15.7) ms following
anagrelide doses of 0.5 mg and 2.5 mg, respectively.
Reference ID: 3791349
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12.3
Pharmacokinetics
Dose proportionality has been found in the dose range 0.5 mg to 2.5 mg.
Absorption
Following oral administration of AGRYLIN, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects,
anagrelide peak plasma concentrations occur within about 1 hour after administration.
Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and
fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased
the AUC by 20%. Food decreased the Cmax of the active metabolite 3-hydroxy-anagrelide by 29%, although it had no
effect on the AUC.
Metabolism
Anagrelide is primarily metabolized by CYP1A2 to the active metabolite, 3-hydroxy-anagrelide, which is subsequently
metabolized by CYP1A2 to the inactive metabolite, RL603. Less than 1% of the administered dose is recovered in the
urine as anagrelide, and approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy-anagrelide and
RL603, respectively.
Elimination
Anagrelide and 3-hydroxy-anagrelide are eliminated with plasma half-lives of approximately 1.5 and 2.5 hours,
respectively. Anagrelide and 3-hydroxy-anagrelide do not accumulate in plasma when the clinical dose regimens are
administered.
Drug Interactions
Aspirin: In two pharmacodynamic interaction studies in healthy subjects, co-administration of single-dose anagrelide 1 mg
and aspirin 900 mg or repeat-dose anagrelide 1 mg once daily and aspirin 75 mg once daily showed greater ex vivo anti-
platelet aggregation effects than administration of aspirin alone. Co-administered anagrelide 1mg and aspirin 900mg
single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).
Digoxin or warfarin: In vivo interaction studies in humans have demonstrated that anagrelide does not affect the
pharmacokinetic properties of digoxin or warfarin, nor does digoxin or warfarin affect the pharmacokinetic properties of
anagrelide.
Specific Populations
Pediatric: Dose-normalized Cmax and AUC of anagrelide were higher in children and adolescents (age range 7-16 years)
with essential thrombocythemia, by 17% and 56%, respectively, than in adult patients (19-57 years).
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Geriatric: Cmax and AUC of anagrelide were 36% and 61% higher, respectively, in elderly patients (age range 65-75
years), than in younger adults (age range 22-50 years), but Cmax and AUC of the active metabolite, 3-hydroxy anagrelide,
were 42% and 37% lower, respectively, in the elderly patients.
Renal Impairment: Pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment
(creatinine clearance <30 mL/min) showed no significant effects on the pharmacokinetics of anagrelide.
Hepatic Impairment: A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic
impairment (Child Pugh score 7-9) showed a 2-fold increase in mean anagrelide Cmax and an 8-fold increase in total
exposure (AUC) to anagrelide compared with healthy subjects. Additionally, subjects with moderate hepatic impairment
showed 24% lower mean 3-hydroxy-anagrelide Cmax and 77% higher mean 3-hydroxy-anagrelide AUC compared to
healthy subjects.
13.
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in
females receiving 30 mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal
phaeochromocytomas were increased relative to controls in males receiving 3 mg/kg/day and above, and in females
receiving 10 mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1 mg twice daily
dose).
Anagrelide hydrochloride was not mutagenic in the bacterial mutagenesis (Ames) assay or the mouse lymphoma cell
(L5178Y, TK+/-) forward mutation assay, and was not clastogenic in the in vitro chromosome aberration assay using
human lymphocytes or the in vivo mouse micronucleus test.
Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (233 times the recommended human dose of 10 mg/day
based on body surface area) had no effect on fertility and reproductive function of male rats. However, in fertility studies
in female rats, oral doses of 30 mg/kg/day (29 times the recommended maximum human dose based on body surface area)
or higher resulted in increased pre- and post-implantation loss and a decrease in the number of live embryos.
13.2
Animal Toxicology and/or Pharmacology
In the 2-year rat study, a significant increase in non-neoplastic lesions was observed in anagrelide treated males and
females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and chamber distension), kidney
(hydronephrosis, tubular dilation and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed
in tissues of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney
(arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular mineralization), and testes
(tubular atrophy and vascular infarct) in anagrelide treated males.
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14
CLINICAL STUDIES
Clinical Studies in Adult Patients:
A total of 942 patients with myeloproliferative neoplasms including 551 patients with Essential Thrombocythemia (ET),
117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous Leukemia (CML), and 96 patients
with other myeloproliferative neoplasms (OMPN), were treated with AGRYLIN in three clinical trials. Patients with
OMPN included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had
unclassified myeloproliferative neoplasms.
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions or ≥ 650,000/µL on two
occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy
for ET, PV, CML, and OMPN patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for
2 years. Patients were treated with AGRYLIN starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the
platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or
near physiologic levels (150,000-400,000/µL). The criteria for defining subjects as “responders” were reduction in
platelets for at least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less than 4
weeks were not considered evaluable. The results are depicted graphically below: graph
Reference ID: 3791349
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Time on Treatment
Weeks
Years
Baseline
4
12
24
48
2
3
4
Mean*
1131
683
575
526
484
460
437
457
N
923†
868
814
662
530
407
207
55
*x 103/µL
†Nine hundred and forty-two subjects with myeloproliferative neoplasms were enrolled in three research studies. Of these,
923 had platelet counts measured over the duration of the studies.
AGRYLIN was effective in phlebotomized patients as well as in patients treated with other concomitant therapies
including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.
Clinical Study in Pediatric Patients:
An open label safety and PK/PD study was conducted in 18 pediatric patients 7-16 years of age (8 patients 7-11 years of
age and 10 patients 12-16 years of age, mean age of 12 years; 8 males and 10 females) with thrombocythemia secondary
to ET as compared to 17 adult patients (mean age of 66 years, 9 males and 8 females). Prior to entry on to the study, 17 of
18 pediatric patients and 12 of 17 adult patients had received anagrelide treatment for an average of 2 years. The median
starting total daily dose, determined by retrospective chart review, for pediatric and adult patients with ET who had
received anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 12-16 year old patients and
adults). The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once daily. At study completion, the
median total daily maintenance doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age,
2.25 mg in patients 12-16 years of age, and 1.5 mg for adults.
16
HOW SUPPLIED/STORAGE AND HANDLING
AGRYLIN is available as:
0.5 mg, opaque, white capsules imprinted “
063” in black ink: NDC 54092-063-01 = bottle of 100
Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room Temperature]. Store in a
light resistant container.
17
PATIENT COUNSELING INFORMATION
• Dose: Tell the patient that their dose will be adjusted on a weekly basis until they are on a dose that lowers their
platelets to an appropriate level. This will also help the patient to adjust to common side effects. Tell the patient to
contact their doctor if they experience tolerability issues, so the dose or dosing frequency can be adjusted
[see Dosage and Administration (2)].
Reference ID: 3791349
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•
Cardiovascular effects: Tell the patient to contact a doctor immediately if they experience chest pain,
palpitations, or feel their heartbeat is irregular [see Warnings and Precautions (5.1)].
• Risk of bleeding: Warn the patient that concomitant aspirin (or other medicines that affect blood clotting) may
increase the risk of bleeding. Tell the patient to contact a doctor immediately if they experience signs or
symptoms of bleeding (e.g. vomit blood, pass bloody or black stools) or experience unexplained bruising/bruise
more easily than usual [see Warnings and Precautions (5.2), Drug Interactions (7.1)].
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA
1-800-828-2088
© 2015 Shire US Inc.
063 0117 020
Printed in USA
Reference ID: 3791349
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|
custom-source
|
2025-02-12T13:47:29.753391
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020333s023lbl.pdf', 'application_number': 20333, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
12,463
|
Flagyl® 375
metronidazole capsules
DESCRIPTION
Metronidazole is an oral synthetic antiproto-
zoal and antibacterial agent, 2-Methyl-5-nitro-
imidazole-1-ethanol, which has the following
structural formula:
Flagyl® 375 capsules contain 375 mg of
metronidazole USP. Inactive ingredients
include corn starch, magnesium stearate,
gelatin, black iron oxide, titanium dioxide,
FD&C Green No. 3, and D&C Yellow No. 10.
CLINICAL PHARMACOLOGY
Disposition of metronidazole in the body is
similar for both oral and intravenous dosage
forms, with an average elimination half-life in
healthy humans of 8 hours.
The major route of elimination of metroni-
dazole and its metabolites is via the urine
(60% to 80% of the dose), with fecal excretion
accounting for 6% to 15% of the dose. The
metabolites that appear in the urine result pri-
marily from side-chain oxidation [1-(ß-hy-
droxyethyl)-2-hydroxymethyl-5-nitroimida-
zole and 2-methyl-5-nitroimidazole-1-yl-acetic
acid] and glucuronide conjugation, with
unchanged metronidazole accounting for
approximately 20% of the total. Renal clear-
ance of metronidazole is approximately
10 mL/min/1.73m2.
Metronidazole is the major component
appearing in the plasma, with lesser quanti-
ties of the 2-hydroxymethyl metabolite also
being present. Less than 20% of the circulat-
ing metronidazole is bound to plasma pro-
teins. Both the parent compound and the
metabolite possess in vitro bactericidal
activity against most strains of anaerobic bac-
teria and in vitro trichomonacidal activity.
Metronidazole appears in cerebrospinal
fluid, saliva, and human milk in concentra-
tions similar to those found in plasma.
Bactericidal concentrations of metronidazole
have also been detected in pus from hepatic
abscesses.
Flagyl® 375 capsules have been shown to
have a rate and extent of absorption similar
to metronidazole tablets (Flagyl®) and were
bioequivalent at an equal single dose of 750
mg. In a study conducted with 23 adult,
healthy, female volunteers, oral administra-
tion of two 375-mg Flagyl® capsules under
fasted conditions produced a mean (± 1 SD)
peak plasma concentration (Cmax) of 21.4
(± 2.8) mcg/mL with a mean Tmax of 1.6 (± 0.7)
hours and a mean area under the plasma con-
centration-time curve (AUC) of 223 (± 44)
mcg·hr/mL. In the same study, three 250-mg
Flagyl® tablets produced a mean Cmax of 20.4
CH3
O 2N
CH 2CH2OH
N
N
P04012-1
818 952 001
Flagyl® 375
metronidazole
capsules
P04012-1
818 952 001
Flagyl® 375
metronidazole
capsules
WARNING
Metronidazole has been shown to be
carcinogenic in mice and rats. (See PRE-
CAUTIONS.) Unnecessary use of the
drug should be avoided. Its use should
be reserved for the conditions described
in the INDICATIONS AND USAGE sec-
tion below.
To reduce the development of drug-resistant
bacteria and maintain the effectiveness of
Flagyl® 375 and other antibacterial drugs,
Flagyl® 375 should be used only to treat or
prevent infections that are proven or strongly
suspected to be caused by bacteria.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Layout and/or size adjusted for
ease of reading and printing.
Flagyl 375
metronidazole capsules
(± 3.8) mcg/mL with a mean Tmax of 1.4
(± 0.4) hours and a mean AUC of 218 (± 50)
mcg·hr/mL.
Administration of Flagyl® 375 capsules with
food does not affect the extent of absorption
of metronidazole; however, the presence of
food results in a lower Cmax and a delayed
Tmax compared to fasted conditions. In a
study of 14 healthy, adult, female volunteers,
administration of Flagyl® 375 capsules under
fasting conditions produced a mean Cmax of
10.9 (± 1.5) mcg/mL, a mean Tmax of 1.5 (± 1.4)
hours, and a mean AUC of 110 (± 34) mcg·
hr/mL compared to a mean Cmax of 8.6 (± 1.6)
mcg/mL, a mean Tmax of 4.2 (± 1.7) hours, and
a mean AUC of 99 (± 14) mcg·hr/mL under fed
conditions.
Decreased renal function does not alter the
single-dose pharmacokinetics of metronida-
zole. However, plasma clearance of metro-
nidazole is decreased in patients with
decreased liver function.
Microbiology:
Metronidazole exerts antimicrobial effects in
an anaerobic environment by the following
possible mechanism: Once metronidazole
enters the organism, the drug is reduced by
intracellular electron transport proteins.
Because of this alteration to the metronida-
zole molecule, a concentration gradient is
maintained which promotes the drug’s intra-
cellular transport. Presumably, free radicals
are formed which, in turn, react with cellular
components resulting in death of the micro-
organism.
Metronidazole has been shown to be active
against most strains of the following micro-
organisms both in vitro and in clinical infec-
tions as described in the INDICATIONS AND
USAGE section.
Gram-positive anaerobes:
Clostridium species
Eubacterium species
Peptococcus niger
Peptostreptococcus species
Gram-negative anaerobes:
Bacteroides fragilis group (B. fragilis, B. dis-
tasonis, B. ovatus, B. thetaiotaomicron,
B. vulgatus)
Fusobacterium species
Protozoal parasites:
Entamoeba histolytica
Trichomonas vaginalis
The following in vitro data are available, but
their clinical significance is unknown:
Metronidazole exhibits in vitro minimal
inhibitory concentrations (MIC’s) of 8 µg/mL
or less against most (˘ 90%) strains of the fol-
lowing microorganisms; however, the safety
and effectiveness of metronidazole in treating
clinical infections due to these microorgan-
isms have not been established in adequate
and well-controlled clinical trials.
Gram-negative anaerobes:
Bacteroides fragilis group (B. caccae, B. uni-
formis)
Prevotella species (P. bivia, P. buccae,
P. disiens)
Metronidazole is active against most obli-
gate anaerobes, but does not possess any
clinically relevant activity against facultative
anaerobes or obligate aerobes.
Susceptibility Tests:
Dilution techniques:
Quantitative methods that are used to deter-
mine minimum inhibitory concentrations pro-
vide reproducible estimates of the suscepti-
bility of bacteria to antimicrobial compounds.
For anaerobic bacteria, the susceptibility to
metronidazole can be determined by the ref-
erence agar dilution method or by alternate
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flagyl 375
metronidazole capsules
standardized test methods1. The MIC values
obtained should be interpreted according to
the following criteria:
MIC (µg/mL)
Interpretation
¯ 8
Susceptible (S)
16
Intermediate (I)
˘ 32
Resistant (R)
For protozoal parasites: Standardized tests do
not exist for use in clinical microbiology
laboratories.
A report of “Susceptible” indicates that the
pathogen is likely to be inhibited by usually
achievable concentrations of the antimicro-
bial compound in the blood. A report of
“Intermediate” indicates that the result
should be considered equivocal, and, if the
microorganism is not fully susceptible to
alternative, clinically feasible drugs, the test
should be repeated. This category implies
possible clinical applicability in body sites
where the drug is physiologically concen-
trated or in situations where high dosage of
drug can be used. This category also provides
a buffer zone which prevents small uncon-
trolled technical factors from causing major
discrepancies in interpretation. A report of
“Resistant” indicates that usually achievable
concentrations of the antimicrobial com-
pound in the blood are unlikely to be inhibi-
tory and other therapy should be selected.
Standardized susceptibility test procedures
require the use of laboratory control micro-
organisms that are used to control the tech-
nical aspects of the laboratory procedures.
Standard metronidazole powder should pro-
vide the following MIC values:
Microorganism
MIC (µg/mL)
Bacteroides fragilis
0.25–1.0
ATCC 25285
Bacteroides thetaiotaomicron
0.5–2.0
ATCC 29741
INDICATIONS AND USAGE
Symptomatic Trichomoniasis. Flagyl® 375
capsules are indicated for the treatment of
symptomatic trichomoniasis in females and
males when the presence of the trichomonad
has been confirmed by appropriate labora-
tory procedures (wet smears and/or cultures).
Asymptomatic Trichomoniasis. Flagyl® 375
capsules are indicated in the treatment of
asymptomatic females when the organism is
associated with endocervicitis, cervicitis, or
cervical erosion. Since there is evidence that
presence of the trichomonad can interfere
with accurate assessment of abnormal cyto-
logical smears, additional smears should be
performed after eradication of the parasite.
Treatment of Asymptomatic Consorts. T. vagi-
nalis infection is a venereal disease. There-
fore, asymptomatic sexual partners of treated
patients should be treated simultaneously if
the organism has been found to be present,
in order to prevent reinfection of the partner.
The decision as to whether to treat an asymp-
tomatic male partner who has a negative cul-
ture or one for whom no culture has been
attempted is an individual one. In making this
decision, it should be noted that there is evi-
dence that a woman may become reinfected
if her consort is not treated. Also, since there
can be considerable difficulty in isolating the
organism from the asymptomatic male car-
rier, negative smears and cultures cannot be
relied upon in this regard. In any event, the
consort should be treated with metronidazole
in cases of reinfection.
Amebiasis. Flagyl® 375 capsules are indicated
in the treatment of acute intestinal amebiasis
(amebic dysentery) and amebic liver abscess.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flagyl 375
metronidazole capsules
In amebic liver abscess, metronidazole
therapy does not obviate the need for aspi-
ration or drainage of pus.
Anaerobic Bacterial Infections. Flagyl® 375
capsules are indicated in the treatment of
serious infections caused by susceptible
anaerobic bacteria. Indicated surgical proce-
dures should be performed in conjunction
with metronidazole therapy. In a mixed aero-
bic and anaerobic infection, antimicrobials
appropriate for the treatment of the aerobic
infection should be used in addition to
Flagyl® 375 capsules.
In the treatment of most serious anaerobic
infections, intravenous metronidazole is
usually administered initially. This may be fol-
lowed by oral therapy with Flagyl® 375 cap-
sules at the discretion of the physician.
INTRA-ABDOMINAL INFECTIONS, including
peritonitis, intra-abdominal abscess, and liver
abscess, caused by Bacteroides species
including the B. fragilis group (B. fragilis,
B. distasonis, B. ovatus, B. thetaiotaomicron,
B. vulgatus), Clostridium species, Eubacte-
rium species, Peptococcus niger, or Pepto-
streptococcus species.
SKIN AND SKIN STRUCTURE INFECTIONS
caused by Bacteroides species including the
B. fragilis group, Clostridium species, Pepto-
coccus niger, Peptostreptococcus species, or
Fusobacterium species.
GYNECOLOGIC INFECTIONS, including endo-
metritis, endomyometritis, tubo-ovarian
abscess, and postsurgical vaginal cuff infec-
tion, caused by Bacteroides species including
the B. fragilis group, Clostridium species,
Peptococcus niger, or Peptostreptococcus
species.
BACTERIAL SEPTICEMIA caused by Bacte-
roides species including the B. fragilis group
or Clostridium species.
BONE AND JOINT INFECTIONS (as adjunctive
therapy) caused by Bacteroides species
including the B. fragilis group.
CENTRAL NERVOUS SYSTEM (CNS) INFEC-
TIONS, including meningitis and brain
abscess, caused by Bacteroides species
including the B. fragilis group.
LOWER RESPIRATORY TRACT INFECTIONS,
including pneumonia, empyema, and lung
abscess, caused by Bacteroides species
including the B. fragilis group.
ENDOCARDITIS caused by Bacteroides
species including the B. fragilis group.
To reduce the development of drug-resistant
bacteria and maintain the effectiveness of
Flagyl® 375 and other antibacterial drugs,
Flagyl® 375 should be used only to treat or
prevent infections that are proven or strongly
suspected to be caused by susceptible bac-
teria. When culture and susceptibility infor-
mation are available, they should be consid-
ered in selecting or modifying antibacterial
therapy. In the absence of such data, local
epidemiology and susceptibility patterns may
contribute to the empiric selection of therapy.
CONTRAINDICATIONS
Flagyl® 375 capsules are contraindicated in
patients with a prior history of hypersensi-
tivity to metronidazole or other nitroimidazole
derivatives.
In patients with trichomoniasis, Flagyl® 375
capsules are contraindicated during the first
trimester of pregnancy. (See PRECAUTIONS.)
WARNINGS
Convulsive seizures and peripheral neuropa-
thy: Convulsive seizures and peripheral neu-
ropathy, the latter characterized mainly by
numbness or paresthesia of an extremity,
have been reported in patients treated with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flagyl 375
metronidazole capsules
metronidazole. The appearance of abnormal
neurologic signs demands the prompt dis-
continuation of metronidazole therapy.
Metronidazole should be administered with
caution to patients with central nervous
system diseases.
PRECAUTIONS
General: Patients with severe hepatic disease
metabolize metronidazole slowly, with resul-
tant accumulation of metronidazole and its
metabolites in the plasma. Accordingly, for
such patients, doses below those usually rec-
ommended should be administered cau-
tiously. Known or previously unrecognized
candidiasis may present more prominent
symptoms during therapy with metronidazole
and requires treatment with a candidacidal
agent.
Prescribing Flagyl® 375 in the absence of
a proven or strongly suspected bacterial
infection or a prophylactic indication is
unlikely to provide benefit to the patient and
increases the risk of the development of drug-
resistant bacteria.
Information for patients: Alcoholic beverages
should be avoided while taking Flagyl® 375
capsules and for at least three days afterward.
(See Drug interactions.)
Patients should be counseled that antibac-
terial drugs including Flagyl® 375 should only
be used to treat bacterial infections. They do
not treat viral infections (e.g., the common
cold). When Flagyl® 375 is prescribed to
treat a bacterial infection, patients should be
told that although it is common to feel better
early in the course of therapy, the medica-
tion should be taken exactly as directed.
Skipping doses or not completing the full
course of therapy may (1) decrease the effec-
tiveness of the immediate treatment and (2)
increase the likelihood that bacteria will
develop resistance and will not be treatable
by Flagyl® 375 or other antibacterial drugs in
the future.
Laboratory tests: Metronidazole is a nitroim-
idazole and should be used with caution in
patients with evidence of or history of blood
dyscrasia. A mild leukopenia has been
observed during its administration; however,
no persistent hematologic abnormalities
attributable to metronidazole have been
observed in clinical studies. Total and differ-
ential leukocyte counts are recommended
before and after therapy for trichomoniasis
and amebiasis, especially if a second course
of therapy is necessary, and before and after
therapy for anaerobic infections.
Drug interactions: Metronidazole has been
reported to potentiate the anticoagulant effect
of warfarin and other oral coumarin antico-
agulants, resulting in a prolongation of pro-
thrombin time. This possible drug interaction
should be considered when metronidazole is
prescribed for patients on this type of anti-
coagulant therapy.
The simultaneous administration of drugs
that induce microsomal liver enzymes, such
as phenytoin or phenobarbital, may acceler-
ate the elimination of metronidazole, result-
ing in reduced plasma levels; impaired clear-
ance of phenytoin has also been reported.
The simultaneous administration of drugs
that decrease microsomal liver enzyme
activity, such as cimetidine, may prolong the
half-life and decrease plasma clearance of
metronidazole. In patients stabilized on rela-
tively high doses of lithium, short-term
metronidazole therapy has been associated
with elevation of serum lithium and, in a few
cases, signs of lithium toxicity. Serum lithium
and serum creatinine levels should be
obtained several days after beginning metro-
nidazole to detect any increase that may
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flagyl 375
metronidazole capsules
precede clinical symptoms of lithium
intoxication.
Alcoholic beverages should not be con-
sumed during metronidazole therapy and for
at least three days afterward because abdom-
inal cramps, nausea, vomiting, headaches,
and flushing may occur.
Psychotic reactions have been reported in
alcoholic patients who are using metronida-
zole and disulfiram concurrently. Metronida-
zole should not be given to patients who
have taken disulfiram within the last 2 weeks.
Drug/Laboratory test interactions: Metroni-
dazole may interfere with certain types of
determinations of serum chemistry values,
such as aspartate aminotransferase (AST,
SGOT), alanine aminotransferase (ALT,
SGPT), lactate dehydrogenase (LDH), triglyc-
erides, and hexokinase glucose. Values of
zero may be observed. All of the assays in
which interference has been reported involve
enzymatic coupling of the assay to oxida-
tion-reduction of nicotinamide adenine dinu-
cleotide (NADÚ § NADH). Interference is due
to the similarity in absorbance peaks of NADH
(340 nm) and metronidazole (322 nm) at pH 7.
Carcinogenesis, mutagenesis, impairment of
fertility: Metronidazole has shown evidence
of carcinogenic activity in a number of stud-
ies involving chronic, oral administration in
mice and rats, but similar studies in the
hamster gave negative results.
Prominent among the effects in the mouse
was the promotion of pulmonary tumorigen-
esis. This has been observed in all six
reported studies in that species, including one
study in which the animals were dosed on an
intermittent schedule (administration during
every fourth week only). At very high dose
levels (approximately 1500 mg/m2 which is
approximately 3 times the most frequently
recommended human dose for a 50 kg adult
based on mg/m2) there was a statistically
significant increase in the incidence of malig-
nant liver tumors in males. Also, the pub-
lished results of one of the mouse studies
indicate an increase in the incidence of malig-
nant lymphomas as well as pulmonary neo-
plasms associated with lifetime feeding of the
drug. All these effects are statistically
significant.
Several long-term, oral-dosing studies in
the rat have been completed. There were sta-
tistically significant increases in the incidence
of various neoplasms, particularly in mam-
mary and hepatic tumors, among female rats
administered metronidazole over those noted
in the concurrent female control groups.
Two lifetime tumorigenicity studies in ham-
sters have been performed and reported to be
negative.
Metronidazole has shown mutagenic
activity in a number of in vitro assay systems.
In vivo studies have failed to demonstrate a
potential for genetic damage.
Fertility studies have been performed in
mice at doses up to six times the maximum
recommended human dose based on mg/m2
and have revealed no evidence of impaired
fertility.
Pregnancy:
Teratogenic effects: Pregnancy Category B.
Metronidazole crosses the placental barrier
and enters the fetal circulation rapidly. Repro-
duction studies have been performed in rats
at doses up to five times the human dose and
have revealed no evidence of impaired fertil-
ity or harm to the fetus due to metronidazole.
No fetotoxicity was observed when metroni-
dazole was administered orally to pregnant
mice at 60 mg/m2/day, which is approxi-
mately 10% of the human dose when
expressed as mg/m2. However, in a single
small study where the drug was administered
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flagyl 375
metronidazole capsules
intraperitoneally, some intrauterine deaths
were observed. The relationship of these find-
ings to the drug is unknown. There are, how-
ever, no adequate and well-controlled studies
in pregnant women. Because animal repro-
duction studies are not always predictive of
human response, and because metronida-
zole is a carcinogen in rodents, this drug
should be used during pregnancy only if
clearly needed. (See CONTRAINDICATIONS.)
Metronidazole use in the second and third
trimesters of pregnancy should be restricted
to those patients in whom alternative treat-
ment has been inadequate. Use of metroni-
dazole in the first trimester should be care-
fully evaluated because metronidazole
crosses the placental barrier and its effects on
human fetal organogenesis are not known.
(See above.)
Nursing mothers: Because of the potential for
tumorigenicity shown for metronidazole in
mouse and rat studies, a decision should be
made whether to discontinue nursing or to
discontinue the drug, taking into account the
importance of the drug to the mother. Metro-
nidazole is secreted in human milk in con-
centrations similar to those found in plasma.
Geriatric use: Decreased renal function does
not alter the single-dose pharmacokinetics of
metronidazole. However, plasma clearance
of metronidazole is decreased in patients
with decreased liver function. Therefore, in
elderly patients, monitoring of serum levels
may be necessary to adjust the metronidazole
dosage accordingly.
Pediatric use: Safety and effectiveness in
pediatric patients have not been established,
except in the treatment of amebiasis.
ADVERSE REACTIONS
The following reactions have also been
reported during treatment with metronida-
zole:
Central Nervous System: Two serious adverse
reactions reported in patients treated with
metronidazole have been convulsive seizures
and peripheral neuropathy, the latter charac-
terized mainly by numbness or paresthesia of
an extremity. Since persistent peripheral neu-
ropathy has been reported in some patients
receiving prolonged administration of metro-
nidazole, patients should be specifically
warned about these reactions and should be
told to stop the drug and report immediately
to their physicians if any neurologic symp-
toms occur. In addition, patients have
reported dizziness, vertigo, incoordination,
ataxia, confusion, irritability, depression,
weakness, and insomnia. (See WARNINGS.)
Gastrointestinal: The most common adverse
reactions reported have been referable to the
gastrointestinal tract, particularly nausea
reported by about 12% of patients, some-
times accompanied by headache, anorexia,
and occasionally vomiting; diarrhea; epigas-
tric distress; and abdominal cramping. Con-
stipation has also been reported.
A sharp, unpleasant metallic taste is not
unusual. Furry tongue, glossitis, and stoma-
titis have occurred; these may be associated
with a sudden overgrowth of Candida which
may occur during therapy. Rare cases of pan-
creatitis, which generally abated on with-
drawal of the drug, have been reported.
Hematopoietic: Reversible neutropenia (leu-
kopenia); rarely, reversible thrombocyto-
penia.
Cardiovascular: Flattening of the T-wave may
be seen in electrocardiographic tracings.
Hypersensitivity: Urticaria, erythematous
rash, flushing, nasal congestion, dryness of
the mouth (or vagina or vulva), and fever.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flagyl 375
metronidazole capsules
Renal: Dysuria, cystitis, polyuria, inconti-
nence, and a sense of pelvic pressure.
Instances of darkened urine have been
reported by approximately one patient in
100,000. Although the pigment which is prob-
ably responsible for this phenomenon has not
been positively identified, it is almost cer-
tainly a metabolite of metronidazole and
seems to have no clinical significance.
Other: Proliferation of Candida in the vagina,
dyspareunia, decrease of libido, proctitis, and
fleeting joint pains sometimes resembling
“serum sickness.” If patients receiving metro-
nidazole drink alcoholic beverages, they may
experience abdominal distress, nausea, vom-
iting, flushing, or headache. A modification of
the taste of alcoholic beverages has also
been reported.
Patients with Crohn’s disease are known to
have an increased incidence of gastrointesti-
nal and certain extraintestinal cancers. There
have been some reports in the medical liter-
ature of breast and colon cancer in Crohn’s
disease patients who have been treated with
metronidazole at high doses for extended
periods of time. A cause and effect relation-
ship has not been established. Crohn’s dis-
ease is not an approved indication for Flagyl®
375 capsules.
OVERDOSAGE
Single oral doses of metronidazole, up to
15 g, have been reported in suicide attempts
and accidental overdoses. Symptoms re-
ported include nausea, vomiting, and ataxia.
Oral metronidazole has been studied as a
radiation sensitizer in the treatment of malig-
nant tumors. Neurotoxic effects, including
seizures and peripheral neuropathy, have
been reported after 5 to 7 days of doses of 6
to 10.4 g every other day.
Treatment: There is no specific antidote for
metronidazole overdose; therefore, manage-
ment of the patient should consist of symp-
tomatic and supportive therapy.
DOSAGE AND ADMINISTRATION
In elderly patients, the pharmacokinetics
of metronidazole may be altered, and, there-
fore, monitoring of serum levels may be nec-
essary to adjust the metronidazole dosage
accordingly.
Trichomoniasis:
In the Female:
Seven-day course of treatment—375 mg two
times daily for seven consecutive days.
A seven-day course of treatment may min-
imize reinfection by protecting the patient
long enough for the sexual contacts to obtain
treatment. Pregnant patients should not be
treated during the first trimester. (See CON-
TRAINDICATIONS and PRECAUTIONS.)
When repeat courses of the drug are
required, it is recommended that an interval
of four to six weeks elapse between courses
and that the presence of the trichomonad be
reconfirmed by appropriate laboratory meas-
ures. Total and differential leukocyte counts
should be made before and after re-treat-
ments.
In the Male: Treatment should be individual-
ized as for the female.
Amebiasis:
Adults:
For acute intestinal amebiasis (acute amebic
dysentery): 750 mg orally three times daily
for 5 to 10 days.
For amebic liver abscess: 750 mg orally three
times daily for 5 to 10 days.
Pediatric patients: 35 to 50 mg/kg/24 hours,
divided into three doses, orally for 10 days.
Anaerobic Bacterial Infections: In the treat-
ment of most serious anaerobic infections,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Flagyl 375
metronidazole capsules
intravenous metronidazole is usually admin-
istered initially.
The usual adult oral dosage is 7.5 mg/kg
every 6 hours. A maximum of 4 g should not
be exceeded during a 24-hour period.
The usual duration of therapy is 7 to 10
days; however, infections of the bone and
joint, lower respiratory tract, and endocar-
dium may require longer treatment.
Patients with severe hepatic disease metab-
olize metronidazole slowly, with resultant
accumulation of metronidazole and its metab-
olites in the plasma. Accordingly, for such
patients, doses below those usually recom-
mended should be administered cautiously.
Close monitoring of plasma metronidazole
levels2 and toxicity is recommended.
The dose of metronidazole should not be
specifically reduced in anuric patients
because accumulated metabolites may be
rapidly removed by dialysis.
HOW SUPPLIED
Flagyl® 375 capsules have an iron gray
opaque body imprinted with 375 mg and a
light green opaque cap imprinted with
FLAGYL, supplied as:
NDC Number
Size
0025-1942-50
Bottle of 50
0025-1942-34
Carton of 100 unit dose
Storage and Stability: Store at controlled
room temperature 15–25°C (59–77°F). Dis-
pense in a well-closed container with a child-
resistant closure.
REFERENCES
1. National Committee for Clinical Laboratory
Standards, Methods for Antimicrobial Sus-
ceptibility Testing of Anaerobic Bacteria –
Third Edition. Approved Standard NCCLS
Document M11-A3, Vol. 13, No. 26, NCCLS,
Villanova, PA, December, 1993.
2. Ralph ED, Kirby WMM. Bioassay of metro-
nidazole with either anaerobic or aerobic
incubation, J. Infect. Dis. 1975; 132 (Nov):
587-591 or Gulaid et al. Determination of
metronidazole and its major metabolites in
biological fluids by high pressure liquid chro-
matography, Br. J. Clin. Pharmacol. 1978;
6:430-432.
%only
Revised: August 2003
G.D. Searle LLC
A subsidiary of Pharmacia Corporation
Chicago, IL 60680, USA
Flagyl® 375
metronidazole capsules
818 952 001
P04012-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:29.826715
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20334slr003_flagyl_lbl.pdf', 'application_number': 20334, 'submission_type': 'SUPPL ', 'submission_number': 3}
|
12,464
|
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
|
2025-02-12T13:47:29.849720
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020337s005lbl.pdf', 'application_number': 20337, 'submission_type': 'SUPPL ', 'submission_number': 5}
|
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Empirical formula
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 1
1
CSL Behring
2
®
3
Stimate
4
(desmopressin acetate)
5
Nasal Spray, 1.5 mg/mL
6
7
Rx only
8
9
DESCRIPTION
10
Stimate® (desmopressin acetate) is a synthetic analogue of the natural pituitary hormone 8
11
arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation.
12
Stimate® Nasal Spray contains 1.5 mg/mL desmopressin acetate in an aqueous solution at a pH
13
of approximately 5. Stimate® Nasal Spray's compression pump delivers 0.1 mL (150 mcg) of
14
solution per spray. It is chemically defined as follows:
15
16
17
18
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
19
20
Stimate® Nasal Spray is provided as an aqueous solution for intranasal use.
21
22
Each mL contains:
Active ingredient:
Desmopressin acetate
Inactive ingredients:
Sodium chloride
Buffer:
Citric acid monohydrate
Disodium phosphate dihydrate
Preservative:
Benzalkonium chloride
Purified water
23
24
CLINICAL PHARMACOLOGY
1.5 mg
7.5 mg
1.7 mg
3 mg
0.1 mg
To 1 mL
25
Stimate® Nasal Spray contains as active substance, desmopressin acetate, which is a synthetic
26
analogue of the natural hormone arginine vasopressin. One spray or 0.1 mL (150 mcg) of
27
Stimate® Nasal Spray solution has an antidiuretic activity of about 600 International Units.
28
29
Desmopressin acetate has been shown to be more potent than arginine vasopressin in increasing
30
plasma levels of Factor VIII activity in patients with hemophilia and von Willebrand's disease
31
Type I.
32
GRDC\Cabinets\RA Labeling\Stimate\USA\Package Insert, Blank [778307] \Rev. 04/2012
VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 2
33
Dose-response studies were performed in healthy persons using doses of 150 to 450 mcg,
34
administered as one to three sprays. The response to Stimate® Nasal Spray is dose-related, with
35
maximal plasma levels of 150 to 250 percent of initial concentrations achieved for both Factor
36
VIII and von Willebrand factor.1 The increase is rapid and evident within 30 minutes, reaching a
37
maximum at about 1.5 hours.1
38
39
The percentage increase of Factor VIII and von Willebrand factor levels in patients with mild
40
hemophilia A and von Willebrand's disease was not notably different from that observed in
41
normal healthy individuals when treated with 300 mcg of Stimate® Nasal Spray. 1-4 In patients
42
with von Willebrand's disease, levels of Factor VIII coagulant activity and von Willebrand factor
43
antigen remained greater than 30 U/dL for 8 hours after a 300 mcg dose of Stimate® Nasal
44
Spray. 5 After 300 mcg of Stimate® Nasal Spray, the percentage increase of Factor VIII and von
45
Willebrand factor levels in patients with mild hemophilia A and von Willebrand's disease was
46
less than observed after 0.3 mcg/kg of intravenous desmopressin acetate.2-4
47
48
Plasminogen activator activity increases rapidly after intravenous desmopressin acetate infusion,
49
but there has been no clinically significant fibrinolysis in patients treated with desmopressin
50
acetate.
51
52
The effect of repeated intravenous desmopressin acetate administration when doses were given
53
every 12 to 24 hours has generally shown a diminution of the Factor VIII activity increase noted
54
after a single dose. It is possible to reproduce the initial response in some patients after an
55
interval of one week, but other patients may require as long as 6 weeks.2,4,6
56
57
The half-life of Stimate® Nasal Spray was between 3.3 and 3.5 hours, over the range of
58
intranasal doses, 150 to 450 mcg.1 Plasma concentrations of Stimate® Nasal Spray were
59
maximal approximately 40 to 45 minutes after dosing.1
60
61
The bioavailability of Stimate® Nasal Spray when administered by the intranasal route as a 1.5
62
mg/mL solution is between 3.3 and 4.1 percent.1
63
64
The change in structure of arginine vasopressin to desmopressin acetate has resulted in a
65
decreased vasopressor action and decreased actions on visceral smooth muscle relative to the
66
enhanced antidiuretic activity, so that clinically effective antidiuretic doses are usually below
67
threshold levels for effects on vascular or visceral smooth muscle.
68
69
INDICATIONS AND USAGE
70
Before the initial therapeutic administration of Stimate® Nasal Spray, the physician should
71
establish that the patient shows an appropriate change in the coagulation profile following a test
72
dose of intranasal administration of Stimate® Nasal Spray. 2-4
73
74
Desmopressin acetate is also available as a solution for injection (DDAVP® Injection) when the
75
intranasal route may be compromised. These situations include nasal congestion and blockage,
76
nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may
77
also be inappropriate where there is an impaired level of consciousness.
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VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 3
78
79
Hemophilia A
80
Stimate® Nasal Spray is indicated for patients with hemophilia A with Factor VIII coagulant
81
activity levels greater than 5%.
82
83
Desmopressin acetate will also stop bleeding in patients with hemophilia A with episodes of
84
spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas or
85
mucosal bleeding.2,3
86
87
In the outpatient setting during two clinical trials where patients recorded bleeding episodes,
88
Stimate® Nasal Spray provided effective hemostasis 100% of the time in 2 of the 5 patients. For
89
those patients not responding in 100% of bleeding occasions, 45% (14 of 31) of bleeding
90
episodes were effectively controlled with Stimate® Nasal Spray.
91
92
Desmopressin acetate is not indicated for the treatment of hemophilia A with Factor VIII
93
coagulant activity levels equal to or less than 5%, or for the treatment of hemophilia B, or in
94
patients who have Factor VIII antibodies.
95
96
von Willebrand's Disease (Type I)
97
Stimate® Nasal Spray is indicated for patients with mild to moderate classic von Willebrand's
98
disease (Type I) with Factor VIII levels greater than 5%.
99
100
Desmopressin acetate will also stop bleeding in mild to moderate von Willebrand's disease
101
patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses,
102
intramuscular hematomas, mucosal bleeding or menorrhagia.2,3
103
104
In the outpatient setting during two clinical trials where patients recorded bleeding episodes,
105
Stimate® Nasal Spray provided effective hemostasis 100% of the time in 75% of the patients
106
(n=16). For those patients not responding in 100% of bleeding occasions, 78% (64 of 82) of
107
bleeding episodes were effectively controlled with Stimate® Nasal Spray.
108
109
Patients may respond in a variable fashion depending on the type of molecular defect they have.
110
Bleeding time and Factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand
111
factor antigen should be checked after initial administration of Stimate® Nasal Spray to ensure
112
that adequate levels have been achieved.
113
114
Stimate® Nasal Spray is not indicated for the treatment of severe classic von Willebrand's
115
disease (Type I) and when there is evidence of an abnormal molecular form of Factor VIII
116
antigen. See WARNINGS.
117
118
CONTRAINDICATIONS
119
None.
120
121
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Package Insert
(desmopressin acetate)
Revised: April 2012
Page 4
122
WARNINGS
123
For intranasal use only.
124
125
Very rare cases of hyponatremia have been reported from world-wide postmarketing experience
126
in patients treated with Stimate (desmopressin acetate). Stimate is a potent antidiuretic which,
127
when administered, may lead to water intoxication and/or hyponatremia. Unless properly
128
diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction is recommended
129
and should be discussed with the patient and/or guardian. Careful medical supervision is
130
required.
131
132
When Stimate Nasal Spray is administered, in particular in pediatric and geriatric patients, fluid
133
intake should be adjusted downward in order to decrease the potential occurrence of water
134
intoxication and hyponatremia (See PRECAUTIONS, Pediatric Use and Geriatric Use.) All
135
patients receiving Stimate therapy should be observed for the following signs or symptoms
136
associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight
137
gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of appetite,
138
irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as
139
hallucinations, decreased consciousness and confusion. Severe symptoms may include one or a
140
combination of the following: seizure, coma and/or respiratory arrest. Particular attention should
141
be paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that
142
may result in seizures that could lead to coma.
143
144
Stimate should be used with caution in patients with habitual or psychogenic polydipsia, who
145
may be more likely to drink excessive amounts of fluids, putting them at greater risk of
146
hyponatremia.
147
148
Stimate® Nasal Spray should not be used to treat patients with Type IIB von Willebrand's
149
disease since platelet aggregation may be induced.
150
151
PRECAUTIONS
152
General
153
Desmopressin acetate has infrequently produced changes in blood pressure causing either a slight
154
elevation in blood pressure or a transient fall in blood pressure and a compensatory increase in
155
heart rate. The drug should be used with caution in patients with coronary artery insufficiency
156
and/or hypertensive cardiovascular disease.
157
158
Stimate® Nasal Spray should be used with caution in patients with conditions associated with
159
fluid and electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders because
160
these patients are prone to hyponatremia.
161
162
There have been rare reports of thrombotic events (thrombosis7, acute cerebrovascular
163
thrombosis, acute myocardial infarction) following desmopressin acetate injection in patients
164
predisposed to thrombus formation. No causality has been determined; however, the drug should
165
be used with caution in these patients.
166
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VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 5
167
Severe allergic reactions have been reported rarely.2,8-10 Fatal anaphylaxis has been reported in
168
one patient who received intravenous DDAVP® (desmopressin acetate). It is not known whether
169
antibodies to desmopressin acetate are produced after repeated administration.
170
171
Since Stimate® Nasal Spray is used intranasally, changes in the nasal mucosa such as scarring,
172
edema, or other disease may cause erratic, unreliable absorption in which case Stimate® Nasal
173
Spray should be discontinued until the nasal problems resolve. For such situations, DDAVP®
174
Injection should be considered.
175
176
Information for Patients
177
Patients should be informed that the bottle accurately delivers 25 sprays of 150 mcg each. Any
178
solution remaining after 25 sprays should be discarded since the amount delivered thereafter may
179
be substantially less than 150 mcg of drug. No attempt should be made to transfer remaining
180
solution to another bottle. Patients should be instructed to read accompanying directions on use
181
of the spray pump carefully before use.
182
183
Patients should also be advised that if bleeding is not controlled, the physician should be
184
contacted.2,3
185
186
Hemophilia A
187
Laboratory tests for assessing patient status include levels of Factor VIII coagulant, Factor VIII
188
antigen and Factor VIII ristocetin cofactor (von Willebrand factor) as well as activated partial
189
thromboplastin time. Factor VIII coagulant activity should be determined before giving Stimate®
190
Nasal Spray for hemostasis. If Factor VIII coagulant activity is present at less than 5% of
191
normal, Stimate® Nasal Spray should not be relied on.
192
193
von Willebrand's Disease
194
Laboratory tests for assessing patient status include levels of Factor VIII coagulant activity,
195
VWF:RCo and VWF:Ag.
196
197
Drug Interactions
198
Although the pressor activity of desmopressin acetate is very low, its use with other pressor
199
agents should be done only with careful patient monitoring. The concomitant administration of
200
drugs that may increase the risk of water intoxication with hyponatremia (e.g., tricyclic
201
antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics,
202
NSAIDS, lamotrigine and carbamazepine) should be performed with caution.
203
204
DDAVP® Injection has been used with epsilon aminocaproic acid without adverse effects.
205
206
Carcinogenicity, Mutagenicity, Impairment of Fertility
207
There have been no long-term studies in animals to assess the carcinogenic, mutagenic or
208
impairment of fertility potential of Stimate® Nasal Spray.
209
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VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 6
210
Pregnancy Category B
211
Reproduction studies performed in rats and rabbits by the subcutaneous route at doses up to 10
212
mcg/kg/day have revealed no evidence of harm to the fetus due to desmopressin acetate. This
213
dose is equivalent to 10 times (for Factor VIII stimulation) or 38 times (for diabetes insipidus)
214
the systemic human dose based on a mg/M2 surface area.
215
216
There are no adequate and well-controlled studies in pregnant women. Several publications of
217
desmopressin acetate's use in the management of diabetes insipidus during pregnancy are
218
available; these include a few anecdotal reports of congenital anomalies and low birth weight
219
babies. However, no causal connection between these events and desmopressin acetate has been
220
established. A 15-year, Swedish epidemiologic study of the use of desmopressin acetate in
221
pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that
222
in the general population. As opposed to preparations containing natural hormones,
223
desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to
224
weigh the therapeutic advantages against the possible risks in each case.
225
226
Nursing Mothers
227
There have been no controlled studies in nursing mothers. A single study in postpartum women
228
demonstrated a marked change in plasma, but little if any change in assayable DDAVP® in breast
229
milk following an intranasal dose of 10 mcg. It is not known whether this drug is excreted in
230
human milk. Because many drugs are excreted in human milk, caution should be exercised when
231
Stimate® Nasal Spray is administered to a nursing woman.
232
233
Pediatric Use
234
Use in infants and children will require careful fluid intake restriction to prevent possible
235
hyponatremia and water intoxication. Stimate® Nasal Spray should not be used in infants
236
younger than 11 months in the treatment of hemophilia A or von Willebrand's disease; safety and
237
effectiveness in children between 11 months and 12 years of age has been demonstrated.2-4
238
239
Geriatric Use
240
Clinical studies of Stimate® did not include sufficient numbers of subjects aged 65 and over to
241
determine whether they respond differently than younger subjects. However, other post
242
marketing experience has indicated the occurrence of hyponatremia with the use of desmopressin
243
acetate and fluid overload.
244
245
Therefore, in elderly patients fluid intake should be adjusted downward in an effort to decrease
246
the potential occurrence of water intoxication and hyponatremia. Particular attention should be
247
paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that
248
may result in seizures, and that could lead to coma.
249
250
Patients who do not have need of antidiuretic hormone for its antidiuretic effect should be
251
cautioned to ingest only enough fluid to satisfy thirst, in an effort to decrease the potential
252
occurrence of water intoxication and hyponatremia.
253
254
As for all patients, dosing for geriatric patients should be appropriate to their clinical condition.
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VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
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CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 7
255
256
ADVERSE REACTIONS
257
Infrequently, DDAVP® Injection has produced transient headache, nausea, mild abdominal
258
cramps and vulval pain. These symptoms disappeared with reduction in dosage. Occasional
259
facial flushing has been reported with the administration of DDAVP® Injection. Infrequently,
260
high doses of intranasal DDAVP® have produced transient headache and nausea. Nasal
261
congestion, rhinitis and flushing have also been reported occasionally along with mild abdominal
262
cramps. These symptoms disappeared with reduction in dosage. Nosebleed, sore throat, cough
263
and upper respiratory infections have also been reported.
264
265
In addition to those listed above, the following have also been reported in clinical trials with
266
Stimate® Nasal Spray: Somnolence, dizziness, itchy or light-sensitive eyes, insomnia, chills,
267
warm feeling, pain, chest pain, palpitations, tachycardia, dyspepsia, edema, vomiting, agitation
268
and balanitis.1-4
269
270
DDAVP® Injection (desmopressin acetate) has infrequently produced changes in blood pressure
271
causing either a slight elevation or a transient fall with a compensatory increase in heart rate.
272
Severe allergic reactions including anaphylaxis have been reported rarely with DDAVP®
273
Injection.
274
275
Post Marketing
276
There have been rare reports of convulsions from hyponatremia associated with concomitant use
277
of desmopressin and the following medications: oxybutynin and imipramine.
278
279
See WARNINGS for the possibility of water intoxication, hyponatremia and coma.11
280
281
To
report
SUSPECTED
ADVERSE
REACTIONS,
contact
CSL
Behring
282
Pharmacovigilance
at
1-866-915-6958
or
FDA
at
1-800-FDA-1088
or
283
www.fda.gov/medwatch.
284
285
OVERDOSAGE
286
Signs of overdose may include confusion, drowsiness, continuing headache, problems with
287
passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In cases of
288
overdosage, the dosage should be reduced, frequency of administration decreased, or the drug
289
withdrawn according to the severity of the condition.
290
291
There is no known specific antidote for desmopressin acetate or Stimate® Nasal Spray.
292
293
An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no
294
effect.
295
296
GRDC\Cabinets\RA Labeling\Stimate\USA\Package Insert, Blank [778307] \Rev. 04/2012
VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 8
297
DOSAGE AND ADMINISTRATION
298
Hemophilia A and von Willebrand's Disease (Type I)
299
Stimate® Nasal Spray is administered by nasal insufflation, one spray per nostril, to provide a
300
total dose of 300 mcg. In patients weighing less than 50 kg, 150 mcg administered as a single
301
spray provided the expected effect on Factor VIII coagulant activity, Factor VIII ristocetin
302
cofactor activity and skin bleeding time.3,4 If Stimate® Nasal Spray is used preoperatively, it
303
should be administered 2 hours prior to the scheduled procedure.12,13
304
305
The necessity for repeat administration of Stimate® Nasal Spray or use of any blood products
306
for hemostasis should be determined by laboratory response as well as the clinical condition of
307
the patient. Fluid restriction should be observed, and fluid intake should be limited to a
308
minimum, from 1 hour before desmopressin administration, until at least 24 hours after
309
administration. The tendency toward tachyphylaxis (lessening of response) with repeated
310
administration given more frequently than once every 48 hours should be considered in treating
311
each patient.
312
313
The nasal spray pump can only deliver doses of 0.1 mL (150 mcg) or multiples of 0.1 mL. If
314
doses other than these are required, DDAVP® Injection may be used.
315
316
The spray pump must be primed prior to the first use. To prime pump, press down 4 times. The
317
bottle should be discarded after 25 sprays since the amount delivered thereafter per spray may be
318
substantially less than 150 mcg of drug.
319
320
HOW SUPPLIED
321
A 2.5 mL bottle with spray pump capable of delivering 25 sprays of 150 mcg (NDC 0053-6871
322
00).
323
324
Store at room temperature not to exceed 25°C (77°F) for the period indicated by the expiration
325
date on the label. Discard six months after being opened. Store bottle in upright position.
326
327
Revised April 2012
IN-8155-08
328
329
Manufactured for:
330
CSL Behring LLC
331
King of Prussia, PA 19406-0901
332
US License No. 1767
333
334
By:
335
Ferring GmbH
336
Kiel, Germany
337
338
GRDC\Cabinets\RA Labeling\Stimate\USA\Package Insert, Blank [778307] \Rev. 04/2012
VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 9
339
REFERENCES
340
1. RHÔNE-POULENC RORER STUDY RG-83884-141:An Open-Label Pharmacokinetic
341
Comparison of Desmopressin Acetate Administration by Intranasal (1.5 mg/mL) and
342
Intravenous Routes: A Dose-Proportionality Trial.
343
2. RHÔNE-POULENC
RORER
STUDY
RG-83884-142:Nasal
Spray
Desmopressin
344
(DDAVP). A simple Technique for Treatment of Mild Hemophilia A and von Willebrand's
345
disease.
346
3. RHÔNE-POULENC RORER STUDY RG-83884-143:Intranasal Desmopressin (DDAVP)
347
by spray in Mild Hemophilia A and von Willebrand's disease Type I.
348
4. RHÔNE-POULENC RORER STUDY RG-83884-144:Evaluation of Intranasal Spray
349
DDAVP in Patients with Mild or Moderate Hemophilia A or von Willebrand's disease:
350
Inpatient Trial.
351
5. Lethagen S, Harris AS and Nilsson IM: Intranasal desmopressin (DDAVP) by spray in mild
352
hemophilia A and von Willebrand's disease type I. Blut, 60:187-191, 1990.
353
6. Lethagen S, Harris AS, Sjörin E and Nilsson IM: Intranasal and intravenous administration
354
of desmopressin: Effect on FVIII/vWF, pharmacokinetics and reproducibility. Thromb.
355
Haemost., 58:1033-1036, 1987.
356
7. Viron B, Michel C, Serrato T and Verdy E: Risque thrombogène du D.D.A.V.P. dans
357
l'insuffisance rénale chronique (Thrombogenic risk of DDAVP in chronic renal failure).
358
Néphrologie, 8:225, 1987.
359
8. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
360
REPORT No. 01-000657; Anaphylaxis, etc.
361
9. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
362
REPORT No. 01-001182; Anaphylactoid reaction.
363
10. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
364
REPORT No. US-870671; Erythema, rash.
365
11. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
366
REPORT No. 01-003827; Coma, grand mal seizure, etc.
367
12. Chistolini A, Dragoni F, Ferrari A, La Verde G, Arcieri R, Mohamud AE and Mazzucconi
368
MG: Intranasal DDAVP: Biological and clinical evaluation in mild Factor VIII deficiency.
369
Haemostasis, 21:273-277, 1991.
370
13. Rose EH and Aledort LM: Nasal spray desmopressin (DDAVP) for mild hemophilia A and
371
von Willebrand's disease. Ann. Int. Med., 114:563-568, 1991.
372
GRDC\Cabinets\RA Labeling\Stimate\USA\Package Insert, Blank [778307] \Rev. 04/2012
VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 10
373
374
PATIENT INSTRUCTION GUIDE
375
376
377
378
Stimate® Nasal Spray
379
(Pronounced Stim-ate)
380
(desmopressin acetate)
381
382
Read this patient information leaflet before you start taking Stimate® Nasal Spray and each time
383
you get a refill. There may be new information. This information does not take the place of
384
talking to your healthcare provider about your medical condition or your treatment.
385
386
What is the most important information I should know about Stimate® Nasal Spray?
387
388
All patients using Stimate® Nasal Spray are at risk for water intoxication, fluid overload
389
and low sodium levels in the blood.
You must follow your healthcare provider’s
390
instructions on limiting the amount of fluid you can drink when taking Stimate® Nasal
391
Spray.
392
Do not drink more than you need to satisfy your thirst.
393
You can have serious side effects such as seizures, coma, and death from drinking too
394
much fluid.
395
Children and elderly patients are at higher risk for these conditions and must follow their
396
healthcare provider’s restrictions on drinking fluids.
397
398
Call your healthcare provider right away if you have any of the following symptoms while using
399
Stimate® Nasal Spray. They may mean that your blood sodium level is low:
400
Headache
Loss of appetite
Nausea
Irritability
Vomiting
Muscle weakness
Weight gain
Muscle spasms or cramps
Restlessness
Hallucinations
Tiredness
Confusion
401
402
Using Stimate® Nasal Spray the wrong way may cause it not to work to control bleeding.
403
Call your healthcare provider right away if you have any uncontrolled bleeding.
404
405
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VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 11
406
What is Stimate® Nasal Spray?
407
Stimate® Nasal Spray is a prescription medicine used to stop some types of bleeding in people
408
with mild hemophilia A or mild to moderate von Willebrand’s disease Type 1.
409
410
Stimate® Nasal Spray should not be used in children under 11 months of age.
411
412
What should I tell my healthcare provider before I use Stimate® Nasal Spray?
413
414
Before taking Stimate® Nasal Spray, tell your healthcare provider about all of your medical
415
conditions, including if you:
416
Have any nasal problems such as a stuffy nose, have ever had surgery on your nose, or
417
have trouble breathing through your nose. You may need to use another form of this
418
medicine.
419
Have or have had any heart, blood circulation, or blood pressure problems.
420
Have a condition that causes fluid or water imbalance problems such as:
421
Cystic fibrosis
422
Heart failure
423
Kidney problems
424
Have or have had a condition that causes you to be very thirsty.
425
Are pregnant or plan to become pregnant. It is not known if Stimate® Nasal Spray will
426
harm your unborn baby.
427
Are breast-feeding or plan to breast-feed. It is not known if Stimate® Nasal Spray passes
428
into your breast milk. You and your healthcare provider should decide if you will take
429
Stimate® Nasal Spray.
430
431
Tell your healthcare provider and pharmacist about all the medicines you take, including
432
prescription and non-prescription medicines, such as over-the-counter medicines, vitamins,
433
supplements and herbal remedies.
434
435
Using Stimate® Nasal Spray with certain other medicines can affect the way Stimate® Nasal
436
Spray works.
437
438
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
439
pharmacist when you get a new medicine.
440
441
It is especially important to tell your healthcare provider if you take:
442
Blood pressure or heart medicines
443
Antidepressants
444
Anti-anxiety medicines
445
Antihistamines
446
Pain relievers such as narcotics or non-steroidal anti-inflammatory medicines (NSAIDs)
447
Seizure medicines
448
Medicines for over-active urinary bladder
449
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VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 12
450
Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of these.
451
452
How should I use Stimate® Nasal Spray?
453
Use Stimate® Nasal Spray exactly as your healthcare provider told you. Do not use more
454
Stimate® Nasal Spray or take it more often than your healthcare provider told you.
455
The Stimate® Nasal Spray pump provides the correct dose of your medicine. For detailed
456
instructions on how to use the nasal spray pump, see the Patient Instructions for Use at
457
the end of this leaflet.
458
The nasal spray pump delivers 25 sprays of Stimate® Nasal Spray and each spray
459
contains a measured amount of medicine. Any medicine left in the spray pump after 25
460
sprays should be thrown away because, at that time, the amount of medicine in each
461
spray may be a lot less than the correct amount. Do not put any leftover medicine into
462
another bottle.
463
If your symptoms do not improve, or if they become worse, contact your healthcare
464
provider. Do not stop taking Stimate® Nasal Spray without talking to your healthcare
465
provider.
466
If you use too much Stimate® Nasal Spray, call your healthcare provider or go to the
467
nearest hospital emergency department right away.
468
469
What are the possible side effects of Stimate® Nasal Spray?
470
471
Stimate® Nasal Spray may cause serious side effects, that come from having too much water
472
in the body. See “What is the most important information I should know about Stimate®
473
Nasal Spray?”.
474
475
Common side effects of Stimate Nasal Spray include:
476
Occasional facial flushing
477
Nasal congestion
478
Runny nose
479
Nosebleed
480
Sore throat
481
Cough
482
Upper respiratory infections.
483
484
Tell your healthcare provider about any side effect that bothers you or does not go away. These
485
are not all the possible side effects of Stimate® Nasal Spray. If you have questions, talk to your
486
healthcare provider.
487
488
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1
489
800-FDA-1088.
490
491
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VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 13
492
How should I store Stimate® Nasal Spray?
493
Store at room temperature, but not higher than 77°F (25°C).
494
Throw away Stimate® Nasal Spray six months after it is opened, or when the expiration
495
date has passed, if this date is before the six months is up.
496
Store Stimate® Nasal Spray standing upright.
497
498
Keep Stimate® Nasal Spray and all medicines out of the reach of children.
499
500
General information about Stimate® Nasal Spray
501
Medicines are sometimes prescribed for conditions that are not mentioned in the patient leaflet.
502
Do not use Stimate® Nasal Spray for a condition for which it was not prescribed. Do not give
503
Stimate® Nasal Spray to other people, even if they have the same symptoms you have. It may
504
harm them.
505
506
This patient information leaflet summarizes the most important information about Stimate®
507
Nasal Spray. If you would like more information about Stimate® Nasal Spray, talk with your
508
healthcare provider. You can ask your healthcare provider or pharmacist for information about
509
Stimate® Nasal Spray that is written for health professionals. For more information, go to
510
www.stimate.com or call CSL Behring Medical Affairs at 1-800-504-5434.
511
512
What are the ingredients in Stimate® Nasal Spray?
513
514
Active ingredients: desmopressin acetate
515
Inactive ingredients: sodium chloride, citric acid monohydrate, disodium phosphate dihydrate,
516
benzalkonium chloride, purified water.
517
518
Patient Instructions for Use
519
520
Read these instructions carefully before you use your Stimate® Nasal Spray pump. The
521
following instructions tell you how to prepare, or prime, your Stimate® Nasal Spray pump so that
522
it is ready to use.
523
524
Using your Stimate® Nasal Spray Pump
525
526
1. Remove the protective cap.
527
528
2. When using Stimate® Nasal Spray for the first time, the spray pump must be primed by
529
pressing down on the ring at the top of the pump 4 times. Hold the spray tip away from
530
your face and eyes. See Figure A.
531
GRDC\Cabinets\RA Labeling\Stimate\USA\Package Insert, Blank [778307] \Rev. 04/2012
VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 14
usage illustration
532
533
Figure A
534
535
536
3. When primed, the Stimate® Nasal Spray pump delivers one dose of medicine each time it
537
is pressed. For the right dose, tilt your Stimate® Nasal Spray pump so that the tube inside
538
the spray pump draws the medicine up from the deepest part of the medicine inside the
539
container. See Figures A and B.
540 usage illustration
541
542
Figure B
543
544
4. Put the spray nozzle tip into your nostril and press the spray pump one time for one dose
545
(150-micrograms). If two doses are prescribed, spray each nostril one time (for a dose of
546
300-micrograms).
547
548
5. When you finish using your Stimate® Nasal Spray, put the cap over the tip of the pump.
549
550
6. If Stimate® Nasal Spray has not been used for one week, you will need to prime the pump
551
again by pressing one time, or until you see a fine mist.
552
553
GRDC\Cabinets\RA Labeling\Stimate\USA\Package Insert, Blank [778307] \Rev. 04/2012
VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring LLC
Stimate®
Package Insert
(desmopressin acetate)
Revised: April 2012
Page 15
554
Use this check-off chart to help you keep track of the number of sprays used. This will help
555
make sure that you receive 25 sprays with each bottle of Stimate® Nasal Spray. There is extra
556
medicine in the bottle to allow for priming. When using the chart to check off sprays, do not
557
count the priming sprays.
558
559
560
Stimate® Nasal Spray
561
25 Spray Check-off Chart usage illustration
562
563
1. Keep this chart with your Stimate® Nasal Spray or put it someplace where you can easily get
564
it.
565
566
2. Check off number 1 on the chart with your first dose of Stimate® Nasal Spray. Check off the
567
numbers after each use of Stimate® Nasal Spray. If your healthcare provider prescribed a 2
568
spray dose (300-micrograms), then two numbers should be checked off.
569
570
3. Throw away the Stimate® Nasal Spray after 25 sprays.
GRDC\Cabinets\RA Labeling\Stimate\USA\Package Insert, Blank [778307] \Rev. 04/2012
VERSION 16.0
Reference ID: 3314418
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:30.040527
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020355s017lbl.pdf', 'application_number': 20355, 'submission_type': 'SUPPL ', 'submission_number': 17}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NAPRELAN® safely and effectively. See full prescribing information for
NAPRELAN® .
NAPRELAN (naproxen sodium) Controlled-Release Tablets for oral
use
Initial U.S. Approval: 1976
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased
risk of serious cardiovascular thrombotic events, including myocardial
infarction and stroke, which can be fatal. This risk may occur early in
treatment and may increase with duration of use (5.1)
NAPRELAN® is contraindicated in the setting of coronary artery
bypass graft (CABG) surgery (4, 5.1)
NSAIDs cause an increased risk of serious gastrointestinal (GI)
adverse events including bleeding, ulceration, and perforation of the
stomach or intestines, which can be fatal. These events can occur at
any time during use and without warning symptoms. Elderly patients
and patients with a prior history of peptic ulcer disease and/or GI
bleeding are at greater risk for serious GI events (5.2)
RECENT MAJOR CHANGES
Boxed Warning
5/2016
Warnings and Precautions, Cardiovascular Thrombotic Events (5.1)
5/2016
Warnings and Precautions, Heart Failure and Edema (5.5)
5/2016
INDICATIONS AND USAGE
NAPRELAN is a nonsteroidal anti-inflammatory drug indicated for the
treatment of:
rheumatoid arthritis (RA)(1)
osteoarthritis (OA)(1)
ankylosing spondylitis(AS)(1)
tendinitis, bursitis(1)
acute gout(1)
primary dysmenorrhea (PD) (1)
the relief of mild to moderate pain(1)
DOSAGE AND ADMINISTRATION
Use the lowest effective dosage for shortest duration consistent with
individual patient treatment goals (2)
RA, OA, and AS: The dosage is two 375 mg or 500 mg tablets
once daily, or one 750 mg tablet once daily.
Management of Pain, PD, and Acute Tendinitis and Bursitis:
The dosage is two 500 mg tablets once daily. For patients
requiring greater analgesic benefit, two 750 mg tablets or three
500 mg tablets may be used for a limited period. Thereafter, the
total daily dose should not exceed two 500 mg tablets
For the treatment of Acute Gout: The dosage is two to three 500
mg tablets once daily on the first day, followed by two 500 mg
tablets once daily, until the attack has subsided.
DOSAGE FORMS AND STRENGTHS
NAPRELAN (naproxen sodium) Controlled-Release Tablets: 375 mg,
500 mg, and 750 mg (3)
CONTRAINDICATIONS
Known hypersensitivity to naproxen or any components of the
drug product (4)
History of asthma, urticaria, or other allergic-type reactions after
taking aspirin or other NSAIDs (4)
In the setting of CABG surgery (4)
Hypertension: Patients taking some antihypertensive medications may
have impaired response to these therapies when taking NSAIDs.
Monitor blood pressure (5.4, 7)
Heart Failure and Edema: Avoid use of NAPRELAN in patients with
severe heart failure unless benefits are expected to outweigh risk of
worsening heart failure (5.5)
Renal Toxicity: Monitor renal function in patients with renal or
hepatic impairment, heart failure, dehydration, or hypovolemia.
Avoid use of NAPRELAN in patients with advanced renal disease
unless benefits are expected to outweigh risk of worsening renal
function (5.6)
Anaphylactic Reactions: Seek emergency help if an anaphylactic
reaction occurs (5.7)
Exacerbation of Asthma Related to Aspirin Sensitivity: NAPRELAN
is contraindicated in patients with aspirin-sensitive asthma. Monitor
patients with preexisting asthma (without aspirin sensitivity) (5.8)
Serious Skin Reactions: Discontinue NAPRELAN at first appearance
of skin rash or other signs of hypersensitivity (5.9)
Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant
women starting at 30 weeks gestation (5.10, 8.1)
Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients
with any signs or symptoms of anemia (5.11, 7)
ADVERSE REACTIONS
The most frequent adverse events were headache (15%), followed by
dyspepsia (14%), and flu syndrome (10%). (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Alvogen at 866
770-3024 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
Monitor patients for bleeding who are concomitantly taking NAPRELAN
with drugs that interfere with hemostasis. Concomitant use of NAPRELAN
and analgesic doses of aspirin is not generally recommended (7)
ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers:
Concomitant use with NAPRELAN may diminish the antihypertensive effect
of these drugs. Monitor blood pressure (7)
ACE Inhibitors and ARBs: Concomitant use with NAPRELAN in elderly,
volume depleted, or those with renal impairment may result in deterioration of
renal function. In such high risk patients, monitor for signs of worsening renal
function (7)
Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide
diuretics. Monitor patients to assure diuretic efficacy including
antihypertensive effects (7)
Digoxin: Concomitant use with NAPRELAN can increase serum
concentration and prolong half-life of digoxin. Monitor serum digoxin levels
(7)
USE IN SPECIFIC POPULATIONS
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk
of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant
women starting at 30 weeks gestation (5.10, 8.1)
Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal
of NAPRELAN in women who have difficulties conceiving (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised 5/2016
WARNINGS AND PRECAUTIONS
Hepatotoxicity: Inform patients of warning signs and symptoms of
hepatotoxicity. Discontinue if abnormal liver tests persist or worsen
or if clinical signs and symptoms of liver disease develop (5.3)
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1.
General Dosing Instructions
2.2
Rheumatoid Arthritis, Osteoarthritis, and Ankylosing
Spondylitis
2.3
Management of Pain, Primary Dysmenorrhea, and
Acute Tendinitis and Bursitis
2.4
Acute Gout
2.5
Dosage Adjustments in Patients with Hepatic
Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Cardiovascular Thrombotic Events
5.2
Gastrointestinal Bleeding, Ulceration, and Perforation
5.3
Hepatotoxicity
5.4
Hypertension
5.5
Heart Failure and Edema
5.6
Renal Toxicity and Hyperkalemia
5.7
Anaphylactic Reactions
5.8
Exacerbation of Asthma Related to Aspirin Sensitivity
5.9
Serious Skin Reactions
5.10
Premature Closure of Fetal Ductus Arteriosus
5.11
Hematologic Toxicity
5.12
Masking of Inflammation and Fever
5.13
Laboratory Monitoring
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 3928425
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 SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
Cardiovascular Thrombotic Events
• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious
cardiovascular thrombotic events, including myocardial infarction and stroke,
which can be fatal. This risk may occur early in treatment and may increase with
duration of use [see Warnings and Precautions (5.1)].
• NAPRELAN is contraindicated in the setting of coronary artery bypass graft
(CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which
can be fatal. These events can occur at any time during use and without warning
symptoms. Elderly patients and patients with a prior history of peptic ulcer disease
and/or GI bleeding are at greater risk for serious GI events [see Warnings and
Precautions (5.2)].
1
INDICATIONS AND USAGE
NAPRELAN Tablets are indicated for the treatment of:
rheumatoid arthritis (RA)
osteoarthritis (OA)
ankylosing spondylitis (AS)
tendinitis, bursitis
acute gout
primary dysmenorrhea (PD)
the relief of mild to moderate pain
[see Warnings and Precautions (5)].
2
DOSAGE AND ADMINISTRATION
2.1.
General Dosing Instructions
Carefully consider the potential benefits and risks of NAPRELAN and other treatment options
before deciding to use NAPRELAN. Use the lowest effective dosage for the shortest duration
consistent with individual patient treatment goals [see Warnings and Precautions (5)].
After observing the response to initial therapy with NAPRELAN, the dose and frequency should be
adjusted to suit an individual patient’s needs.
2.2
Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis
The recommended starting dose of NAPRELAN Tablets in adults is two NAPRELAN 375 mg
tablets (750 mg) once daily, one NAPRELAN 750 mg (750 mg) once daily, or two NAPRELAN 500
mg tablets (1000 mg) once a daily. Patients already taking naproxen 250 mg, 375 mg, or 500 mg
twice daily (morning and evening) may have their total daily dose replaced with NAPRELAN
Tablets as a single daily dose.
During long-term administration, the dose of NAPRELAN Tablets may be adjusted up or down
depending on the clinical response of the patient. In patients who tolerate lower doses of
NAPRELAN Tablets well, the dose may be increased to two NAPRELAN 750 mg tablets (1500 mg),
or three NAPRELAN 500 mg tablets (1500 mg) once daily for limited periods when a higher level of
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
anti-inflammatory/analgesic activity is required. When treating patients, especially at the higher dose
levels, the physician should observe sufficient increased clinical benefit to offset the potential
increased risk [see Clinical Pharmacology (12.3)]. The lowest effective dose should be sought and
used in every patient. Symptomatic improvement in arthritis usually begins within one week;
however, treatment for two weeks may be required to achieve a therapeutic benefit.
2.3
Management of Pain, Primary Dysmenorrhea, and Acute Tendinitis and Bursitis
The recommended starting dose is two NAPRELAN 500 mg tablets (1000 mg) once daily. For
patients requiring greater analgesic benefit, two NAPRELAN 750 mg tablets (1500 mg) or three
NAPRELAN 500 mg tablets (1500 mg) may be used for a limited period. Thereafter, the total daily
dose should not exceed two NAPRELAN 500 mg tablets (1000 mg).
2.4
Acute Gout
The recommended dose on the first day is two to three NAPRELAN 500 mg tablets (1000 - 1500
mg) once daily, followed by two NAPRELAN 500 mg tablets (1000 mg) once daily, until the attack
has subsided.
2.5
Dosage Adjustments in Patients with Hepatic Impairment
A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients
[see Warnings and Precautions (5.3)]. Studies indicate that although total plasma concentration of
naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution
is advised when high doses are required and some adjustment of dosage may be required in elderly
patients. As with other drugs used in the elderly it is prudent to use the lowest effective dose.
3
DOSAGE FORMS AND STRENGTHS
NAPRELAN (naproxen sodium) Controlled-Release Tablets are available as follows:
NAPRELAN 375: white, capsule-shaped tablet with “N” on one side and “375” on the reverse. Each
tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen.
NAPRELAN 500: white, capsule-shaped tablet with “N” on one side and “500” on the reverse. Each
tablet contains 550 mg naproxen sodium equivalent to 500 mg naproxen.
NAPRELAN 750: white, capsule-shaped tablet with “N” on one side and “750” on the reverse.
Each tablet contains 825 mg naproxen sodium equivalent to 750 mg naproxen.
4
CONTRAINDICATIONS
NAPRELAN is contraindicated in the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or
any components of the drug product [see Warnings and Precautions (5.7, 5.9)]
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other
NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in
such patients [see Warnings and Precautions (5.7, 5.8)]
In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and
Precautions (5.1)]
5
WARNINGS AND PRECAUTIONS
5.1 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, including
myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that
the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
thrombotic events over baseline conferred by NSAID use appears to be similar in those with and
without known CV disease or risk factors for CV disease. However, patients with known CV
disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due
to their increased baseline rate. Some observational studies found that this increased risk of serious
CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic
risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest
effective dose for the shortest duration possible. Physicians and patients should remain alert for the
development of such events, throughout the entire treatment course, even in the absence of previous
CV symptoms. Patients should be informed about the 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,
such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and
Precautions (5.2)].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
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. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that
patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-
related death, and all-cause mortality beginning in the first week of treatment. In this same
cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-
treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although
the absolute rate of death declined somewhat after the first year post-MI, the increased relative
risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of NAPRELAN in patients with a recent MI unless the benefits are expected to
outweigh the risk of recurrent CV thrombotic events. If NAPRELAN is used in patients with a
recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or
large intestine, which can be fatal. These serious adverse events can occur at any time, with or
without warning symptoms, in patients treated with NSAIDs. Only one in five patients who
develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers,
gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated
for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term
NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a
greater than 10-fold increased risk for developing a GI bleed compared to patients without these
risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs
include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin,
anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older
age; and poor general health status. Most postmarketing reports of fatal GI events occurred in
elderly or debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Strategies to Minimize the GI Risks in NSAID-treated patients:
Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the
increased risk of bleeding. For such patients, as well as those with active GI bleeding,
consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID
therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and
discontinue NAPRELAN until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor
patients more closely for evidence of GI bleeding [see Drug Interactions (7)].
5.3 Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been
reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare,
sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and
hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated
with NSAIDs including naproxen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If
clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations
occur (e.g., eosinophilia, rash, etc.), discontinue NAPRELAN immediately, and perform a clinical
evaluation of the patient.
5.4 Hypertension
NSAIDs, including NAPRELAN, can lead to new onset or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients
taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may
have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course
of therapy.
5.5 Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled
trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX
2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated
patients. In a Danish National Registry study of patients with heart failure, NSAID use increased
the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs.
Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical
conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug
Interactions (7)].
Avoid the use of NAPRELAN in patients with severe heart failure unless the benefits are expected
to outweigh the risk of worsening heart failure. If NAPRELAN is used in patients with severe heart
failure, monitor patients for signs of worsening heart failure.
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.6 Renal Toxicity and Hyperkalemia
Renal Toxicity
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 an 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, dehydration, hypovolemia, heart failure, liver dysfunction,
those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID
therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of NAPRELAN in
patients with advanced renal disease. The renal effects of NAPRELAN may hasten the progression
of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPRELAN.
Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or
hypovolemia during use of NAPRELAN [see Drug Interactions (7)]. Avoid the use of
NAPRELAN in patients with advanced renal disease unless the benefits are expected to outweigh
the risk of worsening renal function. If NAPRELAN is used in patients with advanced renal
disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use
of NSAIDs, even in some patients without renal impairment. In patients with normal renal function,
these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
5.7 Anaphylactic Reactions
Naproxen has been associated with anaphylactic reactions in patients with and without known
hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4)
and Warnings and Precautions (5.8)].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include
chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or
intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other
NSAIDs has been reported in such aspirin-sensitive patients, NAPRELAN is contraindicated in
patients with this form of aspirin sensitivity [see Contraindications (4)]. When NAPRELAN is used
in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for
changes in the signs and symptoms of asthma.
5.9 Serious Skin Reactions
NSAIDs, including naproxen can cause serious skin adverse reactions such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be
fatal. These serious events may occur without warning. Inform patients about the signs and
symptoms of serious skin reactions, and to discontinue the use of NAPRELAN at the first
appearance of skin rash or any other sign of hypersensitivity.
NAPRELAN is contraindicated in patients with previous serious skin reactions to NSAIDs [see
Contraindications (4)].
Reference ID: 3928425
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5.10 Premature Closure of Fetal Ductus Arteriosus
Naproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs,
including NAPRELAN, in pregnant women starting at 30 weeks of gestation (third trimester)
[see Use in Specific Populations (8.1)].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid
retention, or an incompletely described effect on erythropoiesis. If a patient treated with
NAPRELAN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including NAPRELAN, may increase the risk of bleeding events. Co-morbid comditions
such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet
agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake
inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug
Interactions (7)].
5.12 Masking of Inflammation and Fever
The pharmacological activity of NAPRELAN in reducing inflammation, and possibly fever, may
diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms
or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry
profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
Hepatotoxicity [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Heart Failure and Edema [see Warnings and Precautions (5.5)]
Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
Anaphylactic Reactions [see Warnings and Precautions (5.7)]
Serious Skin Reactions [see Warnings and Precautions (5.9)]
Hematologic Toxicity [see Warnings and Precautions (5.11)]
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.
As with all drugs in this class, the frequency and severity of adverse events depends on several
factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the
patient; any concurrent medical diagnoses or individual risk factors. The following adverse reactions
are divided into three parts based on frequency and whether or not the possibility exists of a causal
relationship between drug usage and these adverse events. In those reactions listed as “Probable
Causal Relationship” there is at least one case for each adverse reaction where there is evidence to
suggest that there is a causal relationship between drug usage and the reported event. The adverse
reactions reported were based on the results from two double-blind controlled clinical trials of three
months duration with an additional nine month open-label extension. A total of 542 patients received
NAPRELAN Tablets either in the double-blind period or in the nine month open-label extension. Of
these 542 patients, 232 received NAPRELAN Tablets, 167 were initially treated with Naprosyn®***
Reference ID: 3928425
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and 143 were initially treated with placebo. Adverse reactions reported by patients who received
NAPRELAN Tablets are shown by body system. Those adverse reactions observed with naproxen but
not reported in controlled trials with NAPRELAN Tablets are italicized.
The most frequent adverse events from the double-blind and open-label clinical trials were headache
(15%), followed by dyspepsia (14%), and flu syndrome (10%). The incidence of other adverse events
occurring in 3% - 9% of the patients are marked with an asterisk.
Those reactions occurring in less than 3% of the patients are unmarked.
Incidence greater than 1% (probable causal relationship)
Body as a Whole—Pain (back)*, pain*, infection*, fever, injury (accident), asthenia, pain chest,
headache (15%), flu syndrome (10%).
Gastrointestinal—Nausea*, diarrhea*, constipation*, abdominal pain*, flatulence, gastritis, vomiting,
dysphagia, dyspepsia (14%), heartburn*, stomatitis.
Hematologic—Anemia, ecchymosis.
Respiratory—Pharyngitis*, rhinitis*, sinusitis*, bronchitis, cough increased.
Renal—Urinary tract infection*, cystitis.
Dermatologic—Skin rash*, skin eruptions*, ecchymoses*, purpura.
Metabolic and Nutrition—Peripheral edema, hyperglycemia.
Central Nervous System—Dizziness, paresthesia, insomnia, drowsiness*, lightheadedness.
Cardiovascular—Hypertension, edema*, dyspnea*, palpitations.
Musculoskeletal—Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder.
Special Senses—Tinnitus*, hearing disturbances, visual disturbances.
General—Thirst.
Incidence less than 1% (probable causal relationship)
Body as a Whole—Abscess, monilia, neck rigid, pain neck, abdomen enlarged, carcinoma, cellulitis,
edema general, LE syndrome, malaise, mucous membrane disorder, allergic reaction, pain pelvic.
Gastrointestinal—Anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal
hemorrhage, stomatitis aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach, periodontal abscess,
cardiospasm, colitis, esophagitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder,
hepatosplenomegaly, liver function abnormality, melena, ulcer esophagus, hematemesis, jaundice,
pancreatitis, necrosis.
Renal—Dysmenorrhea, dysuria, kidney function abnormality, nocturia, prostate disorder,
pyelonephritis, carcinoma breast, urinary incontinence, kidney calculus, kidney failure, menorrhagia,
metrorrhagia, neoplasm breast, nephrosclerosis, hematuria, pain kidney, pyuria, urine abnormal,
urinary frequency, urinary retention, uterine spasm, vaginitis, glomerular nephritis, hyperkalemia,
interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis.
Hematologic—Leukopenia, bleeding time increased, eosinophilia, abnormal RBC, abnormal WBC,
thrombocytopenia, agranulocytosis, granulocytopenia.
Reference ID: 3928425
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Central Nervous System—Depression, anxiety, hypertonia, nervousness, neuralgia, neuritis, vertigo,
amnesia, confusion, co-ordination, abnormal diplopia, emotional lability, hematoma subdural,
paralysis, dream abnormalities, inability to concentrate, muscle weakness.
Dermatologic: Angiodermatitis, herpes simplex, dry skin, sweating, ulcer skin, acne, alopecia,
dermatitis contact, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, pruritus,
urticaria, neoplasm skin, photosensitive dermatitis, photosensitivity reactions resembling porphyria
cutaneous tarda, epidermolysis bullosa.
Special Senses—Amblyopia, scleritis, cataract, conjunctivitis, deaf, ear disorder, keratoconjunctivitis,
lacrimation disorder, otitis media, pain eye.
Cardiovascular—Angina pectoris, coronary artery disease, myocardial infarction, deep
thrombophlebitis, vasodilation, vascular anomaly, arrhythmia, bundle branch block, abnormal ECG,
heart failure right, hemorrhage, migraine, aortic stenosis, syncope, tachycardia, congestive heart
failure.
Respiratory—Asthma, dyspnea, lung edema, laryngitis, lung disorder, epistaxis, pneumonia,
respiratory distress, respiratory disorder, eosinophilic pneumonitis.
Musculoskeletal—Myasthenia, bone disorder, spontaneous bone fracture, fibrotendinitis, bone pain,
ptosis, spasm general, bursitis.
Metabolic and Nutrition—Creatinine increase, glucosuria, hypercholesteremia, albuminuria, alkalosis,
BUN increased, dehydration, edema, glucose tolerance decrease, hyperuricemia, hypokalemia, SGOT
increase, SGPT increase, weight decrease.
General—Anaphylactoid reactions, angioneurotic edema, menstrual disorders, hypoglycemia, pyrexia
(chills and fevers).
Incidence less than 1% (causal relationship unknown)
Other adverse reactions listed in the naproxen package label, but not reported by those who received
NAPRELAN Tablets are shown in italics. These observations are being listed as alerting information
to the physician.
Hematologic—Aplastic anemia, hemolytic anemia.
Central Nervous System—Aseptic meningitis, cognitive dysfunction.
Dermatologic—Epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.
Gastrointestinal—Non-peptic GI ulceration, ulcerative stomatitis.
Cardiovascular—Vasculitis.
7
DRUG INTERACTIONS
See Table 1 for clinically significant drug interactions with naproxen.
Table 1: Clinically Significant Drug Interactions with naproxen
Drugs That Interfere with Hemostasis
Clinical Impact: Naproxen
and anticoagulants such as warfarin have a synergistic effect on
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bleeding. The concomitant use of naproxen and anticoagulants have an
increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and
cohort epidemiological studies showed that concomitant use of drugs that interfere
with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than
an NSAID alone.
Intervention: Monitor patients with concomitant use of NAPRELAN with anticoagulants (e.g.,
warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors
(SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding
[see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic
doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs
alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated
with a significantly increased incidence of GI adverse reactions as compared to use of the
NSAID alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of NAPRELAN
and analgesic doses of aspirin is not generally
recommended because of the increased risk of bleeding [see Warnings and Precautions
(5.11)].
NAPRELAN is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme
(ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including
propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or
have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs
may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Intervention: During concomitant use of NAPRELAN
and ACE-inhibitors, ARBs, or beta-
blockers, monitor blood pressure to ensure that the desired blood pressure is
obtained.
During concomitant use of NAPRELAN and ACE-inhibitors or ARBs in patients
who are elderly, volume-depleted, or have impaired renal function, monitor for signs
of worsening renal function [see Warnings and Precautions (5.6)].
When these drugs are administered concomitantly, patients should be adequately
hydrated. Assess renal function at the beginning of the concomitant treatment and
periodically thereafter.
Diuretics
Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced
the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some
patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin
synthesis.
Intervention: During concomitant use of NAPRELAN with diuretics, observe patients for signs of
worsening renal function, in addition to assuring diuretic efficacy including
antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum
concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of NAPRELAN and digoxin, monitor serum digoxin levels.
Lithium
Reference ID: 3928425
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Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal
lithium clearance. The mean minimum lithium concentration increased 15%, and the
renal clearance decreased by approximately 20%. This effect has been attributed to
NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of NAPRELAN and lithium, monitor patients for signs of
lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate
toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of NAPRELAN and methotrexate, monitor patients for
methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of NAPRELAN
and cyclosporine may increase cyclosporine’s
nephrotoxicity.
Intervention: During concomitant use of NAPRELAN and cyclosporine, monitor patients for signs
of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of naproxen
with other NSAIDs or salicylates (e.g., diflunisal,
salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see
Warnings and Precautions (5.2)].
Intervention: The concomitant use of naproxen
with other NSAIDs or salicylates is not
recommended.
Pemetrexed
Clinical Impact:
Concomitant use of NAPRELAN
and pemetrexed may increase the risk of
pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed
prescribing information).
Intervention: During concomitant use of NAPRELAN and pemetrexed, in patients with renal
impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for
myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be
avoided for a period of two days before, the day of, and two days following
administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs
with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs
should interrupt dosing for at least five days before, the day of, and two days following
pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:
Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and
sucralfate can delay the absorption of naproxen.
Intervention:
Concomitant administration of antacids such as magnesium oxide or aluminum hydroxid, and
sucralfate with NAPRELAN is not recommended.
Cholestyramine
Clinical Impact:
Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:
Concomitant administration of cholestyramine with NAPRELAN is not recommended.
Probenecid
Clinical Impact:
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma
half-life significantly.
Intervention:
Patients simultaneously receiving NAPRELAN and probenecid should be observed for
adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction
with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas,
hydantoins, other NSAIDs, and aspirin.
Intervention:
Patients simultaneously receiving NAPRELAN and a hydantoin, sulphonamide or sulphonylurea
should be observed for adjustment of dose if required.
Reference ID: 3928425
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Drug/Laboratory Test Interactions
Bleeding times
Clinical Impact:
Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:
This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:
The administration of naproxen may result in increased urinary values for 17-ketogenic steroids
because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in
this assay.
Intervention:
Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be
artifactually altered, it is suggested that therapy with NAPRELAN be temporarily discontinued
72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:
This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid are determined.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Use of NSAIDs, including NAPRELAN, during the third trimester of pregnancy increases the risk
of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including NAPRELAN,
in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of NAPRELAN in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in women in
the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all
clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4%
for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats,
rabbit, and mice no evidence of teratogenicity or fetal harm when naproxen was administered
during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended
human daily dose of 1500 mg/day, respectively. Based on animal data, prostaglandins have been
shown to have an important role in endometrial vascular permeability, blastocyst implantation, and
decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as
naproxen sodium resulted in increased pre- and post-implantation loss.
Clinical Considerations
Labor or Delivery
There are no studies on the effects of NAPRELAN during labor or delivery. In animal studies,
NSAIDS, including naproxen sodium, inhibit prostaglandin synthesis, cause delayed parturition,
increase incidence of dystocia and increase the incidence of stillbirth.
Data
Human Data
There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay
preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis,
patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to
delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and
abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs of this class
on the human fetal cardiovascular system (closure of the ductus arteriosus), use during third trimester
should be avoided.
Animal data
Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum
Reference ID: 3928425
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recommended human daily dose of 1500 mg/day based on body surface area comparison) rabbits
at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface
area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily
dose based on body surface area comparison) with no evidence of impaired fertility or harm to the
fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important
role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal
studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in
increased pre- and post-implantation loss.
8.2 Lactation
Risk Summary
The naproxen anion has been found in the milk of lactating women at a concentration of
approximately 1% of that found in the plasma. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for NAPRELAN and any
potential adverse effects on the breastfed infant from the NAPRELAN or from the underlying
maternal condition.
8.3 Females and Males of Reproductive Potential
Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including
NAPRELAN, may delay or prevent rupture of ovarian follicles, which has been associated with
reversible infertility in some women. Published animal studies have shown that administration of
prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular
rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a
reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPRELAN, in women
who have difficulties conceiving or who are undergoing investigation of infertility.
8.4 Pediatric Use
The safety and effectiveness of NAPRELAN in pediatric populations has not been established.
8.5 Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious
cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the
elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and
monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)].
Naproxen 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, use caution in this patient
population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]
10 OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to lethargy,
drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with
supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure,
respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1,
5.2, 5.4, 5.6)].
A few patients have experienced seizures, but it is not clear whether or not these were drug-related. It
is not known what dose of the drug would be life threatening.
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are
no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen
because of the high degree of its protein binding. Consider emesis and/or activated charcoal (60 to
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100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic
cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large
overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine,
hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1-800
222-1222).
11 DESCRIPTION
NAPRELAN (naproxen sodium) Controlled-Release Tablets is a nonsteroidal anti-inflammatory
drug, available as controlled-release tablets in 375 mg, 500 mg, and 750 mg strengths for oral
administration. The chemical name is 2-naphthaleneacetic acid, 6-methoxy--methyl-sodium salt,
(S)-. The molecular weight is 252.24. Its molecular formula is C14H13NaO3, and it has the
following chemical structure. structural formula
Naproxen sodium is an odorless crystalline powder, white to creamy in color. It is soluble in
methanol and water. NAPRELAN Tablets contain 412.5 mg, 550 mg, or 825 mg of naproxen
sodium, equivalent to 375 mg, 500 mg, and 750 mg of naproxen, and 37.5 mg, 50 mg, and 75 mg
sodium respectively. Each NAPRELAN Tablet also contains the following inactive ingredients:
ammoniomethacrylate copolymer Type A, ammoniomethacrylate copolymer Type B, citric acid,
crospovidone, magnesium stearate, methacrylic acid copolymer Type A, microcrystalline cellulose,
povidone, and talc. The tablet coating contains hydroxypropyl methylcellulose, polyethylene glycol,
and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Naproxen has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of NAPRELAN, like that of other NSAIDs, is not completely
understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Naproxen sodium is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen sodium
concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize
afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.
Prostaglandins are mediators of inflammation. Because naproxen sodium is an inhibitor of
prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in
peripheral tissues.
12.3 Pharmacokinetics
Although naproxen itself is well absorbed, the sodium salt form is more rapidly absorbed, resulting
in higher peak plasma levels for a given dose. Approximately 30% of the total naproxen sodium dose
in NAPRELAN Tablets is present in the dosage form as an immediate release component. The
remaining naproxen sodium is coated as microparticles to provide sustained release properties. After
oral administration, plasma levels of naproxen are detected within 30 minutes of dosing, with peak
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plasma levels occurring approximately 5 hours after dosing. The observed terminal elimination half-
life of naproxen from both immediate release naproxen sodium and NAPRELAN Tablets is
approximately 15 hours. Steady state levels of naproxen are achieved in 3 days and the degree of
naproxen accumulation in the blood is consistent with this.
graph
Pharmacokinetic Parameters at Steady State Day 5 (Mean of 24 Subjects)
Parameter
(units)
naproxen 500 mg
Q12h/5 days (1000 mg)
NAPRELAN 2 x 500 mg tablets
(1000 mg) Q24h/5 days
Mean SD
Range
Mean
SD
Range
AUC 0-24
(mcgxh/mL)
1446 168 1167 - 1858
1448
145
1173 - 1774
Cmax (mcg/mL)
95
13
71 - 117
94
13
74 - 127
Cavg (mcg/mL)
60
7
49 - 77
60
6
49 - 74
Cmin (mcg/mL)
36
9
13 - 51
33
7
23 - 48
Tmax (hrs)
3
1
1 - 4
5
2
2-10
Absorption
Naproxen itself is rapidly and completely absorbed from the GI tract with an in vivo bioavailability
of 95%. Based on the pharmacokinetic profile, the absorption phase of NAPRELAN Tablets occurs
in the first 4-6 hours after administration. This coincides with disintegration of the tablet in the
stomach, the transit of the sustained release microparticles through the small intestine and into the
proximal large intestine. An in vivo imaging study has been performed in healthy volunteers that
confirms rapid disintegration of the tablet matrix and dispersion of the microparticles.
The absorption rate from the sustained release particulate component of NAPRELAN Tablets is
slower than that for conventional naproxen sodium tablets. It is this prolongation of drug absorption
processes that maintains plasma levels and allows for once daily dosing.
Food Effects
No significant food effects were observed when twenty-four subjects were given a single dose of
NAPRELAN Tablets 500 mg either after an overnight fast or 30 minutes after a meal. In common
with conventional naproxen and naproxen sodium formulations, food causes a slight decrease in the
rate of naproxen absorption following NAPRELAN Tablets administration.
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Distribution
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is greater than
99% albumin-bound. At doses of naproxen greater than 500 mg/day, there is a less than proportional
increase in plasma levels due to an increase in clearance caused by saturation of plasma protein
binding at higher doses. However the concentration of unbound naproxen continues to increase
proportionally to dose. NAPRELAN Tablets exhibit similar dose proportional characteristics.
Elimination
Metabolism
Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites
do not induce metabolizing enzymes.
Excretion
The elimination half-life of NAPRELAN Tablets and conventional naproxen is approximately 15
hours. Steady state conditions are attained after 2-3 doses of NAPRELAN Tablets. Most of the
drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-0-desmethyl
naproxen (less than 1%) and their glucuronide or other conjugates (66-92%). A small amount
(<5%) of the drug is excreted in the feces. The rate of excretion has been found to coincide
closely with the rate of clearance from the plasma. In patients with renal failure, metabolites may
accumulate.
Specific Populations
Pediatric:
No pediatric studies have been performed with NAPRELAN Tablets, thus safety of NAPRELAN
Tablets in pediatric populations has not been established.
Hepatic Impairment:
Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma
proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma
concentration of unbound naproxen is increased. Caution is advised when high doses are
required and some adjustment of dosage may be required in these patients. It is prudent to use
the lowest effective dose.
Renal Impairment:
Naproxen pharmacokinetics have not been determined in subjects with renal insufficiency. Given
that naproxen is metabolized and conjugates are primarily excreted by the kidneys, the potential
exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination
of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products
are not recommended for use in patients with moderate to severe and severe renal impairment
(creatinine clearance <30mL/min) see Warnings and Precautions (5.6)].
Drug Interaction Studies
Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were
reduced, although the clearance of free NSAID was not altered. The clinical significance of this
interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with
aspirin [see Drug Interactions (7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of
8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum
recommended human daily dose of 1500 mg/day based on a body surface area comparison). No
evidence of tumorigenicity was found.
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mutagenesis
Studies to evaluate the mutagenic potential of Naprosyn Suspension have not been completed.
Impairment of Fertility
Studies to evaluate the impact of naproxen on male or female fertility have not been completed.
14 CLINICAL STUDIES
Rheumatoid Arthritis
The use of NAPRELAN Tablets for the management of the signs and symptoms of rheumatoid
arthritis was assessed in a 12 week double-blind, randomized, placebo, and active-controlled study in
348 patients. Two NAPRELAN 500 mg tablets (1000 mg) once daily and naproxen 500 mg tablets
twice daily (1000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at
one week and continued for the duration of the study.
Osteoarthritis
The use of NAPRELAN Tablets for the management of the signs and symptoms of osteoarthritis of
the knee was assessed in a 12 week double-blind, placebo, and active-controlled study in 347
patients. Two NAPRELAN 500 mg tablets (1000 mg) once daily and naproxen 500 mg tablets twice
daily (1000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at one
week and continued for the duration of the study.
Analgesia
The onset of the analgesic effect of NAPRELAN Tablets was seen within 30 minutes in a
pharmacokinetic/pharmacodynamic study of patients with pain following oral surgery. In controlled
clinical trials, naproxen has been used in combination with gold, D-penicillamine, methotrexate, and
corticosteroids. Its use in combination with salicylate is not recommended because there is evidence
that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that
naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition,
as with other NSAIDs the combination may result in higher frequency of adverse events than
demonstrated for either product alone.
Special Studies
In a double-blind randomized, parallel group study, 19 subjects received either two NAPRELAN 500
mg tablets (1000 mg) once daily or naproxen 500 mg tablets (1000 mg) twice daily for 7 days.
Mucosal biopsy scores and endoscopic scores were lower in the subjects who received NAPRELAN
Tablets. In another double-blind, randomized, crossover study, 23 subjects received two
NAPRELAN 500 mg tablets (1000 mg) once daily, naproxen 500 mg tablets (1000 mg) twice daily
and aspirin 650 mg four times daily (2600 mg) for 7 days each. There were significantly fewer
duodenal erosions seen with NAPRELAN Tablets than with either naproxen or aspirin. There were
significantly fewer gastric erosions with both NAPRELAN Tablets and naproxen than with aspirin.
The clinical significance of these findings is unknown
16 HOW SUPPLIED/STORAGE AND HANDLING
NAPRELAN (naproxen sodium) 375 mg, 500 mg, and 750 mg are controlled-release tablets
supplied as:
NAPRELAN 375: white, capsule-shaped tablet with “N” on one side and “375” on the reverse; in
bottles of 100; NDC 52427-272-01. Each tablet contains 412.5 mg naproxen sodium equivalent to
375 mg naproxen.
NAPRELAN 500: white, capsule-shaped tablet with “N” on one side and “500” on the reverse; in
bottles of 75; NDC 52427-273-75. Each tablet contains 550 mg naproxen sodium equivalent to 500
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mg naproxen.
NAPRELAN 750: white, capsule-shaped tablet with “N” on one side and “750” on the reverse; in
bottles of 30; NDC 52427-274-30. Each tablet contains 825 mg naproxen sodium equivalent to 750
mg naproxen
Storage
Store at room temperature, 20° to 25° C (68° to 77° F), excursions permitted 15° to 30° C (59° to
86° F)[see USP Controlled Room Temperature].
PHARMACIST: Dispense in a well-closed container.
.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies
each prescription dispensed. Inform patients, families, or their caregivers of the following
information before initiating therapy with NAPRELAN and periodically during the course of
ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest
pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to
their health care provider immediately [see Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
NAPRELAN, 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. Advise patients to
report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and
hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for
cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI
bleeding [see Warnings and Precautions (5.2)].
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, instruct patients to stop NAPRELAN and seek immediate medical therapy [see
Warnings and Precautions (5.3)].
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of
breath, unexplained weight gain, or edema and to contact their healthcare provider if such
symptoms occur [see Warnings and Precautions (5.5)].
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the
face or throat). Instruct patients to seek immediate emergency help if these occur [see
Contraindications (4) and Warnings and Precautions (5.7)].
Serious Skin Reactions
NAPRELAN, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis,
SJS, and TEN, which may result in hospitalization and even death. Advise patients to stop
NAPRELAN immediately if they develop any type of rash and to contact their healthcare provider
as soon as possible [see Warnings and Precautions (5.9)].
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including
NAPRELAN, may be associated with a reversible delay in ovulation [see Use in Specific Populations
(8.3)].
Fetal Toxicity
Inform pregnant women to avoid use of NAPRELAN and other NSAIDs starting at 30 weeks
gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings
and Precautions (5.10) and Use in Specific Populations (8.1)].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of NAPRELAN with other NSAIDs or salicylates (e.g.,
diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and
little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)].
Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds,
fever, or insomnia.
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with NAPRELAN until they talk to their
healthcare provider [see Drug Interactions (7)].
*Registered Trademark of Alvogen Pharma US, Inc.
**Registered Trademark of Alkermes Pharma Ireland Limited
***Naprosyn® is a registered trademark of Syntex Pharmaceuticals International Limited
To request medical information or to report SUSPECTED ADVERSE REACTIONS, contact
Alvogen, Inc. at 1-866-770-3024 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Manufactured by: Alkermes Pharma Ireland Limited (APIL)
Athlone, Ireland
Distributed by: Almatica Pharma, Inc.
Pine Brook, NJ 07058 USA
PI272-0x
Rev. 5/2016
Reference ID: 3928425
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)
What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment
and may increase:
o with increasing doses of NSAIDs
o with longer use of NSAIDs
Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)."
Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may
have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the
mouth to the stomach), stomach and intestines:
o anytime during use
o without warning symptoms
o that may cause death
The risk of getting an ulcer or bleeding increases with:
O past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
o increasing doses of NSAIDs
o older age
o longer use of NSAIDs
o poor health
o smoking
o advanced liver disease
o drinking alcohol
o bleeding problems
NSAIDs should only be used:
o exactly as prescribed
o at the lowest dose possible for your treatment
o for the shortest time needed
What are NSAIDs?
NSAIDs 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 NSAIDs?
Do not take NSAIDs:
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
right before or after heart bypass surgery.
Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you:
have liver or kidney problems
have high blood pressure
have asthma
are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking
NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.
are breastfeeding or plan to breast feed.
Tell your healthcare provider about all of the medicines you take, including prescription or over-the
counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with
each other and cause serious side effects. Do not start taking any new medicine without talking to your
healthcare provider first.
What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See “What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?
new or worse high blood pressure
heart failure
liver problems including liver failure
kidney problems including kidney failure
low red blood cells (anemia)
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued or Revi
life-threatening skin reactions
life-threatening allergic reactions
Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea,
vomiting, and dizziness.
Get emergency help right away if you get any of the following symptoms:
shortness of breath or trouble breathing
slurred speech
chest pain
swelling of the face or throat
weakness in one part or side of your body
Stop taking your NSAID and call your healthcare provider right away if you get any of the following
symptoms:
nausea
vomit blood
more tired or weaker than usual
there is blood in your bowel movement or
diarrhea
it is black and sticky like tar
itching
unusual weight gain
your skin or eyes look yellow
skin rash or blisters with fever
indigestion or stomach pain
swelling of the arms, legs, hands and
flu-like symptoms
feet
If you take too much of your NSAID, call your healthcare provider or get medical help right away.
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or
pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Other information about NSAIDs
Aspirin is an NSAID 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 NSAIDs 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.
General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the
same symptoms that you have. It may harm them.
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist
or healthcare provider for information about NSAIDs that is written for health professionals.
Manufactured by: Alkermes Pharma Ireland Limited, Athlone, Ireland
Distributed by: Almatica Pharma, Inc., Pine Brook, NJ 07058 USA
For more information, call 1-866-770-3024
This Medication Guide has been approved by the U.S. Food and Drug Administration.
PL272-0x
Rev. 05/2016
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3928425
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:30.188173
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020353s031s032lbl.pdf', 'application_number': 20353, 'submission_type': 'SUPPL ', 'submission_number': 32}
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CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 1
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
Stimate®
(desmopressin acetate)
Nasal Spray, 1.5 mg/mL
Rx only
DESCRIPTION
Stimate® (desmopressin acetate) is a synthetic analogue of the natural pituitary hormone 8-
arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation.
Stimate® Nasal Spray contains 1.5 mg/mL desmopressin acetate in an aqueous solution at a pH
of approximately 5.0.
Stimate® Nasal Spray's compression pump delivers 0.1 mL (150 mcg) of solution per spray. It
is chemically defined as follows:
Mol. Wt. 1183.34 Empirical formula: C46H64N14O12S2 •C2H4O2•3H2O
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
Stimate® Nasal Spray is provided as an aqueous solution for intranasal use.
Each mL contains:
Active ingredient:
Desmopressin acetate
1.5 mg
Inactive ingredients:
Sodium chloride
7.5 mg
Buffer:
Citric acid monohydrate
1.7 mg
Disodium phosphate dihydrate
3.0 mg
Preservative:
Benzalkonium chloride
0.1 mg
Purified water
To 1 mL
CLINICAL PHARMACOLOGY
Stimate® Nasal Spray contains as active substance, desmopressin acetate, which is a synthetic
analogue of the natural hormone arginine vasopressin. One spray or 0.1 mL (150 mcg) of
Stimate® Nasal Spray solution has an antidiuretic activity of about 600 IU.
Desmopressin acetate has been shown to be more potent than arginine vasopressin in increasing
plasma levels of Factor VIII activity in patients with hemophilia and von Willebrand's disease
Type I.
PHARMACIST
TEAR HERE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 2
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
Dose-response studies were performed in healthy persons using doses of 150 to 450 mcg,
administered as one to three sprays. The response to Stimate® Nasal Spray is dose-related, with
maximal plasma levels of 150 to 250 percent of initial concentrations achieved for both Factor
VIII and von Willebrand factor.1 The increase is rapid and evident within 30 minutes, reaching a
maximum at about 1.5 hours.1
The percentage increase of Factor VIII and von Willebrand factor levels in patients with mild
hemophilia A and von Willebrand's disease was not notably different from that observed in
normal healthy individuals when treated with 300 mcg of Stimate® Nasal Spray.1-4 In patients
with von Willebrand's disease, levels of Factor VIII coagulant activity and von Willebrand factor
antigen remained greater than 30 U/dL for 8 hours after a 300 mcg dose of Stimate® Nasal
Spray.5 After 300 mcg of Stimate® Nasal Spray, the percentage increase of Factor VIII and von
Willebrand factor levels in patients with mild hemophilia A and von Willebrand's disease was
less than observed after 0.3 mcg/kg of intravenous desmopressin acetate.2-4
Plasminogen activator activity increases rapidly after intravenous desmopressin acetate infusion,
but there has been no clinically significant fibrinolysis in patients treated with desmopressin
acetate.
The effect of repeated intravenous desmopressin acetate administration when doses were given
every 12 to 24 hours has generally shown a diminution of the Factor VIII activity increase noted
after a single dose. It is possible to reproduce the initial response in some patients after an
interval of one week, but other patients may require as long as 6 weeks.2,4,6
The half-life of Stimate® Nasal Spray was between 3.3 and 3.5 hours, over the range of
intranasal doses, 150 to 450 mcg.1 Plasma concentrations of Stimate® Nasal Spray were
maximal approximately 40 to 45 minutes after dosing.1
The bioavailability of Stimate® Nasal Spray when administered by the intranasal route as a 1.5
mg/mL solution is between 3.3 and 4.1 percent.1
The change in structure of arginine vasopressin to desmopressin acetate has resulted in a
decreased vasopressor action and decreased actions on visceral smooth muscle relative to the
enhanced antidiuretic activity, so that clinically effective antidiuretic doses are usually below
threshold levels for effects on vascular or visceral smooth muscle.
INDICATIONS AND USAGE
Before the initial therapeutic administration of Stimate® Nasal Spray, the physician should
establish that the patient shows an appropriate change in the coagulation profile following a test
dose of intranasal administration of Stimate® Nasal Spray.2-4
Desmopressin acetate is also available as a solution for injection (DDAVP® Injection) when the
intranasal route may be compromised. These situations include nasal congestion and blockage,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 3
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may
also be inappropriate where there is an impaired level of consciousness.
Hemophilia A
Stimate® Nasal Spray is indicated for patients with hemophilia A with Factor VIII coagulant
activity levels greater than 5%.
Desmopressin acetate will also stop bleeding in patients with hemophilia A with episodes of
spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas or
mucosal bleeding.2,3
In the outpatient setting during two clinical trials where patients recorded bleeding episodes,
Stimate® Nasal Spray provided effective hemostasis 100% of the time in 2 of the 5 patients. For
those patients not responding in 100% of bleeding occasions, 45% (14 of 31) of bleeding
episodes were effectively controlled with Stimate® Nasal Spray.
Desmopressin acetate is not indicated for the treatment of hemophilia A with Factor VIII
coagulant activity levels equal to or less than 5%, or for the treatment of hemophilia B, or in
patients who have Factor VIII antibodies.
von Willebrand's Disease (Type I)
Stimate® Nasal Spray is indicated for patients with mild to moderate classic von Willebrand's
disease (Type I) with Factor VIII levels greater than 5%.
Desmopressin acetate will also stop bleeding in mild to moderate von Willebrand's disease
patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses,
intramuscular hematomas, mucosal bleeding or menorrhagia.2,3
In the outpatient setting during two clinical trials where patients recorded bleeding episodes,
Stimate® Nasal Spray provided effective hemostasis 100% of the time in 75% of the patients
(n=16). For those patients not responding in 100% of bleeding occasions, 78% (64 of 82) of
bleeding episodes were effectively controlled with Stimate® Nasal Spray.
Patients may respond in a variable fashion depending on the type of molecular defect they have.
Bleeding time and Factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand
factor antigen should be checked after initial administration of Stimate® Nasal Spray to ensure
that adequate levels have been achieved.
Stimate® Nasal Spray is not indicated for the treatment of severe classic von Willebrand's
disease (Type I) and when there is evidence of an abnormal molecular form of Factor VIII
antigen. See WARNINGS.
CONTRAINDICATIONS
Stimate® Nasal Spray is contraindicated in individuals with known hypersensitivity to
desmopressin acetate or to any of the components of Stimate® Nasal Spray.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 4
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
WARNINGS
For intranasal use only.
Patients who do not have need of antidiuretic hormone for its antidiuretic effect, in particular
those who are young or elderly, should be cautioned to ingest only enough fluid to satisfy thirst,
in order to decrease the potential occurrence of water intoxication and hyponatremia.
Fluid intake should be adjusted downward, particularly in very young and elderly patients, in
order to decrease the potential occurrence of water intoxication and hyponatremia.1
Particular attention should be paid to the possibility of the rare occurrence of an extreme
decrease in plasma osmolality that may result in seizures which could lead to coma.
Stimate® Nasal Spray should not be used to treat patients with Type IIB von Willebrand's
disease since platelet aggregation may be induced.
PRECAUTIONS
General
Desmopressin acetate has infrequently produced changes in blood pressure causing either a slight
elevation in blood pressure or a transient fall in blood pressure and a compensatory increase in
heart rate. The drug should be used with caution in patients with coronary artery insufficiency
and/or hypertensive cardiovascular disease.
Stimate® Nasal Spray should be used with caution in patients with conditions associated with
fluid and electrolyte imbalance, such as cystic fibrosis, because these patients are prone to
hyponatremia.
There have been rare reports of thrombotic events (thrombosis7, acute cerebrovascular
thrombosis, acute myocardial infarction) following desmopressin acetate injection in patients
predisposed to thrombus formation. No causality has been determined; however, the drug should
be used with caution in these patients.
Severe allergic reactions have been reported rarely.2,8-10 Fatal anaphylaxis has been reported in
one patient who received intravenous DDAVP® (desmopressin acetate). It is not known whether
antibodies to desmopressin acetate are produced after repeated administration.
Since Stimate® Nasal Spray is used intranasally, changes in the nasal mucosa such as scarring,
edema, or other disease may cause erratic, unreliable absorption in which case Stimate® Nasal
Spray should be discontinued until the nasal problems resolve. For such situations, DDAVP®
Injection should be considered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 5
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
Information for Patients
Patients should be informed that the bottle accurately delivers 25 doses of 150 mcg each. Any
solution remaining after 25 doses should be discarded since the amount delivered thereafter may
be substantially less than 150 mcg of drug. No attempt should be made to transfer remaining
solution to another bottle. Patients should be instructed to read accompanying directions on use
of the spray pump carefully before use.
Patients should also be advised that if bleeding is not controlled, the physician should be
contacted.2,3
Hemophilia A
Laboratory tests for assessing patient status include levels of Factor VIII coagulant, Factor VIII
antigen and Factor VIII ristocetin cofactor (von Willebrand factor) as well as activated partial
thromboplastin time. Factor VIII coagulant activity should be determined before giving
Stimate® Nasal Spray for hemostasis. If Factor VIII coagulant activity is present at less than 5%
of normal, Stimate® Nasal Spray should not be relied on.
von Willebrand's Disease
Laboratory tests for assessing patient status include levels of Factor VIII coagulant activity,
Factor VIII ristocetin cofactor activity, and Factor VIII von Willebrand factor antigen. The skin
bleeding time may be helpful in following these patients.
Drug Interactions
Although the pressor activity of desmopressin acetate is very low, its use with other pressor
agents should be done only with careful patient monitoring.
DDAVP® Injection has been used with epsilon aminocaproic acid without adverse effects.
Carcinogenicity, Mutagenicity, Impairment of Fertility
There have been no long-term studies in animals to assess the carcinogenic, mutagenic or
impairment of fertility potential of Stimate® Nasal Spray.
Pregnancy Category B
Reproduction studies performed in rats and rabbits by the subcutaneous route at doses up to 10
mcg/kg/day have revealed no evidence of harm to the fetus due to desmopressin acetate. This
dose is equivalent to 10 times (for Factor VIII stimulation) or 38 times (for diabetes insipidus)
the systemic human dose based on a mg/M2 surface area.
There are no adequate and well-controlled studies in pregnant women. Several publications of
desmopressin acetate's use in the management of diabetes insipidus during pregnancy are
available; these include a few anecdotal reports of congenital anomalies and low birth weight
babies. However, no causal connection between these events and desmopressin acetate has been
established. A 15-year, Swedish epidemiologic study of the use of desmopressin acetate in
pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 6
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
in the general population. As opposed to preparations containing natural hormones,
desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to
weigh the therapeutic advantages against the possible risks in each case.
Nursing Mothers
There have been no controlled studies in nursing mothers. A single study in postpartum women
demonstrated a marked change in plasma, but little if any change in assayable DDAVP® in breast
milk following an intranasal dose of 10 mcg. 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
Stimate® Nasal Spray is administered to a nursing woman.
Pediatric Use
Use in infants and children will require careful fluid intake restriction to prevent possible
hyponatremia and water intoxication. Stimate® Nasal Spray should not be used in infants
younger than 11 months in the treatment of hemophilia A or von Willebrand's disease; safety and
effectiveness in children between 11 months and 12 years of age has been demonstrated.2-4
Geriatric Use
Clinical studies of Stimate® did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently than younger subjects. However, other post-
marketing experience has reported the occurrence of hyponatremia with the use of desmopressin
acetate and fluid overload.
Therefore, in elderly patients fluid intake should be adjusted downward in an effort to decrease
the potential occurrence of water intoxication and hyponatremia. Particular attention should be
paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that
may result in seizures, which could lead to coma.
Patients who do not have need of antidiuretic hormone for its antidiuretic effect should be
cautioned to ingest only enough fluid to satisfy thirst, in an effort to decrease the potential
occurrence of water intoxication and hyponatremia.
As for all patients, dosing for geriatric patients should be appropriate to their overall situation.
ADVERSE REACTIONS
Infrequently, DDAVP® Injection has produced transient headache, nausea, mild abdominal
cramps and vulval pain. These symptoms disappeared with reduction in dosage. Occasional
facial flushing has been reported with the administration of DDAVP® Injection. Infrequently,
high doses of intranasal DDAVP® have produced transient headache and nausea. Nasal
congestion, rhinitis and flushing have also been reported occasionally along with mild abdominal
cramps. These symptoms disappeared with reduction in dosage. Nosebleed, sore throat, cough
and upper respiratory infections have also been reported.
In addition to those listed above, the following have also been reported in clinical trials with
Stimate® Nasal Spray: Somnolence, dizziness, itchy or light-sensitive eyes, insomnia, chills,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 7
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
warm feeling, pain, chest pain, palpitations, tachycardia, dyspepsia, edema, vomiting, agitation
and balanitis.1-4
DDAVP® Injection (desmopressin acetate) has infrequently produced changes in blood pressure
causing either a slight elevation or a transient fall and a compensatory increase in heart rate.
Severe allergic reactions including anaphylaxis have been reported rarely with DDAVP®
Injection.
See WARNINGS for the possibility of water intoxication, hyponatremia and coma.11
OVERDOSAGE
See ADVERSE REACTIONS above. In cases of overdosage, the dosage should be reduced,
frequency of administration decreased, or the drug withdrawn according to the severity of the
condition.
There is no known specific antidote for desmopressin acetate or Stimate® Nasal Spray.
An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no
effect.
DOSAGE AND ADMINISTRATION
Hemophilia A and von Willebrand's Disease (Type I)
Stimate® Nasal Spray is administered by nasal insufflation, one spray per nostril, to provide a
total dose of 300 mcg. In patients weighing less than 50 kg, 150 mcg administered as a single
spray provided the expected effect on Factor VIII coagulant activity, Factor VIII ristocetin
cofactor activity and skin bleeding time.3-4 If Stimate® Nasal Spray is used preoperatively, it
should be administered 2 hours prior to the scheduled procedure.12,13
The necessity for repeat administration of Stimate® Nasal Spray or use of any blood products
for hemostasis should be determined by laboratory response as well as the clinical condition of
the patient. The tendency toward tachyphylaxis (lessening of response) with repeated
administration given more frequently than every 48 hours should be considered in treating each
patient.
The nasal spray pump can only deliver doses of 0.1 mL (150 mcg) or multiples of 0.1 mL. If
doses other than these are required, DDAVP® Injection may be used.
The spray pump must be primed prior to the first use. To prime pump, press down 4 times. The
bottle should be discarded after 25 doses since the amount delivered thereafter per spray may be
substantially less than 150 mcg of drug.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 8
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
HOW SUPPLIED
A 2.5 mL bottle with spray pump capable of delivering 25 doses of 150 mcg (NDC 0053-2453-
00).
Store at room temperature not to exceed 25°C (77°F) for the period indicated by the expiration
date on the label. Discard six months after being opened. Store bottle in upright position.
Revised July 2007
IN-8155-06
Manufactured for:
CSL Behring LLC
King of Prussia, PA 19406-0901
US License No. 1767
By:
Ferring AB
Limhamn, Sweden
REFERENCES
1. RHÔNE-POULENC RORER STUDY RG-83884-141:An Open-Label Pharmacokinetic
Comparison of Desmopressin Acetate Administration by Intranasal (1.5 mg/mL) and
Intravenous Routes: A Dose-Proportionality Trial.
2. RHÔNE-POULENC
RORER
STUDY
RG-83884-142:Nasal
Spray
Desmopressin
(DDAVP). A simple Technique for Treatment of Mild Hemophilia A and von Willebrand's
disease.
3. RHÔNE-POULENC RORER STUDY RG-83884-143:Intranasal Desmopressin (DDAVP)
by spray in Mild Hemophilia A and von Willebrand's disease Type I.
4. RHÔNE-POULENC RORER STUDY RG-83884-144:Evaluation of Intranasal Spray
DDAVP in Patients with Mild or Moderate Hemophilia A or von Willebrand's disease:
Inpatient Trial.
5. Lethagen S, Harris AS and Nilsson IM: Intranasal desmopressin (DDAVP) by spray in mild
hemophilia A and von Willebrand's disease type I. Blut, 60:187-191, 1990.
6. Lethagen S, Harris AS, Sjörin E and Nilsson IM: Intranasal and intravenous administration
of desmopressin: Effect on FVIII/vWF, pharmacokinetics and reproducibility. Thromb.
Haemost., 58:1033-1036, 1987.
7. Viron B, Michel C, Serrato T and Verdy E: Risque thrombogène du D.D.A.V.P. dans
l'insuffisance rénale chronique (Thrombogenic risk of DDAVP in chronic renal failure).
Néphrologie, 8:225, 1987.
8. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
REPORT No. 01-000657; Anaphylaxis, etc.
9. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
REPORT No. 01-001182; Anaphylactoid reaction.
10. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
REPORT No. US-870671; Erythema, rash.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 9
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
11. RHÔNE-POULENC RORER PHARMACEUTICALS INC. ADVERSE REACTION
REPORT No. 01-003827; Coma, grand mal seizure, etc.
12. Chistolini A, Dragoni F, Ferrari A, La Verde G, Arcieri R, Mohamud AE and Mazzucconi
MG: Intranasal DDAVP: Biological and clinical evaluation in mild Factor VIII deficiency.
Haemostasis, 21:273-277, 1991.
13. Rose EH and Aledort LM: Nasal spray desmopressin (DDAVP) for mild hemophilia A and
von Willebrand's disease. Ann. Int. Med., 114:563-568, 1991.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 10
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
14.
IN-8155-06
PATIENT INSTRUCTION GUIDE
Stimate®
(desmopressin acetate)
Nasal Spray, 1.5 mg/mL
A better way to deliver
desmopressin acetate
Delivering desmopressin acetate more efficiently
Your doctor has prescribed Stimate® Nasal Spray for the treatment of mild hemophilia A or
mild to moderate von Willebrand’s disease (Type 1). Follow the dosage schedule that is
specified. The convenient nasal spray pump provides an efficient, reliable way to administer
your medication. It is important, however, to adhere completely to the following instructions so
that you will always receive a consistent dose of your medication.
CAUTION: The nasal spray pump accurately delivers 25 doses of 150 micrograms per spray.
Any solution remaining after 25 sprays should be discarded since the amount delivered thereafter
per spray may be substantially less than 150 micrograms of drug. Do not transfer any remaining
solution to another bottle. Please read the following instructions carefully before using the spray
pump.
Using your Stimate® Nasal Spray Pump
1. Remove protective cap.
2. When using for the first time, the spray pump must be primed by pressing down 4
times.
3. Once primed, the spray pump delivers 150 micrograms of medication each time it is pressed.
To ensure dosing accuracy, tilt bottle so that dip tube inside the bottle draws from the deepest
portion of the medication.
PHARMACIST
TEAR HERE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 11
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
To administer a 150-microgram dose, place the spray nozzle in nostril and press the spray pump
once. If a 300-microgram dose has been prescribed, spray once in each nostril. The spray pump
cannot be used for doses less than 150 micrograms or doses other than multiples of 150
micrograms.
4. Replace the protective cap on bottle after use, and store at room temperature not to exceed
25°C (77°F). If the product has not been used for a period of one week, re-prime the pump by
pressing once.
5. We have included a convenient check-off chart to assist you in keeping track of medication
sprays used. This will help assure that you receive 25 “full sprays” of medication. Please note
that the bottle has been filled with extra solution to accommodate the priming activity. When
checking off sprays used, do not include the priming sprays.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CSL Behring
Stimate®
US Package Insert
(desmopressin acetate)
Revised: July 2007
Page 12
GRDC\RALABELING\COAGULATION\STIMATE\USA\PACKAGE INSERT, BLANK [80123ab1]\REV. 07/2007-RESPONSE TO CDER REQUEST DATED
20JUN07 and COMBINED ROOM TEMPERATURE STORAGE AND CSL NAME CHANGE
VERSION 7.0
Stimate ®
(desmopressin acetate)
Nasal Spray, 1.5 mg/mL
25-Spray Check-off
1. Retain with medication or affix in convenient location.
2. Starting with spray #1, check off after each administration. If your doctor has prescribed a 2-
spray dose (300-micrograms), two sprays must be checked off.
3. Discard medication after 25 sprays.
Store at room temperature not to exceed 25°C (77°F) for the period indicated by the expiration
date on the label. Discard six months after being opened. Store bottle in upright position.
Manufactured for:
CSL Behring LLC
King of Prussia, PA 19406-0901
US License No. 1767
By:
Ferring AB
Limhamn, Sweden
Revised July 2007
IN-8155-06
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.5 mL
CSL Behring LLC
CR-8151-04
CR-8151-04-PR4 MS
Black
PMS Cyan
PMS 185 Red
Dieline
2.5 mL
2.5 mL
2.5 mL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Discard six months after being opened.
PRINT SCALE 80%
CSL Behring LLC
L-8152-04
L-8152-04-PR3 MS
PMS Cyan
Black
Dieline
Varnish
X
100%
200%
FPO
CSL Behring LLC
L-8152-04
X
FPO
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Discard six months after being opened.
CSL Behring LLC
L-8156-04-PR3 MS
PMS Cyan
Black
Dieline
L-8156-04
x
CSL Behring LLC
L-8156-04
x
200%
100%
FPO
FPO
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Discard six months after being opened.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Discard six months after being opened.
|
custom-source
|
2025-02-12T13:47:30.278809
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020355s007lbl.pdf', 'application_number': 20355, 'submission_type': 'SUPPL ', 'submission_number': 7}
|
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Attachment 1
Page 1
Class Suicidality Labeling Language for Antidepressants
[This section should be located at the beginning of the package insert with bolded font and
enclosed in a black box]
[Insert established name]
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of [Insert established name] or any other
antidepressant in a child or adolescent must balance this risk with the clinical need. Patients
who are started on therapy should be observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. [Insert established name] is not approved
for use in pediatric patients. (See Warnings and Precautions: Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs
(SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive
compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over
4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or
behavior (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%,
twice the placebo risk of 2%. No suicides occurred in these trials.
[This section should be located under WARNINGS. Please note that the title of this
section should be bolded, and it should be the first paragraph in this section.]
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. There has been a long-standing concern that antidepressants
may have a role in inducing worsening of depression and the emergence of suicidality in certain
patients. A causal role for antidepressants in inducing suicidality has been established in pediatric
patients.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in
children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving
over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or
thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
There was considerable variation in risk among drugs, but a tendency toward an increase for almost
all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there
were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive
disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is
unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond
several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes, either increases or
decreases. Such observation would generally include at least weekly face-to-face contact with
patients or their family members or caregivers during the first 4 weeks of treatment, then every
other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12
weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and suicidality,
especially during the initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being treated with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between
the emergence of such symptoms and either the worsening of depression and/or the emergence of
suicidal impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted
about the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality, and
to report such symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for [Insert established name] should be
written for the smallest quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose. Families and caregivers of adults being treated for depression should be similarly
advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled trials) that treating
such an episode with an antidepressant alone may increase the likelihood of precipitation of a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 3
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described
above represent such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a
family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established
name] is not approved for use in treating bipolar depression.
[This section should be located under PRECAUTIONS, Information for Patients.]
Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with [Insert established name] and should
counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in
Children and Adolescents is available for [Insert established name]. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide
and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur
while taking [Insert established name].
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other
unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during
antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients
should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes
may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior
and indicate a need for very close monitoring and possibly changes in the medication.
[This section should be located under PRECAUTIONS, Pediatric Use.]
Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX
WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of
[Insert established name] in a child or adolescent must balance the potential risks with the clinical
need.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 1
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal
thoughts and actions can also be caused by depression, a serious medical condition that is commonly
treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called
suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with depression or
other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to
4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar
pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became
suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or
his moods or actions, especially if the changes occur suddenly. Other important people in your child's
life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other
important people). The changes to look out for are listed in Section 3, on what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see other side)
You should call your child's healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child's healthcare provider right away if your child exhibits any of the following signs for
the first time, or if they seem worse, or worry you, your child, or your child's teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without first talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can
lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal
thinking or actions. It is important to discuss all the risks of treating depression and also the risks of
not treating it. You and your child should discuss all treatment choices with your healthcare provider,
not just the use of antidepressants.
Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric
depression.
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) .
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 3
Your healthcare provider may suggest other antidepressants based on the past experience of your child
or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants.
Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is
prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare
provider or pharmacist where to find more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:30.387636
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/18644s030,20358s034,21515s009,20711s021lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
12,468
|
PRODUCT INFORMATION
1
WELLBUTRIN SR®
2
(bupropion hydrochloride)
3
Sustained-Release Tablets
4
5
“Information for the Patient” enclosed.
6
7
DESCRIPTION: WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the
8
aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake
9
inhibitor, or other known antidepressant agents. Its structure closely resembles that of
10
diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-
11
[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The
12
molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline,
13
and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on
14
the oral mucosa. The structural formula is:
15
16
17
18
WELLBUTRIN SR Tablets are supplied for oral administration as 100-mg (blue), 150-mg
19
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
20
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
21
hydrochloride, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose,
22
polyethylene glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In
23
addition, the 100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C
24
Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40
25
Lake.
26
27
CLINICAL PHARMACOLOGY:
28
Pharmacodynamics: Bupropion is a relatively weak inhibitor of the neuronal uptake of
29
norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. While the
30
mechanism of action of bupropion, as with other antidepressants, is unknown, it is presumed that
31
this action is mediated by noradrenergic and/or dopaminergic mechanisms.
32
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and
33
pharmacokinetics of the individual enantiomers have not been studied.
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
2
Following oral administration of WELLBUTRIN SR Tablets to healthy volunteers, peak plasma
35
concentrations of bupropion are achieved within 3 hours. Food increased Cmax and AUC of
36
bupropion by 11% and 17%, respectively, indicating that there is no clinically significant food
37
effect.
38
In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up
39
to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that
40
for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is
41
about half that seen with bupropion.
42
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the
43
radioactive dose were recovered in the urine and feces, respectively. The fraction of the oral dose
44
of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive
45
metabolism of bupropion.
46
The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and
47
steady-state plasma concentrations of bupropion are reached within 8 days.
48
Bupropion is extensively metabolized in humans. Three metabolites have been shown to be
49
active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion,
50
and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are
51
formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome P450IIB6
52
(CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion, while
53
cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion. Oxidation
54
of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic
55
acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the
56
metabolites relative to bupropion have not been fully characterized. Nevertheless, they may be
57
clinically important because their plasma concentrations are higher than those of bupropion.
58
Because bupropion is extensively metabolized, there is the potential for drug-drug interactions,
59
particularly with those agents that are metabolized by the cytochrome P450IIB6 (CYP2B6)
60
isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is
61
the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized
62
by this isoenzyme (see PRECAUTIONS: Drug Interactions).
63
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
64
approximately 6 hours after administration of WELLBUTRIN SR Tablets. Peak plasma
65
concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug
66
at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and
67
its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for
68
the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
69
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37
70
(±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
71
respectively.
72
In a study comparing chronic dosing with WELLBUTRIN SR Tablets 150 mg twice daily to the
73
immediate-release formulation of bupropion at 100 mg three times daily, peak plasma
74
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
3
concentrations of bupropion at steady state for WELLBUTRIN SR Tablets were approximately
75
85% of those achieved with the immediate-release formulation. There was equivalence for
76
bupropion AUCs, as well as equivalence for both peak plasma concentration and AUCs for all
77
three of the detectable bupropion metabolites. Thus, at steady state, WELLBUTRIN SR Tablets,
78
given twice daily, and the immediate-release formulation of bupropion, given three times daily,
79
are essentially bioequivalent for both bupropion and the three quantitatively important metabolites.
80
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to
81
450 mg/day.
82
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
83
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be
84
expected to influence the degree and extent of accumulation of the active metabolites of bupropion.
85
The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic
86
function because they are moderately polar compounds and are likely to undergo further
87
metabolism or conjugation in the liver prior to urinary excretion.
88
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
89
characterized in two single-dose studies, one in patients with alcoholic liver disease and one in
90
patients with mild to severe cirrhosis. The first study showed that the half-life of
91
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in 8
92
healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically
93
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
94
greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for
95
bupropion and the other metabolites in the two patient groups were minimal.
96
The second study showed that there were no statistically significant differences in the
97
pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate
98
hepatic cirrhosis compared to 8 healthy volunteers. There was, however, more variability
99
observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its
100
active metabolites (t½) in patients with mild to moderate hepatic cirrhosis. In addition, in patients
101
with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean
102
difference: by approximately 70% and 3-fold, respectively) and more variable when compared to
103
values in healthy volunteers; the mean bupropion half-life was also longer (by approximately
104
40%). For the metabolites, the mean Cmax was lower (by approximately 30% to 70%), the mean
105
AUC tended to be higher (by approximately 30% to 50%), the median Tmax was later (by
106
approximately 20 hours), and the mean half-lives were longer (by approximately 2- to 4-fold) in
107
patients with severe hepatic cirrhosis than in healthy volunteers (see WARNINGS,
108
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
109
Renal: The effect of renal disease on the pharmacokinetics of bupropion has not been studied.
110
The elimination of the major metabolites of bupropion may be affected by reduced renal function.
111
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in 14
112
depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray),
113
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
4
no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared to healthy
114
normal volunteers, was revealed.
115
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
116
been fully characterized, but an exploration of steady-state bupropion concentrations from several
117
depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three
118
times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
119
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition
120
of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These
121
data suggest there is no prominent effect of age on bupropion concentration; however, another
122
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
123
risk for accumulation of bupropion and its metabolites (see PRECAUTIONS: Geriatric Use).
124
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
125
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
126
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied
127
in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were
128
nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no
129
statistically significant difference in Cmax, half-life, tmax, AUC, or clearance of bupropion or its
130
active metabolites between smokers and nonsmokers.
131
132
CLINICAL TRIALS: The efficacy of the immediate-release formulation of bupropion as a
133
treatment for depression was established in two 4-week, placebo-controlled trials in adult
134
inpatients with depression and in one 6-week, placebo-controlled trial in adult outpatients with
135
depression. In the first study, patients were titrated in a bupropion dose range of 300 to
136
600 mg/day on a three times daily schedule; 78% of patients received maximum doses of
137
450 mg/day or less. This trial demonstrated the effectiveness of the immediate-release formulation
138
of bupropion on the Hamilton Depression Rating Scale (HDRS) total score, the depressed mood
139
item (item 1) from that scale, and the Clinical Global Impressions (CGI) severity score. A second
140
study included two fixed doses of the immediate-release formulation of bupropion (300 and
141
450 mg/day) and placebo. This trial demonstrated the effectiveness of the immediate-release
142
formulation of bupropion, but only at the 450-mg/day dose; the results were positive for the HDRS
143
total score and the CGI severity score, but not for HDRS item 1. In the third study, outpatients
144
received 300 mg/day of the immediate-release formulation of bupropion. This study demonstrated
145
the effectiveness of the immediate-release formulation of bupropion on the HDRS total score,
146
HDRS item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the
147
CGI improvement score.
148
Although there are not as yet independent trials demonstrating the antidepressant effectiveness
149
of the sustained-release formulation of bupropion, studies have demonstrated the bioequivalence
150
of the immediate-release and sustained-release forms of bupropion under steady-state conditions,
151
i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg
152
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
5
three times daily of the immediate-release formulation of bupropion, with regard to both rate and
153
extent of absorption, for parent drug and metabolites.
154
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder,
155
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
156
twice daily) were randomized to continuation of their same WELLBUTRIN SR dose or placebo,
157
for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI
158
Improvement score of 1 (very much improved) or 2 (much improved) for each of the final three
159
weeks. Relapse during the double-blind phase was defined as the investigator’s judgement that
160
drug treatment was needed for worsening depressive symptoms. Patients receiving continued
161
WELLBUTRIN SR treatment experienced significantly lower relapse rates over the subsequent
162
44 weeks compared to those receiving placebo.
163
164
INDICATIONS AND USAGE: WELLBUTRIN SR is indicated for the treatment of depression.
165
The efficacy of bupropion in the treatment of depression was established in two 4-week
166
controlled trials of depressed inpatients and in one 6-week controlled trial of depressed
167
outpatients whose diagnoses corresponded most closely to the Major Depression category of the
168
APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY).
169
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of
170
interest or pleasure; in addition, at least five of the following symptoms have been present during
171
the same 2-week period and represent a change from previous functioning: depressed mood,
172
markedly diminished interest or pleasure in usual activities, significant change in weight and/or
173
appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue,
174
feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or
175
suicidal ideation.
176
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
177
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
178
(see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use
179
WELLBUTRIN SR for extended periods should periodically reevaluate the long-term usefulness
180
of the drug for the individual patient.
181
182
CONTRAINDICATIONS: WELLBUTRIN SR is contraindicated in patients with a seizure
183
disorder.
184
WELLBUTRIN SR is contraindicated in patients treated with ZYBAN® (bupropion
185
hydrochloride) Sustained-Release Tablets, or any other medications that contain bupropion
186
because the incidence of seizure is dose dependent.
187
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia or
188
anorexia nervosa because of a higher incidence of seizures noted in patients treated for bulimia
189
with the immediate-release formulation of bupropion.
190
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
6
The concurrent administration of WELLBUTRIN SR Tablets and a monoamine oxidase (MAO)
191
inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO
192
inhibitor and initiation of treatment with WELLBUTRIN SR Tablets.
193
WELLBUTRIN SR is contraindicated in patients who have shown an allergic response to
194
bupropion or the other ingredients that make up WELLBUTRIN SR Tablets.
195
196
WARNINGS: Patients should be made aware that WELLBUTRIN SR contains the same
197
active ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that
198
WELLBUTRIN SR should not be used in combination with ZYBAN, or any other medications
199
that contain bupropion.
200
Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures is
201
also related to patient factors, clinical situations, and concomitant medications, which must be
202
considered in selection of patients for therapy with WELLBUTRIN SR. WELLBUTRIN SR
203
should be discontinued and not restarted in patients who experience a seizure while on
204
treatment.
205
• Dose: At doses of WELLBUTRIN SR up to a dose of 300 mg/day, the incidence of
206
seizure is approximately 0.1% (1/1000) and increases to approximately 0.4% (4/1000) at
207
the maximum recommended dose of 400 mg/day.
208
Data for the immediate-release formulation of bupropion revealed a seizure incidence
209
of approximately 0.4% (i.e., 13 of 3200 patients followed prospectively) in patients
210
treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of this dose
211
range is close to the currently recommended maximum dose of 400 mg/day for
212
WELLBUTRIN SR Tablets. This seizure incidence (0.4%) may exceed that of other
213
marketed antidepressants and WELLBUTRIN SR Tablets up to 300 mg/day by as much
214
as fourfold. This relative risk is only an approximate estimate because no direct
215
comparative studies have been conducted.
216
Additional data accumulated for the immediate-release formulation of bupropion
217
suggested that the estimated seizure incidence increases almost tenfold between 450 and
218
600 mg/day, which is twice the usual adult dose and one and one-half the maximum
219
recommended daily dose (400 mg) of WELLBUTRIN SR Tablets. This disproportionate
220
increase in seizure incidence with dose incrementation calls for caution in dosing.
221
Data for WELLBUTRIN SR Tablets revealed a seizure incidence of approximately
222
0.1% (i.e., 3 of 3100 patients followed prospectively) in patients treated at doses in a
223
range of 100 to 300 mg/day. It is not possible to know if the lower seizure incidence
224
observed in this study involving the sustained-release formulation of bupropion resulted
225
from the different formulation or the lower dose used. However, as noted above, the
226
immediate-release and sustained-release formulations are bioequivalent with regard to
227
both rate and extent of absorption during steady state (the most pertinent condition to
228
estimating seizure incidence), since most observed seizures occur under steady-state
229
conditions.
230
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
7
• Patient factors: Predisposing factors that may increase the risk of seizure with bupropion
231
use include history of head trauma or prior seizure, central nervous system (CNS) tumor,
232
the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure
233
threshold.
234
• Clinical situations: Circumstances associated with an increased seizure risk include,
235
among others, excessive use of alcohol; abrupt withdrawal from alcohol or other
236
sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants
237
and anorectics; and diabetes treated with oral hypoglycemics or insulin.
238
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
239
theophylline, systemic steroids) and treatment regimens (e.g., abrupt discontinuation of
240
benzodiazepines) are known to lower seizure threshold.
241
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
242
clinical experience gained during the development of bupropion suggests that the risk of
243
seizure may be minimized if
244
• the total daily dose of WELLBUTRIN SR Tablets does not exceed 400 mg,
245
• the daily dose is administered twice daily, and
246
• the rate of incrementation of dose is gradual.
247
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion
248
and/or its metabolites.
249
WELLBUTRIN SR should be administered with extreme caution to patients with a
250
history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients
251
treated with other agents (e.g., antipsychotics, other antidepressants, theophylline,
252
systemic steroids, etc.) or treatment regimens (e.g., abrupt discontinuation of a
253
benzodiazepine) that lower seizure threshold.
254
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
255
with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,
256
as peak bupropion levels are substantially increased and accumulation is likely to occur in
257
such patients to a greater extent than usual. The dose should not exceed 100 mg every day or
258
150 mg every other day in these patients (see CLINICAL PHARMACOLOGY,
259
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
260
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was
261
an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs
262
receiving large doses of bupropion chronically, various histologic changes were seen in the liver,
263
and laboratory tests suggesting mild hepatocellular injury were noted.
264
265
PRECAUTIONS:
266
General: Agitation and Insomnia: Patients in placebo-controlled trials with
267
WELLBUTRIN SR Tablets experienced agitation, anxiety, and insomnia as shown in Table 1.
268
269
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
8
Table 1: Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
270
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Insomnia
11%
16%
6%
271
In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment
272
with sedative/hypnotic drugs.
273
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of
274
patients treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 0.8% of
275
patients treated with placebo.
276
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed patients
277
treated with an immediate-release formulation of bupropion or with WELLBUTRIN SR Tablets
278
have been reported to show a variety of neuropsychiatric signs and symptoms, including delusions,
279
hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these
280
symptoms abated upon dose reduction and/or withdrawal of treatment.
281
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
282
in bipolar disorder patients during the depressed phase of their illness and may activate latent
283
psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.
284
Altered Appetite and Weight: In placebo-controlled studies, patients experienced weight
285
gain or weight loss as shown in Table 2.
286
287
Table 2: Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
288
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
3%
2%
4%
Lost >5 lbs
14%
19%
6%
289
In studies conducted with the immediate-release formulation of bupropion, 35% of patients
290
receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the
291
immediate-release formulation of bupropion. If weight loss is a major presenting sign of a
292
patient’s depressive illness, the anorectic and/or weight-reducing potential of WELLBUTRIN SR
293
Tablets should be considered.
294
Suicide: The possibility of a suicide attempt is inherent in depression and may persist until
295
significant remission occurs. Accordingly, prescriptions for WELLBUTRIN SR Tablets should be
296
written for the smallest number of tablets consistent with good patient management.
297
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
9
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
298
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in
299
clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports
300
of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with
301
bupropion. A patient should stop taking WELLBUTRIN SR and consult a doctor if experiencing
302
allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, edema,
303
and shortness of breath) during treatment.
304
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
305
hypersensitivity have been reported in association with bupropion. These symptoms may resemble
306
serum sickness.
307
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
308
acute treatment, has been reported in patients receiving bupropion alone and in combination with
309
nicotine replacement therapy. These events have been observed in both patients with and without
310
evidence of preexisting hypertension.
311
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN
312
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
313
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
314
incidence of treatment-emergent hypertension in patients treated with the combination of sustained-
315
release bupropion and NTS. In this study, 6.1% of patients treated with the combination of
316
sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%,
317
1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo,
318
respectively. The majority of these patients had evidence of preexisting hypertension. Three
319
patients (1.2%) treated with the combination of ZYBAN and NTS and one patient (0.4%) treated
320
with NTS had study medication discontinued due to hypertension compared to none of the patients
321
treated with ZYBAN or placebo. Monitoring of blood pressure is recommended in patients who
322
receive the combination of bupropion and nicotine replacement.
323
There is no clinical experience establishing the safety of WELLBUTRIN SR Tablets in patients
324
with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be
325
exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who
326
had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and
327
was also generally well tolerated in a group of 36 depressed inpatients with stable congestive
328
heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in
329
the study of patients with CHF, resulting in discontinuation of treatment in two patients for
330
exacerbation of baseline hypertension.
331
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
332
with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required.
333
WELLBUTRIN SR should be used with caution in patients with hepatic impairment (including
334
mild to moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in
335
patients with mild to moderate hepatic cirrhosis.
336
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
10
All patients with hepatic impairment should be closely monitored for possible adverse effects
337
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
338
WARNINGS, and DOSAGE AND ADMINISTRATION).
339
Renal Impairment: No studies have been conducted in patients with renal impairment.
340
Bupropion is extensively metabolized in the liver to active metabolites, which are further
341
metabolized and excreted by the kidneys. WELLBUTRIN SR should be used with caution in
342
patients with renal impairment and a reduced frequency and/or dose should be considered as
343
bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The
344
patient should be closely monitored for possible adverse effects that could indicate high drug or
345
metabolite levels
346
Information for Patients: See the tear-off leaflet at the end of this labeling for Information for
347
the Patient.
348
Patients should be made aware that WELLBUTRIN SR contains the same active ingredient
349
found in ZYBAN, used as an aid to smoking cessation treatment, and that WELLBUTRIN SR
350
should not be used in combination with ZYBAN or any other medications that contain bupropion
351
hydrochloride.
352
Physicians are advised to discuss the following issues with patients:
353
As dose is increased during initial titration to doses above 150 mg/day, patients should be
354
instructed to take WELLBUTRIN SR Tablets in two divided doses, preferably with at least
355
8 hours between successive doses, to minimize the risk of seizures.
356
Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if they
357
experience a seizure while on treatment.
358
Patients should be told that any CNS-active drug like WELLBUTRIN SR Tablets may impair
359
their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until
360
they are reasonably certain that WELLBUTRIN SR Tablets do not adversely affect their
361
performance, they should refrain from driving an automobile or operating complex, hazardous
362
machinery.
363
Patients should be told that the use and cessation of use of alcohol may alter the seizure
364
threshold, and, therefore, that the consumption of alcohol should be minimized, and, if possible,
365
avoided completely.
366
Patients should be advised to inform their physicians if they are taking or plan to take any
367
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR Tablets
368
and other drugs may affect each other’s metabolism.
369
Patients should be advised to notify their physicians if they become pregnant or intend to
370
become pregnant during therapy.
371
Patients should be advised to swallow WELLBUTRIN SR Tablets whole so that the release
372
rate is not altered. Do not chew, divide, or crush tablets.
373
Laboratory Tests: There are no specific laboratory tests recommended.
374
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
11
Drug Interactions: Few systemic data have been collected on the metabolism of
375
WELLBUTRIN SR following concomitant administration with other drugs or, alternatively, the
376
effect of concomitant administration of WELLBUTRIN SR on the metabolism of other drugs.
377
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
378
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
379
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction
380
between WELLBUTRIN SR and drugs that affect the CYP2B6 isoenzyme (e.g., orphenadrine and
381
cyclophosphamide). The threohydrobupropion metabolite of bupropion does not appear to be
382
produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of
383
cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24
384
healthy young male volunteers. Following oral administration of two 150-mg WELLBUTRIN SR
385
Tablets with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and
386
hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and
387
Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
388
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
389
carbamazepine, phenobarbital, phenytoin).
390
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
391
humans. In one study, following chronic administration of bupropion, 100 mg three times daily to
392
eight healthy male volunteers for 14 days, there was no evidence of induction of its own
393
metabolism. Nevertheless, there may be the potential for clinically important alterations of blood
394
levels of coadministered drugs.
395
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including most
396
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
397
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme,
398
bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a study of 15
399
male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme,
400
daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg
401
desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of approximately two-,
402
five-, and two-fold, respectively. The effect was present for at least 7 days after the last dose of
403
bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been
404
formally studied.
405
Therefore, co-administration of bupropion with drugs that are metabolized by CYP2D6
406
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
407
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
408
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
409
should be approached with caution and should be initiated at the lower end of the dose range of the
410
concomitant medication. If bupropion is added to the treatment regimen of a patient already
411
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication
412
should be considered, particularly for those concomitant medications with a narrow therapeutic
413
index.
414
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
12
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
415
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
416
Levodopa: Limited clinical data suggest a higher incidence of adverse experiences in patients
417
receiving concurrent administration of bupropion and levodopa. Administration of
418
WELLBUTRIN SR Tablets to patients receiving levodopa concurrently should be undertaken with
419
caution, using small initial doses and gradual dose increases.
420
Drugs That Lower Seizure Threshold: Concurrent administration of WELLBUTRIN SR
421
Tablets and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids,
422
etc.) or treatment regimens (e.g., abrupt discontinuation of benzodiazepines) that lower seizure
423
threshold should be undertaken only with extreme caution (see WARNINGS). Low initial dosing
424
and gradual dose increases should be employed.
425
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
426
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
427
were performed in rats and mice at doses up to 300 and 150 mg/kg per day, respectively. These
428
doses are approximately seven and two times the maximum recommended human dose (MRHD),
429
respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative
430
lesions of the liver at doses of 100 to 300 mg/kg per day (approximately two to seven times the
431
MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such
432
lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions
433
were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs
434
was seen in either study.
435
Bupropion produced a positive response (two to three times control mutation rate) in two of
436
five strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in
437
one of three in vivo rat bone marrow cytogenetic studies.
438
A fertility study in rats at doses up to 300 mg/kg revealed no evidence of impaired fertility.
439
Pregnancy: Teratogenic Effects: Pregnancy Category B. Teratology studies have been
440
performed at doses up to 450 mg/kg in rats, and at doses up to 150 mg/kg in rabbits (approximately
441
7 to 11 and 7 times the MRHD, respectively, on a mg/m2 basis), and have revealed no evidence of
442
harm to the fetus due to bupropion. There are no adequate and well-controlled studies in pregnant
443
women. Because animal reproduction studies are not always predictive of human response, this
444
drug should be used during pregnancy only if clearly needed.
445
To monitor fetal outcomes of pregnant women exposed to WELLBUTRIN SR, GlaxoSmithKline.
446
maintains a Bupropion Pregnancy Registry. Health care providers are encouraged to register
447
patients by calling (800) 336-2176.
448
Labor and Delivery: The effect of WELLBUTRIN SR Tablets on labor and delivery in humans
449
is unknown.
450
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
451
milk. Because of the potential for serious adverse reactions in nursing infants from
452
WELLBUTRIN SR Tablets, a decision should be made whether to discontinue nursing or to
453
discontinue the drug, taking into account the importance of the drug to the mother.
454
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
13
Pediatric Use: The safety and effectiveness of WELLBUTRIN SR Tablets in pediatric patients
455
below 18 years old have not been established. The immediate-release formulation of bupropion
456
was studied in 104 pediatric patients (age range, 6 to 16) in clinical trials of the drug for other
457
indications. Although generally well tolerated, the limited exposure is insufficient to assess the
458
safety of bupropion in pediatric patients.
459
Geriatric Use: Of the approximately 6000 patients who participated in clinical trials with
460
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
461
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
462
clinical trials using the immediate-release formulation of bupropion (depression studies). No
463
overall differences in safety or effectiveness were observed between these subjects and younger
464
subjects, and other reported clinical experience has not identified differences in responses
465
between the elderly and younger patients, but greater sensitivity of some older individuals cannot
466
be ruled out.
467
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
468
metabolites in elderly subjects was similar to that of younger subjects; however, another
469
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
470
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
471
Bupropion is extensively metabolized in the liver to active metabolites, which are further
472
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
473
patients with impaired renal function. Because elderly patients are more likely to have decreased
474
renal function, care should be taken in dose selection, and it may be useful to monitor renal
475
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
476
477
ADVERSE REACTIONS: (See also WARNINGS and PRECAUTIONS).
478
The information included under the Incidence in Controlled Trials subsection of ADVERSE
479
REACTIONS is based primarily on data from controlled clinical trials with WELLBUTRIN SR
480
Tablets. Information on additional adverse events associated with the sustained-release
481
formulation of bupropion in smoking cessation trials, as well as the immediate-release formulation
482
of bupropion, is included in a separate section (see Other Events Observed During the Clinical
483
Development and Postmarketing Experience of Bupropion).
484
Incidence in Controlled Trials With WELLBUTRIN SR: Adverse Events Associated
485
With Discontinuation of Treatment Among Patients Treated With
486
WELLBUTRIN SR Tablets: In placebo-controlled clinical trials, 9% and 11% of patients
487
treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 4% of patients
488
treated with placebo discontinued treatment due to adverse events. The specific adverse events in
489
these trials that led to discontinuation in at least 1% of patients treated with either 300 or
490
400 mg/day of WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed in
491
Table 3.
492
493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
14
Table 3: Treatment Discontinuations Due to Adverse Events in Placebo-Controlled
494
Trials
495
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Rash
2.4%
0.9%
0.0%
Nausea
0.8%
1.8%
0.3%
Agitation
0.3%
1.8%
0.3%
Migraine
0.0%
1.8%
0.3%
496
Adverse Events Occurring at an Incidence of 1% or More Among Patients
497
Treated With WELLBUTRIN SR Tablets: Table 4 enumerates treatment-emergent adverse
498
events that occurred among patients treated with 300 and 400 mg/day of WELLBUTRIN SR
499
Tablets and with placebo in placebo-controlled trials. Events that occurred in either the 300- or
500
400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo
501
group are included. Reported adverse events were classified using a COSTART-based
502
Dictionary.
503
Accurate estimates of the incidence of adverse events associated with the use of any drug are
504
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
505
judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward
506
events in the course of usual medical practice where patient characteristics and other factors differ
507
from those that prevailed in the clinical trials. These incidence figures also cannot be compared
508
with those obtained from other clinical studies involving related drug products as each group of
509
drug trials is conducted under a different set of conditions.
510
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
511
and/or clinical importance of the events. A better perspective on the serious adverse events
512
associated with the use of WELLBUTRIN SR Tablets is provided in the WARNINGS and
513
PRECAUTIONS sections.
514
515
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
15
Table 4: Treatment-Emergent Adverse Events in Placebo-Controlled Trials*
516
Body System/
Adverse Event
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
16
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous
system stimulation
2%
1%
1%
Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Amblyopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal hemorrhage†
0%
2%
—
Urinary tract infection
1%
0%
—
* Adverse events that occurred in at least 1% of patients treated with either 300 or
517
400 mg/day of WELLBUTRIN SR Tablets, but equally or more frequently in the placebo
518
group, were: abnormal dreams, accidental injury, acne, appetite increased, back pain,
519
bronchitis, dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain,
520
respiratory disorder, rhinitis, and tooth disorder.
521
† Incidence based on the number of female patients.
522
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
523
524
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:
525
Adverse events from Table 4 occurring in at least 5% of patients treated with WELLBUTRIN SR
526
Tablets and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg/day
527
dose groups.
528
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and
529
tremor.
530
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
17
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry
531
mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
532
frequency.
533
Other Events Observed During the Clinical Development and Postmarketing
534
Experience of Bupropion: In addition to the adverse events noted above, the following events
535
have been reported in clinical trials and postmarketing experience with the sustained-release
536
formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical
537
trials and postmarketing clinical experience with the immediate-release formulation of bupropion.
538
Adverse events for which frequencies are provided below occurred in clinical trials with the
539
sustained-release formulation of bupropion. The frequencies represent the proportion of patients
540
who experienced a treatment-emergent adverse event on at least one occasion in
541
placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1013), or patients
542
who experienced an adverse event requiring discontinuation of treatment in an open-label
543
surveillance study with WELLBUTRIN SR Tablets (n = 3100). All treatment-emergent adverse
544
events are included except those listed in Tables 1 through 4, those events listed in other
545
safety-related sections, those adverse events subsumed under COSTART terms that are either
546
overly general or excessively specific so as to be uninformative, those events not reasonably
547
associated with the use of the drug, and those events that were not serious and occurred in fewer
548
than two patients. Events of major clinical importance are described in the WARNINGS and
549
PRECAUTIONS sections of the labeling.
550
Events are further categorized by body system and listed in order of decreasing frequency
551
according to the following definitions of frequency: Frequent adverse events are defined as those
552
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
553
1/1000 patients, while rare events are those occurring in less than 1/1000 patients.
554
Adverse events for which frequencies are not provided occurred in clinical trials or
555
postmarketing experience with bupropion. Only those adverse events not previously listed for
556
sustained-release bupropion are included. The extent to which these events may be associated with
557
WELLBUTRIN SR is unknown.
558
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and
559
photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash
560
and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum
561
sickness (see PRECAUTIONS).
562
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and vasodilation.
563
Rare was syncope. Also observed were complete atrioventricular block, extrasystoles,
564
hypotension, hypertension (in some cases severe, see PRECAUTIONS), myocardial infarction,
565
phlebitis, and pulmonary embolism.
566
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
567
glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of
568
tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage,
569
hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
570
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
18
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
571
inappropriate antidiuretic hormone.
572
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
573
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia.
574
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed
575
was glycosuria.
576
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle
577
rigidity/fever/rhabdomyolysis and muscle weakness.
578
Nervous System: Infrequent were abnormal coordination, decreased libido,
579
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
580
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also
581
observed were abnormal electroencephalogram (EEG), akinesia, aphasia, coma, delirium,
582
dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased
583
libido, manic reaction, neuralgia, neuropathy, paranoid reaction, and unmasking tardive
584
dyskinesia.
585
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
586
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative
587
dermatitis, and hirsutism.
588
Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed
589
were deafness, diplopia, and mydriasis.
590
Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed were
591
abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection,
592
salpingitis, urinary incontinence, urinary retention, and vaginitis.
593
594
DRUG ABUSE AND DEPENDENCE:
595
Controlled Substance Class: Bupropion is not a controlled substance.
596
Humans: Controlled clinical studies of bupropion conducted in normal volunteers, in subjects
597
with a history of multiple drug abuse, and in depressed patients showed some increase in motor
598
activity and agitation/excitement.
599
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
600
bupropion produced mild amphetamine-like activity as compared to placebo on the
601
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score
602
intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales
603
measure general feelings of euphoria and drug desirability.
604
Findings in clinical trials, however, are not known to reliably predict the abuse potential of
605
drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
606
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing
607
to amphetamine or stimulant abusers. However, higher doses that could not be tested because of
608
the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
609
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
19
Animals: Studies in rodents and primates have shown that bupropion exhibits some
610
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
611
locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of responding
612
in several schedule-controlled behavior paradigms. In primate models to assess the positive
613
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
614
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
615
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
616
617
OVERDOSAGE:
618
Human Overdose Experience: There has been very limited experience with overdosage of
619
WELLBUTRIN SR Tablets; three cases were reported during clinical trials. One patient ingested
620
3000 mg of WELLBUTRIN SR Tablets and vomited quickly after the overdose; the patient
621
experienced blurred vision and lightheadedness. A second patient ingested a "handful" of
622
WELLBUTRIN SR Tablets and experienced confusion, lethargy, nausea, jitteriness, and seizure. A
623
third patient ingested 3600 mg of WELLBUTRIN SR Tablets and a bottle of wine; the patient
624
experienced nausea, visual hallucinations, and “grogginess.” None of the patients experienced
625
further sequelae.
626
There has been extensive experience with overdosage of the immediate-release formulation of
627
bupropion. Thirteen overdoses occurred during clinical trials. Twelve patients ingested 850 to
628
4200 mg and recovered without significant sequelae. Another patient who ingested 9000 mg of the
629
immediate-release formulation of bupropion and 300 mg of tranylcypromine experienced a grand
630
mal seizure and recovered without further sequelae.
631
Since introduction, overdoses of up to 17,500 mg of the immediate-release formulation of
632
bupropion have been reported. Seizure was reported in approximately one third of all cases. Other
633
serious reactions reported with overdoses of the immediate-release formulation of bupropion
634
alone included hallucinations, loss of consciousness, and sinus tachycardia. Fever, muscle rigidity,
635
rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported when the
636
immediate-release formulation of bupropion was part of multiple drug overdoses.
637
Although most patients recovered without sequelae, deaths associated with overdoses of the
638
immediate-release formulation of bupropion alone have been reported rarely in patients ingesting
639
massive doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and
640
cardiac arrest prior to death were reported in these patients.
641
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation. Monitor
642
cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours post-
643
ingestion. General supportive and symptomatic measures are also recommended. Induction of
644
emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate
645
airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic
646
patients.
647
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
20
Activated charcoal should be administered. There is no experience with the use of forced
648
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
649
overdoses. No specific antidotes for bupropion are known.
650
Due to the dose-related risk of seizures with WELLBUTRIN SR, hospitalization following
651
suspected overdose should be considered. Based on studies in animals, it is recommended that
652
seizures be treated with intravenous benzodiazepine administration and other supportive measures,
653
as appropriate.
654
In managing overdosage, consider the possibility of multiple drug involvement. The physician
655
should consider contacting a poison control center for additional information on the treatment of
656
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’
657
Desk Reference (PDR).
658
659
DOSAGE AND ADMINISTRATION:
660
General Dosing Considerations: It is particularly important to administer WELLBUTRIN SR
661
Tablets in a manner most likely to minimize the risk of seizure (see WARNINGS). Gradual
662
escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen
663
during the initial days of treatment, are to be minimized. If necessary, these effects may be
664
managed by temporary reduction of dose or the short-term administration of an intermediate to
665
long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of
666
treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward
667
effects supervene, dose escalation should be stopped. WELLBUTRIN SR should be swallowed
668
whole and not crushed, divided, or chewed.
669
Initial Treatment: The usual adult target dose for WELLBUTRIN SR Tablets is 300 mg/day,
670
given as 150 mg twice daily. Dosing with WELLBUTRIN SR Tablets should begin at 150 mg/day
671
given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, an
672
increase to the 300-mg/day target dose, given as 150 mg twice daily, may be made as early as day
673
4 of dosing. There should be an interval of at least 8 hours between successive doses.
674
Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full
675
antidepressant effect of WELLBUTRIN SR Tablets may not be evident until 4 weeks of treatment
676
or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may
677
be considered for patients in whom no clinical improvement is noted after several weeks of
678
treatment at 300 mg/day.
679
Maintenance Treatment: It is generally agreed that acute episodes of depression require
680
several months or longer of sustained pharmacological therapy beyond response to the acute
681
episode. In a study in which patients with major depressive disorder, recurrent type, who had
682
responded during 8 weeks of acute treatment with WELLBUTRIN SR were assigned randomly to
683
placebo or to the same dose of WELLBUTRIN SR (150 mg twice daily) during 44 weeks of
684
maintenance treatment as they had received during the acute stabilization phase, longer-term
685
efficacy was demonstrated (see CLINICAL TRIALS under CLINICAL PHARMACOLOGY).
686
Based on these limited data, it is unknown whether or not the dose of WELLBUTRIN SR needed
687
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
21
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
688
should be periodically reassessed to determine the need for maintenance treatment and the
689
appropriate dose for such treatment.
690
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN SR
691
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not
692
exceed 100 mg every day or 150 mg every other day in these patients. WELLBUTRIN SR should
693
be used with caution in patients with hepatic impairment (including mild to moderate hepatic
694
cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild to
695
moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and
696
PRECAUTIONS).
697
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN SR
698
should be used with caution in patients with renal impairment and a reduced frequency and/or dose
699
should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
700
701
HOW SUPPLIED: WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion
702
hydrochloride, are blue, round, biconvex, film-coated tablets printed with
703
“WELLBUTRIN SR 100” in bottles of 60 (NDC 0173-0947-55) tablets.
704
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are purple,
705
round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150" in bottles of 60 (NDC
706
0173-0135-55) tablets.
707
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are light
708
pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of 60
709
(NDC 0173-0722-00) tablets.
710
711
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in a
712
tight, light-resistant container as defined in the USP.
713
714
715
716
Distributed by:
717
GlaxoSmithKline, Research Triangle Park, NC 27709
718
719
Manufactured by:
720
GlaxoSmithKline
721
Research Triangle Park, NC 27709
722
or
723
Catalytica Pharmaceuticals, Inc.
724
Greenville, NC 27834
725
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
22
726
727
© 2002,GlaxoSmithKline
728
All rights reserved.
729
730
(Date of Issue)
RL-
731
732
PHARMACIST--DETACH HERE AND GIVE LEAFLET TO PATIENT.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
733
Information for the Patient
734
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
735
736
Please read this information before you start taking WELLBUTRIN SR. Also read this leaflet each
737
time you renew your prescription, in case anything has changed. This information is not intended to
738
take the place of discussions between you and your doctor. You and your doctor should discuss
739
WELLBUTRIN SR as it relates to the treatment of your depression. Do not let anyone else use
740
your WELLBUTRIN SR.
741
742
IMPORTANT WARNING:
743
At a dose of up to 300 mg each day, there is a chance that approximately 1 out of every 1000
744
people taking bupropion hydrochloride, the active ingredient in WELLBUTRIN SR, will have a
745
seizure. At a dose of 400 mg each day, there is a chance that approximately 4 out of every 1000
746
people will have a seizure. The chance of this happening increases if you:
747
• have or have had a seizure disorder (for example, epilepsy);
748
• have or have had an eating disorder (for example, bulimia or anorexia nervosa);
749
• take more than the recommended amount of WELLBUTRIN SR; or
750
• take other medicines with the same active ingredient that is in WELLBUTRIN SR, such as
751
ZYBAN® (bupropion hydrochloride) Sustained-Release Tablets (used to help people quit
752
smoking).
753
You can reduce the chance of experiencing a seizure by following your doctor’s directions on
754
how to take WELLBUTRIN SR. If you experience a seizure while taking WELLBUTRIN SR, stop
755
taking the tablets immediately, contact your doctor, and do not restart WELLBUTRIN SR. In
756
addition, tell your doctor if you have or have had other medical conditions. You should also
757
discuss with your doctor whether WELLBUTRIN SR is right for you.
758
759
1. What is WELLBUTRIN SR?
760
WELLBUTRIN SR is a prescription medicine used to treat depression.
761
2. Who should not take WELLBUTRIN SR?
762
You should not take WELLBUTRIN SR if you:
763
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
23
• have or have had a seizure disorder (for example, epilepsy);
764
• are already taking ZYBAN or any other medicines that contain bupropion hydrochloride;
765
• have or have had an eating disorder (for example, bulimia or anorexia nervosa);
766
• are currently taking or have recently taken a monoamine oxidase inhibitor (MAOI); or
767
• are allergic to bupropion.
768
3. Are there special concerns for women?
769
WELLBUTRIN SR is not recommended for women who are pregnant or breast-feeding. Women
770
should notify their doctor if they become pregnant or intend to become pregnant while taking
771
WELLBUTRIN SR.
772
4. Are there any concerns for patients with liver or kidney problems?
773
If you have liver or kidney problems, tell your doctor before taking WELLBUTRIN SR.
774
Depending on the severity of your condition, your doctor may need to adjust your dosage.
775
5. How should I take WELLBUTRIN SR?
776
• You should take WELLBUTRIN SR as directed by your doctor. The usual recommended
777
dosing is to begin treatment with WELLBUTRIN SR by taking one 150-mg tablet in the
778
morning. As early as day 4 of treatment, your doctor may increase your dose to one 150-mg
779
tablet in the morning and one 150-mg tablet in the early evening (for a total of 300 mg each
780
day).
781
If your depression does not improve after several weeks, your doctor may increase the dose
782
of WELLBUTRIN SR to a total of 400 mg each day (taken as 200 mg in the morning and
783
200 mg in the early evening). Doses should be taken at least 8 hours apart.
784
• Never take an “extra” dose of WELLBUTRIN SR Tablets for any reason, even if you
785
miss a dose. If you forget to take a dose, do not take an extra tablet to “catch up” for the dose
786
you forgot. Wait and take your next tablet at the regular time. Do not take more tablets than your
787
doctor prescribed. This is important so you do not increase your chance of having a seizure.
788
• It is important to swallow WELLBUTRIN SR Tablets whole. Do not chew, divide, or crush
789
tablets.
790
6. How long should I take WELLBUTRIN SR?
791
Only you and your doctor can determine how long you should take WELLBUTRIN SR. You and
792
your doctor should discuss your signs and symptoms of depression regularly to determine how
793
long you should take WELLBUTRIN SR. Do not stop taking your medicine or decrease the amount
794
of medicine you are taking without talking to your doctor first.
795
7. What are possible side effects of WELLBUTRIN SR?
796
Like all medicines, WELLBUTRIN SR may cause side effects. Do not rely on this summary
797
alone for information about side effects. Your doctor can discuss with you a more complete list of
798
side effects that may be relevant to you.
799
• Hypertension (high blood pressure), in some cases severe, has been reported in patients taking
800
WELLBUTRIN SR alone and in combination with nicotine replacement therapy (for example,
801
a nicotine patch) used to help patients stop smoking. Tell your doctor if you are using or plan
802
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
24
to use nicotine replacement therapy because your doctor will probably want to check your
803
blood pressure regularly to make sure that it stays within acceptable levels.
804
• The most common side effects of WELLBUTRIN SR in clinical studies were:
805
At 300 mg/day: Loss of appetite, dry mouth, skin rash, sweating, ringing in the ears, and
806
shakiness.
807
At 400 mg/day: Abdominal (stomach) pain, agitation, anxiety, dizziness, dry mouth, difficulty
808
sleeping, muscle pain, nausea, rapid heart beat, sore throat, sweating, ringing in the ears, and
809
urinating more often.
810
• The side effects of WELLBUTRIN SR are generally mild and often disappear after a few
811
weeks. If you have nausea, you may want to take your medicine with food. If you have
812
difficulty sleeping, avoid taking your medicine too close to bedtime.
813
• The most common side effects that caused people to stop taking WELLBUTRIN SR during
814
clinical studies were skin rash, nausea, agitation, and migraine (a severe type of headache).
815
• Stop taking WELLBUTRIN SR and contact your doctor or health care professional if you have
816
signs of an allergic reaction such as a skin rash, or difficulty in breathing. It is not possible to
817
predict whether a mild rash will develop into a more serious reaction. Therefore, if you
818
experience a skin rash, hives, fever, swollen lymph glands, painful sores in the mouth or
819
around the eyes, or swelling of lips or tongue, tell a doctor immediately, since these symptoms
820
may be the first signs of a serious reaction. Discuss any other troublesome side effects with
821
your doctor.
822
• Use caution before driving a car or operating complex, hazardous machinery until you know if
823
WELLBUTRIN SR affects your ability to perform these tasks.
824
8. Will taking WELLBUTRIN SR change my body weight?
825
In clinical studies with WELLBUTRIN SR, some people lost weight and other people gained
826
weight.
827
For people who lost weight, 14 out of 100 people taking 300 mg/day of WELLBUTRIN SR lost
828
more than 5 lbs, 19 out of 100 people taking 400 mg/day lost more than 5 lbs, and 6 out of 100
829
people taking placebo (a sugar pill) lost more than 5 lbs.
830
For people who gained weight, 3 out of 100 people taking 300 mg/day of WELLBUTRIN SR
831
gained more than 5 lbs, 2 out of 100 people taking 400 mg/day gained more than 5 lbs, and 4 out of
832
100 people taking placebo (a sugar pill) gained more than 5 lbs.
833
Since weight change (loss or gain) also can be a symptom of depression, you should discuss
834
with your doctor whether WELLBUTRIN SR is right for you.
835
9. Should I drink alcohol while I am taking WELLBUTRIN SR?
836
It is best to not drink alcohol at all or to drink very little while taking WELLBUTRIN SR. If you
837
usually drink a lot of alcohol, or if you drink a lot of alcohol and suddenly stop, you may increase
838
your chance of having a seizure. Therefore, it is important to discuss your use of alcohol with your
839
doctor before you begin taking WELLBUTRIN SR.
840
10. Will WELLBUTRIN SR affect other medicines I am taking?
841
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WELLBUTRIN SR® (bupropion hydrochloride) Sustained-Release Tablets
25
WELLBUTRIN SR may affect other medicines you’re taking. It is important not to take
842
medicines that may increase the chance for you to have a seizure. Therefore, you should make sure
843
that your doctor knows about all medicines—prescription and over-the-counter—you are taking or
844
plan to take.
845
11. Do WELLBUTRIN SR Tablets have a characteristic odor?
846
WELLBUTRIN SR Tablets may have a characteristic odor. If present, this odor is normal.
847
12. How should I store WELLBUTRIN SR?
848
• Store WELLBUTRIN SR at room temperature, out of direct sunlight.
849
• Keep WELLBUTRIN SR in a tightly closed container.
850
• Keep WELLBUTRIN SR out of the reach of children.
851
852
This summary provides important information about WELLBUTRIN SR. This summary cannot
853
replace the more detailed information that you need from your doctor. If you have any questions or
854
concerns about either WELLBUTRIN SR or depression, talk to your doctor or other health care
855
professional.
856
857
858
Distributed by:
859
GlaxoSmithKline, Research Triangle Park, NC 27709
860
861
Manufactured by:
862
GlaxoSmithKline
863
Research Triangle Park, NC 27709
864
or
865
Catalytica Pharmaceuticals, Inc.
866
Greenville, NC 27834
867
868
© 2002, GlaxoSmithKline
869
All rights reserved.
870
871
(Date of Issue)
RL-
872
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Russell Katz
6/14/02 09:29:55 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:47:30.389473
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20358s27lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 27}
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PRESCRIBING INFORMATION
WELLBUTRIN SR®
(bupropion hydrochloride)
Sustained-Release Tablets
Suicidality and Antidepressant Drugs
6
Antidepressants increased the risk compared to placebo of suicidal thinking and
7
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
8
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
9
use of WELLBUTRIN SR or any other antidepressant in a child, adolescent, or young
10
adult must balance this risk with the clinical need. Short-term studies did not show an
11
increase in the risk of suicidality with antidepressants compared to placebo in adults
12
beyond age 24; there was a reduction in risk with antidepressants compared to placebo in
13
adults aged 65 and older. Depression and certain other psychiatric disorders are
14
themselves associated with increases in the risk of suicide. Patients of all ages who are
15
started on antidepressant therapy should be monitored appropriately and observed closely
16
for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers
17
should be advised of the need for close observation and communication with the prescriber.
18
WELLBUTRIN SR is not approved for use in pediatric patients. (See WARNINGS:
19
Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and
20
PRECAUTIONS: Pediatric Use.)
21
22
23
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30
DESCRIPTION
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class, is
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
structural formula is:
31
32
33
34
35
WELLBUTRIN SR Tablets are supplied for oral administration as 100-mg (blue), 150-mg
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
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hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the
100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
CLINICAL PHARMACOLOGY
Pharmacodynamics: Bupropion is a relatively weak inhibitor of the neuronal uptake of
norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of
serotonin. While the mechanism of action of bupropion, as with other antidepressants, is
unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic
mechanisms.
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and
pharmacokinetics of the individual enantiomers have not been studied. The mean elimination
half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma
concentrations of bupropion are reached within 8 days. In a study comparing chronic dosing with
WELLBUTRIN SR Tablets 150 mg twice daily to the immediate-release formulation of
bupropion at 100 mg 3 times daily, peak plasma concentrations of bupropion at steady state for
WELLBUTRIN SR Tablets were approximately 85% of those achieved with the
immediate-release formulation. There was equivalence for bupropion AUCs, as well as
equivalence for both peak plasma concentration and AUCs for all 3 of the detectable bupropion
metabolites. Thus, at steady state, WELLBUTRIN SR Tablets, given twice daily, and the
immediate-release formulation of bupropion, given 3 times daily, are essentially bioequivalent
for both bupropion and the 3 quantitatively important metabolites.
Absorption: Following oral administration of WELLBUTRIN SR Tablets to healthy
volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. Food
increased Cmax and AUC of bupropion by 11% and 17%, respectively, indicating that there is no
clinically significant food effect.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been
shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group
of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion,
while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of
meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency
and toxicity of the metabolites relative to bupropion have not been fully characterized. However,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
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it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is
one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-
fold less potent than bupropion. This may be of clinical importance because the plasma
concentrations of the metabolites are as high or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug
interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6
(CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6
(CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered
with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
approximately 6 hours after administration of WELLBUTRIN SR Tablets. Peak plasma
concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug
at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours,
and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations
for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37
(±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300
to 450 mg/day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent
with the extensive metabolism of bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be
expected to influence the degree and extent of accumulation of the active metabolites of
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
renal or hepatic function because they are moderately polar compounds and are likely to undergo
further metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
patients with mild to severe cirrhosis. The first study showed that the half-life of
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
8 healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for
bupropion and the other metabolites in the 2 patient groups were minimal.
The second study showed no statistically significant differences in the pharmacokinetics of
bupropion and its active metabolites in 9 patients with mild to moderate hepatic cirrhosis
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compared to 8 healthy volunteers. However, more variability was observed in some of the
pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½)
in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic
cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by
approximately 70% and 3-fold, respectively) and more variable when compared to values in
healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with
severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion,
the mean Cmax was approximately 69% lower. For the combined amino-alcohol isomers
threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower.
The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for
threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for
hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for
hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively,
in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
renal impairment. An inter-study comparison between normal subjects and patients with end-
stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in
the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3-
and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. The
elimination of the major metabolites of bupropion may be reduced by impaired renal function
(see PRECAUTIONS: Renal Impairment).
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in
14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on
x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed,
compared to healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
been fully characterized, but an exploration of steady-state bupropion concentrations from
several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on
a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly
are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
Geriatric Use).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17
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were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion
or its active metabolites between smokers and nonsmokers.
CLINICAL TRIALS
The efficacy of the immediate-release formulation of bupropion as a treatment for depression
was established in two 4-week, placebo-controlled trials in adult inpatients with depression and
in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study,
patients were titrated in a bupropion dose range of 300 to 600 mg/day on a 3 times daily
schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial
demonstrated the effectiveness of the immediate-release formulation of bupropion on the
Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from
that scale, and the Clinical Global Impressions (CGI) severity score. A second study included
2 fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and
placebo. This trial demonstrated the effectiveness of the immediate-release formulation of
bupropion, but only at the 450-mg/day dose; the results were positive for the HDRS total score
and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received
300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the
effectiveness of the immediate-release formulation of bupropion on the HDRS total score, HDRS
item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI
improvement score.
Although there are not as yet independent trials demonstrating the antidepressant effectiveness
of the sustained-release formulation of bupropion, studies have demonstrated the bioequivalence
of the immediate-release and sustained-release forms of bupropion under steady-state conditions,
i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg
3 times daily of the immediate-release formulation of bupropion, with regard to both rate and
extent of absorption, for parent drug and metabolites.
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder,
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
twice daily) were randomized to continuation of their same WELLBUTRIN SR dose or placebo,
for up to 44 weeks of observation for relapse. Response during the open phase was defined as
CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final
3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that
drug treatment was needed for worsening depressive symptoms. Patients receiving continued
WELLBUTRIN SR treatment experienced significantly lower relapse rates over the subsequent
44 weeks compared to those receiving placebo.
INDICATIONS AND USAGE
WELLBUTRIN SR is indicated for the treatment of major depressive disorder.
The efficacy of bupropion in the treatment of a major depressive episode was established in
two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of
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depressed outpatients whose diagnoses corresponded most closely to the Major Depression
category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL
PHARMACOLOGY).
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss
of interest or pleasure; in addition, at least 5 of the following symptoms have been present during
the same 2-week period and represent a change from previous functioning: depressed mood,
markedly diminished interest or pleasure in usual activities, significant change in weight and/or
appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue,
feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt
or suicidal ideation.
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
(see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use
WELLBUTRIN SR for extended periods should periodically reevaluate the long-term usefulness
of the drug for the individual patient.
CONTRAINDICATIONS
WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
WELLBUTRIN SR is contraindicated in patients treated with ZYBAN® (bupropion
hydrochloride) Sustained-Release Tablets; WELLBUTRIN® (bupropion hydrochloride), the
immediate-release formulation; WELLBUTRIN XL® (bupropion hydrochloride), the extended-
release formulation; or any other medications that contain bupropion because the incidence of
seizure is dose dependent.
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia
or anorexia nervosa because of a higher incidence of seizures noted in patients treated for
bulimia with the immediate-release formulation of bupropion.
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
alcohol or sedatives (including benzodiazepines).
The concurrent administration of WELLBUTRIN SR Tablets and a monoamine oxidase
(MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an
MAO inhibitor and initiation of treatment with WELLBUTRIN SR Tablets.
WELLBUTRIN SR is contraindicated in patients who have shown an allergic response to
bupropion or the other ingredients that make up WELLBUTRIN SR Tablets.
WARNINGS
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
both adult and pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
are taking antidepressant medications, and this risk may persist until significant remission
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-standing
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concern, however, that antidepressants may have a role in inducing worsening of depression and
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
patients. There was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger patients for almost all drugs studied. There were differences in
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of cases of
suicidality per 1,000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
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No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
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The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to health care
providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for WELLBUTRIN SR should be written for the smallest quantity of tablets
consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that WELLBUTRIN SR is not approved for use in treating bipolar
depression.
Patients should be made aware that WELLBUTRIN SR contains the same active
ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that
WELLBUTRIN SR should not be used in combination with ZYBAN, or any other
medications that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride),
the immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the
extended-release formulation.
Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures
is also related to patient factors, clinical situations, and concomitant medications, which
must be considered in selection of patients for therapy with WELLBUTRIN SR.
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WELLBUTRIN SR should be discontinued and not restarted in patients who experience a
seizure while on treatment.
• Dose: At doses of WELLBUTRIN SR up to a dose of 300 mg/day, the incidence of
seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000)
at the maximum recommended dose of 400 mg/day.
Data for the immediate-release formulation of bupropion revealed a seizure incidence
of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients
treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of this
dose range is close to the currently recommended maximum dose of 400 mg/day for
WELLBUTRIN SR Tablets. This seizure incidence (0.4%) may exceed that of other
marketed antidepressants and WELLBUTRIN SR Tablets up to 300 mg/day by as
much as 4-fold. This relative risk is only an approximate estimate because no direct
comparative studies have been conducted.
Additional data accumulated for the immediate-release formulation of bupropion
suggested that the estimated seizure incidence increases almost tenfold between 450 and
600 mg/day, which is twice the usual adult dose and one and one-half the maximum
recommended daily dose (400 mg) of WELLBUTRIN SR Tablets. This
disproportionate increase in seizure incidence with dose incrementation calls for
caution in dosing.
Data for WELLBUTRIN SR Tablets revealed a seizure incidence of approximately
0.1% (i.e., 3 of 3,100 patients followed prospectively) in patients treated at doses in a
range of 100 to 300 mg/day. It is not possible to know if the lower seizure incidence
observed in this study involving the sustained-release formulation of bupropion
resulted from the different formulation or the lower dose used. However, as noted
above, the immediate-release and sustained-release formulations are bioequivalent with
regard to both rate and extent of absorption during steady state (the most pertinent
condition to estimating seizure incidence), since most observed seizures occur under
steady-state conditions.
• Patient factors: Predisposing factors that may increase the risk of seizure with
bupropion use include history of head trauma or prior seizure, central nervous system
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications
that lower seizure threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include,
among others, excessive use of alcohol or sedatives (including benzodiazepines);
addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and
anorectics; and diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
theophylline, systemic steroids) are known to lower seizure threshold.
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Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
clinical experience gained during the development of bupropion suggests that the risk of
seizure may be minimized if
• the total daily dose of WELLBUTRIN SR Tablets does not exceed 400 mg,
• the daily dose is administered twice daily, and
• the rate of incrementation of dose is gradual.
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion
and/or its metabolites.
WELLBUTRIN SR should be administered with extreme caution to patients with a
history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients
treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
steroids, etc.) that lower seizure threshold.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
likely to occur in such patients to a greater extent than usual. The dose should not exceed
100 mg every day or 150 mg every other day in these patients (see CLINICAL
PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there
was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In
dogs receiving large doses of bupropion chronically, various histologic changes were seen in the
liver, and laboratory tests suggesting mild hepatocellular injury were noted.
PRECAUTIONS
General: Agitation and Insomnia: Patients in placebo-controlled trials with
WELLBUTRIN SR Tablets experienced agitation, anxiety, and insomnia as shown in Table 2.
Table 2. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Insomnia
11%
16%
6%
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In clinical studies, these symptoms were sometimes of sufficient magnitude to require
treatment with sedative/hypnotic drugs.
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of
patients treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 0.8%
of patients treated with placebo.
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Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
patients treated with an immediate-release formulation of bupropion or with WELLBUTRIN SR
Tablets have been reported to show a variety of neuropsychiatric signs and symptoms, including
delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
in bipolar disorder patients during the depressed phase of their illness and may activate latent
psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.
Altered Appetite and Weight: In placebo-controlled studies, patients experienced weight
gain or weight loss as shown in Table 3.
Table 3. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
3%
2%
4%
Lost >5 lbs
14%
19%
6%
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In studies conducted with the immediate-release formulation of bupropion, 35% of patients
receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the
immediate-release formulation of bupropion. If weight loss is a major presenting sign of a
patient’s depressive illness, the anorectic and/or weight-reducing potential of
WELLBUTRIN SR Tablets should be considered.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported
in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing
reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated
with bupropion. A patient should stop taking WELLBUTRIN SR and consult a doctor if
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives,
chest pain, edema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
hypersensitivity have been reported in association with bupropion. These symptoms may
resemble serum sickness.
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
acute treatment, has been reported in patients receiving bupropion alone and in combination with
nicotine replacement therapy. These events have been observed in both patients with and without
evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
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incidence of treatment-emergent hypertension in patients treated with the combination of
sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the
combination of sustained-release bupropion and NTS had treatment-emergent hypertension
compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS,
and placebo, respectively. The majority of these patients had evidence of preexisting
hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and
1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension
compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure
is recommended in patients who receive the combination of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of WELLBUTRIN SR Tablets in
patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care
should be exercised if it is used in these groups. Bupropion was well tolerated in depressed
patients who had previously developed orthostatic hypotension while receiving tricyclic
antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with
stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine
blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in
2 patients for exacerbation of baseline hypertension.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required.
WELLBUTRIN SR should be used with caution in patients with hepatic impairment (including
mild to moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in
patients with mild to moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse effects
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
WARNINGS, and DOSAGE AND ADMINISTRATION).
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
patients with renal impairment. An inter-study comparison between normal subjects and patients
with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage
renal failure. Bupropion is extensively metabolized in the liver to active metabolites, which are
further metabolized and subsequently excreted by the kidneys. WELLBUTRIN SR should be
used with caution in patients with renal impairment and a reduced frequency and/or dose should
be considered as bupropion and the metabolites of bupropion may accumulate in such patients to
a greater extent than usual. The patient should be closely monitored for possible adverse effects
that could indicate high drug or metabolite levels.
Information for Patients: Prescribers or other health professionals should inform patients,
their families, and their caregivers about the benefits and risks associated with treatment with
WELLBUTRIN SR and should counsel them in its appropriate use. A patient Medication Guide
about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
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Thoughts or Actions” and other important information about using WELLBUTRIN SR is
available for WELLBUTRIN SR. The prescriber or health professional should instruct patients,
their families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete text of
the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking WELLBUTRIN SR.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of such
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
close monitoring and possibly changes in the medication.
Patients should be made aware that WELLBUTRIN SR contains the same active ingredient
found in ZYBAN, used as an aid to smoking cessation treatment, and that WELLBUTRIN SR
should not be used in combination with ZYBAN or any other medications that contain bupropion
hydrochloride (such as WELLBUTRIN, the immediate-release formulation and WELLBUTRIN
XL, the extended-release formulation).
As dose is increased during initial titration to doses above 150 mg/day, patients should be
instructed to take WELLBUTRIN SR Tablets in 2 divided doses, preferably with at least 8 hours
between successive doses, to minimize the risk of seizures.
Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if
they experience a seizure while on treatment.
Patients should be told that any CNS-active drug like WELLBUTRIN SR Tablets may impair
their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently,
until they are reasonably certain that WELLBUTRIN SR Tablets do not adversely affect their
performance, they should refrain from driving an automobile or operating complex, hazardous
machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives
(including benzodiazepines) may alter the seizure threshold. Some patients have reported lower
alcohol tolerance during treatment with WELLBUTRIN SR. Patients should be advised that the
consumption of alcohol should be minimized or avoided.
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Patients should be advised to inform their physicians if they are taking or plan to take any
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR
Tablets and other drugs may affect each other’s metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to swallow WELLBUTRIN SR Tablets whole so that the release
rate is not altered. Do not chew, divide, or crush tablets.
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
following concomitant administration with other drugs or, alternatively, the effect of
concomitant administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug
interaction between WELLBUTRIN SR and drugs that are substrates or inhibitors of the
CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, in vitro
studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir,
ritonavir, and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been
performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not
appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant
administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites
were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg
WELLBUTRIN SR Tablets with and without 800 mg of cimetidine, the pharmacokinetics of
bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases
in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and
erythrohydrobupropion.
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single dose
pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to
8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be the potential for clinically important alterations of blood levels of
coadministered drugs.
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including most
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a
study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6
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isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of
50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
has not been formally studied.
Therefore, co-administration of bupropion with drugs that are metabolized by CYP2D6
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
should be approached with caution and should be initiated at the lower end of the dose range of
the concomitant medication. If bupropion is added to the treatment regimen of a patient already
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original
medication should be considered, particularly for those concomitant medications with a narrow
therapeutic index.
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of WELLBUTRIN SR Tablets to patients receiving either levodopa or
amantadine concurrently should be undertaken with caution, using small initial doses and
gradual dose increases.
Drugs That Lower Seizure Threshold: Concurrent administration of
WELLBUTRIN SR Tablets and agents (e.g., antipsychotics, other antidepressants, theophylline,
systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme
caution (see WARNINGS). Low initial dosing and gradual dose increases should be employed.
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
Alcohol: In postmarketing experience, there have been rare reports of adverse
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
during treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with
WELLBUTRIN SR should be minimized or avoided (also see CONTRAINDICATIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These
doses are approximately 7 and 2 times the maximum recommended human dose (MRHD),
respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative
lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a
mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen
in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
either study.
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Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in
the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in
vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
fertility.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the maximum recommended human dose [MRHD], respectively,
on a mg/m2 basis), during the period of organogenesis. No clear evidence of teratogenic activity
was found in either species; however, in rabbits, slightly increased incidences of fetal
malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day,
approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were
seen at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately
7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation,
there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women. This retrospective, managed-care database
study assessed the risk of congenital malformations overall, and cardiovascular malformations
specifically, following exposure to bupropion in the first trimester compared to the risk of these
malformations following exposure to other antidepressants in the first trimester and bupropion
outside of the first trimester. This study included 7,005 infants with antidepressant exposure
during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study
showed no greater risk for congenital malformations overall, or cardiovascular malformations
specifically, following first trimester bupropion exposure compared to exposure to all other
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of
this study have not been corroborated. WELLBUTRIN SR should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
To monitor fetal outcomes of pregnant women exposed to WELLBUTRIN SR,
GlaxoSmithKline maintains a Bupropion Pregnancy Registry. Health care providers are
encouraged to register patients by calling (800) 336-2176.
Labor and Delivery: The effect of WELLBUTRIN SR Tablets on labor and delivery in
humans is unknown.
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
milk. Because of the potential for serious adverse reactions in nursing infants from
WELLBUTRIN SR Tablets, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone
considering the use of WELLBUTRIN SR in a child or adolescent must balance the potential
risks with the clinical need.
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Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
clinical trials using the immediate-release formulation of bupropion (depression studies). No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals cannot
be ruled out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
metabolites in elderly subjects was similar to that of younger subjects; however, another
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to monitor renal
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS (See also WARNINGS and PRECAUTIONS.)
The information included under the Incidence in Controlled Trials subsection of ADVERSE
REACTIONS is based primarily on data from controlled clinical trials with WELLBUTRIN SR
Tablets. Information on additional adverse events associated with the sustained-release
formulation of bupropion in smoking cessation trials, as well as the immediate-release
formulation of bupropion, is included in a separate section (see Other Events Observed During
the Clinical Development and Postmarketing Experience of Bupropion).
Incidence in Controlled Trials With WELLBUTRIN SR: Adverse Events Associated
With Discontinuation of Treatment Among Patients Treated With
WELLBUTRIN SR Tablets: In placebo-controlled clinical trials, 9% and 11% of patients
treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 4% of patients
treated with placebo discontinued treatment due to adverse events. The specific adverse events in
these trials that led to discontinuation in at least 1% of patients treated with either 300 or
400 mg/day of WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed
in Table 4.
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18
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Table 4. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Rash
2.4%
0.9%
0.0%
Nausea
0.8%
1.8%
0.3%
Agitation
0.3%
1.8%
0.3%
Migraine
0.0%
1.8%
0.3%
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
Adverse Events Occurring at an Incidence of 1% or More Among Patients
Treated With WELLBUTRIN SR Tablets: Table 5 enumerates treatment-emergent adverse
events that occurred among patients treated with 300 and 400 mg/day of WELLBUTRIN SR
Tablets and with placebo in placebo-controlled trials. Events that occurred in either the 300- or
400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo
group are included. Reported adverse events were classified using a COSTART-based
Dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug are
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward
events in the course of usual medical practice where patient characteristics and other factors
differ from those that prevailed in the clinical trials. These incidence figures also cannot be
compared with those obtained from other clinical studies involving related drug products as each
group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
and/or clinical importance of the events. A better perspective on the serious adverse events
associated with the use of WELLBUTRIN SR Tablets is provided in the WARNINGS and
PRECAUTIONS sections.
Table 5. Treatment-Emergent Adverse Events in Placebo-Controlled Trials*
Body System/
Adverse Event
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
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19
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous
system stimulation
2%
1%
1%
Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
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20
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Blurred vision or
diplopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal hemorrhage†
0%
2%
—
Urinary tract
infection
1%
0%
—
* Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day
of WELLBUTRIN SR Tablets, but equally or more frequently in the placebo group, were:
abnormal dreams, accidental injury, acne, appetite increased, back pain, bronchitis,
dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory
disorder, rhinitis, and tooth disorder.
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
† Incidence based on the number of female patients.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:
Adverse events from Table 5 occurring in at least 5% of patients treated with
WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed below for the
300- and 400-mg/day dose groups.
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and
tremor.
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry
mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
frequency.
Other Events Observed During the Clinical Development and Postmarketing
Experience of Bupropion: In addition to the adverse events noted above, the following
events have been reported in clinical trials and postmarketing experience with the
sustained-release formulation of bupropion in depressed patients and in nondepressed smokers,
as well as in clinical trials and postmarketing clinical experience with the immediate-release
formulation of bupropion.
Adverse events for which frequencies are provided below occurred in clinical trials with the
sustained-release formulation of bupropion. The frequencies represent the proportion of patients
who experienced a treatment-emergent adverse event on at least one occasion in
placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients
who experienced an adverse event requiring discontinuation of treatment in an open-label
surveillance study with WELLBUTRIN SR Tablets (n = 3,100). All treatment-emergent adverse
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730
events are included except those listed in Tables 2 through 5, those events listed in other
safety-related sections, those adverse events subsumed under COSTART terms that are either
overly general or excessively specific so as to be uninformative, those events not reasonably
associated with the use of the drug, and those events that were not serious and occurred in fewer
than 2 patients. Events of major clinical importance are described in the WARNINGS and
PRECAUTIONS sections of the labeling.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions of frequency: Frequent adverse events are defined as those
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
Adverse events for which frequencies are not provided occurred in clinical trials or
postmarketing experience with bupropion. Only those adverse events not previously listed for
sustained-release bupropion are included. The extent to which these events may be associated
with WELLBUTRIN SR is unknown.
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and
photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash
and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble
serum sickness (see PRECAUTIONS).
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
vasodilation. Rare was syncope. Also observed were complete atrioventricular block,
extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS),
myocardial infarction, phlebitis, and pulmonary embolism.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of
tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage,
hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
inappropriate antidiuretic hormone.
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT
and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
observed when bupropion was coadministered with warfarin.
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed
was glycosuria.
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle
rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Infrequent were abnormal coordination, decreased libido,
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also
observed were abnormal electroencephalogram (EEG), akinesia, aggression, aphasia, coma,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome,
hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid
ideation, restlessness, and unmasking tardive dyskinesia.
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative
dermatitis, and hirsutism.
Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed
were deafness, diplopia, increased intraocular pressure, and mydriasis.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed were
abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection,
salpingitis, urinary incontinence, urinary retention, and vaginitis.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Bupropion is not a controlled substance.
Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted
in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients
showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
bupropion produced mild amphetamine-like activity as compared to placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of
drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing
to amphetamine or stimulant abusers. However, higher doses that could not be tested because of
the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Animals: Studies in rodents and primates have shown that bupropion exhibits some
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of
responding in several schedule-controlled behavior paradigms. In primate models to assess the
positive reinforcing effects of psychoactive drugs, bupropion was self-administered
intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative
stimulus effects in drug discrimination paradigms used to characterize the subjective effects of
psychoactive drugs.
OVERDOSAGE
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
reported. Seizure was reported in approximately one third of all cases. Other serious reactions
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Fever, muscle
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported
mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
in these patients.
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first
48 hours post-ingestion. General supportive and symptomatic measures are also recommended.
Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with
appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in
symptomatic patients.
Activated charcoal should be administered. There is no experience with the use of forced
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
overdoses. No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with WELLBUTRIN SR, hospitalization following
suspected overdose should be considered. Based on studies in animals, it is recommended that
seizures be treated with intravenous benzodiazepine administration and other supportive
measures, as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center for additional information on the treatment of
any overdose. Telephone numbers for certified poison control centers are listed in the
Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
General Dosing Considerations: It is particularly important to administer
WELLBUTRIN SR Tablets in a manner most likely to minimize the risk of seizure (see
WARNINGS). Gradual escalation in dosage is also important if agitation, motor restlessness,
and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary,
these effects may be managed by temporary reduction of dose or the short-term administration of
an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required
beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses.
If distressing, untoward effects supervene, dose escalation should be stopped.
WELLBUTRIN SR should be swallowed whole and not crushed, divided, or chewed.
Initial Treatment: The usual adult target dose for WELLBUTRIN SR Tablets is 300 mg/day,
given as 150 mg twice daily. Dosing with WELLBUTRIN SR Tablets should begin at
150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately
tolerated, an increase to the 300-mg/day target dose, given as 150 mg twice daily, may be made
as early as day 4 of dosing. There should be an interval of at least 8 hours between successive
doses.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full
antidepressant effect of WELLBUTRIN SR Tablets may not be evident until 4 weeks of
treatment or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg
twice daily, may be considered for patients in whom no clinical improvement is noted after
several weeks of treatment at 300 mg/day.
Maintenance Treatment: It is generally agreed that acute episodes of depression require
several months or longer of sustained pharmacological therapy beyond response to the acute
episode. In a study in which patients with major depressive disorder, recurrent type, who had
responded during 8 weeks of acute treatment with WELLBUTRIN SR were assigned randomly
to placebo or to the same dose of WELLBUTRIN SR (150 mg twice daily) during 44 weeks of
maintenance treatment as they had received during the acute stabilization phase, longer-term
efficacy was demonstrated (see CLINICAL TRIALS under CLINICAL PHARMACOLOGY).
Based on these limited data, it is unknown whether or not the dose of WELLBUTRIN SR needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment and the
appropriate dose for such treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN SR
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should
not exceed 100 mg every day or 150 mg every other day in these patients. WELLBUTRIN SR
should be used with caution in patients with hepatic impairment (including mild to moderate
hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with
mild to moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and
PRECAUTIONS).
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN SR
should be used with caution in patients with renal impairment and a reduced frequency and/or
dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are blue,
round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
(NDC 0173-0947-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
purple, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150" in bottles of
60 (NDC 0173-0135-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are light
pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of 60
(NDC 0173-0722-00) tablets.
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in a
tight, light-resistant container as defined in the USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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MEDICATION GUIDE
WELLBUTRIN SR® (WELL byu-trin)
(bupropion hydrochloride) Sustained-Release Tablets
Read this Medication Guide carefully before you start using WELLBUTRIN SR and each time
you get a refill. There may be new information. This information does not take the place of
talking with your doctor about your medical condition or your treatment. If you have any
questions about WELLBUTRIN SR, ask your doctor or pharmacist.
IMPORTANT: Be sure to read both sections of this Medication Guide. The first section is
about the risk of suicidal thoughts and actions with antidepressant medicines; the second
section is entitled “What other important information should I know about
WELLBUTRIN SR?”
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of suicidal thoughts and actions with
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started or
when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Call a healthcare provider right away if you or your family member has any of the
following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare provider.
Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating it.
Patients and their families or other caregivers should discuss all treatment choices with the
healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines
that you or your family member takes. Keep a list of all medicines to show the healthcare
provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child’s healthcare provider for more information.
WELLBUTRIN SR has not been studied in children under the age of 18 and is not approved for
use in children and teenagers.
What other important information should I know about WELLBUTRIN SR?
There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN SR, especially
in people:
• with certain medical problems.
• who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN SR. For more
information, see the sections “Who should not take WELLBUTRIN SR?” and “What should I
tell my doctor before using WELLBUTRIN SR?” Tell your doctor about all of your medical
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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conditions and all the medicines you take. Do not take any other medicines while you are
using WELLBUTRIN SR unless your doctor has said it is okay to take them.
If you have a seizure while taking WELLBUTRIN SR, stop taking the tablets and call your
doctor right away. Do not take WELLBUTRIN SR again if you have a seizure.
What is WELLBUTRIN SR?
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type of
depression called major depressive disorder.
Who should not take WELLBUTRIN SR?
Do not take WELLBUTRIN SR if you
• have or had a seizure disorder or epilepsy.
• are taking ZYBAN® (used to help people stop smoking) or any other medicines that
contain bupropion hydrochloride, such as WELLBUTRIN® Tablets or WELLBUTRIN
XL® Extended-Release Tablets. Bupropion is the same active ingredient that is in
WELLBUTRIN SR.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these
make you sleepy) or benzodiazepines and you stop using them all of a sudden.
• have taken within the last 14 days medicine for depression called a monoamine oxidase
inhibitor (MAOI), such as NARDIL®*(phenelzine sulfate), PARNATE®(tranylcypromine
sulfate), or MARPLAN®*(isocarboxazid).
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of the
inactive ingredients. See the end of this leaflet for a complete list of ingredients in
WELLBUTRIN SR.
What should I tell my doctor before using WELLBUTRIN SR?
• Tell your doctor about your medical conditions. Tell your doctor if you:
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN SR can
harm your unborn baby. If you can use WELLBUTRIN SR while you are pregnant, talk
to your doctor about how you can be on the Bupropion Pregnancy Registry.
• are breastfeeding. WELLBUTRIN SR passes through your milk. It is not known if
WELLBUTRIN SR can harm your baby.
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
• have an eating disorder such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
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• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
• drink a lot of alcohol.
• abuse prescription medicines or street drugs.
• Tell your doctor about all the medicines you take, including prescription and non-
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
chances of having seizures or other serious side effects if you take them while you are using
WELLBUTRIN SR.
How should I take WELLBUTRIN SR?
• Take WELLBUTRIN SR exactly as prescribed by your doctor.
• Do not chew, cut, or crush WELLBUTRIN SR Tablets. You must swallow the tablets
whole. Tell your doctor if you cannot swallow medicine tablets.
• Take WELLBUTRIN SR at the same time each day.
• Take your doses of WELLBUTRIN SR at least 8 hours apart.
• You may take WELLBUTRIN SR with or without food.
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and
take your next tablet at the regular time. This is very important. Too much
WELLBUTRIN SR can increase your chance of having a seizure.
• If you take too much WELLBUTRIN SR, or overdose, call your local emergency room or
poison control center right away.
• Do not take any other medicines while using WELLBUTRIN SR unless your doctor has
told you it is okay.
• It may take several weeks for you to feel that WELLBUTRIN SR is working. Once you feel
better, it is important to keep taking WELLBUTRIN SR exactly as directed by your doctor.
Call your doctor if you do not feel WELLBUTRIN SR is working for you.
• Do not change your dose or stop taking WELLBUTRIN SR without talking with your doctor
first.
What should I avoid while taking WELLBUTRIN SR?
• Do not drink a lot of alcohol while taking WELLBUTRIN SR. If you usually drink a lot of
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking
alcohol, you may increase your chance of having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR affects
you. WELLBUTRIN SR can impair your ability to perform these tasks.
What are possible side effects of WELLBUTRIN SR?
• Seizures. Some patients get seizures while taking WELLBUTRIN SR. If you have a seizure
while taking WELLBUTRIN SR, stop taking the tablets and call your doctor right
away. Do not take WELLBUTRIN SR again if you have a seizure.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
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• Hypertension (high blood pressure). Some patients get high blood pressure, sometimes
severe, while taking WELLBUTRIN SR. The chance of high blood pressure may be
increased if you also use nicotine replacement therapy (for example, a nicotine patch) to help
you stop smoking.
• Severe allergic reactions: Stop taking WELLBUTRIN SR and call your doctor right
away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the
mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble
breathing. These could be signs of a serious allergic reaction.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
taking WELLBUTRIN SR, including delusions (believe you are someone else),
hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are
against you), or feeling confused. If this happens to you, call your doctor.
The most common side effects of WELLBUTRIN SR are loss of appetite, dry mouth, skin rash,
sweating, ringing in the ears, shakiness, stomach pain, agitation, anxiety, dizziness, trouble
sleeping, muscle pain, nausea, fast heartbeat, sore throat, and urinating more often.
If you have nausea, you may want to take your medicine with food. If you have trouble sleeping,
do not take your medicine too close to bedtime.
Tell your doctor right away about any side effects that bother you.
These are not all the side effects of WELLBUTRIN SR. For a complete list, ask your doctor or
pharmacist.
How should I store WELLBUTRIN SR?
• Store WELLBUTRIN SR at room temperature. Store out of direct sunlight. Keep
WELLBUTRIN SR in its tightly closed bottle.
• WELLBUTRIN SR tablets may have an odor.
General Information about WELLBUTRIN SR.
• Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use WELLBUTRIN SR for a condition for which it was not prescribed. Do
not give WELLBUTRIN SR to other people, even if they have the same symptoms you have.
It may harm them. Keep WELLBUTRIN SR out of the reach of children.
This Medication Guide summarizes important information about WELLBUTRIN SR. For more
information, talk with your doctor. You can ask your doctor or pharmacist for information about
WELLBUTRIN SR that is written for health professionals.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
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What are the ingredients in WELLBUTRIN SR?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. In
addition, the 100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C
Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40
Lake. The tablets are printed with edible black ink.
*The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc.
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This Medication Guide has been approved by the U.S. Food and Drug Administration.
June 2007
WLS:4MG
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Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
or DSM Pharmaceuticals, Inc.
Greenville, NC 27834
©2007, GlaxoSmithKline. All rights reserved.
June 2007
WLS:2PI
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:30.576557
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020358s043lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 43}
|
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NDA 18-644/S-039
NDA 18-644/S-040
NDA 20-358/S-046
NDA 20-358/S-047
Page 33
PRESCRIBING INFORMATION
WELLBUTRIN SR®
(bupropion hydrochloride)
Sustained-Release Tablets
WARNING
Suicidality and Antidepressant Drugs
Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared
to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone
considering the use of WELLBUTRIN SR or any other antidepressant in a child, adolescent, or
young adult must balance this risk with the clinical need. Short-term studies did not show an
increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age
24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
older. Depression and certain other psychiatric disorders are themselves associated with increases
in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening, suicidality, or unusual
changes in behavior. Families and caregivers should be advised of the need for close observation
and communication with the prescriber. WELLBUTRIN SR is not approved for use in pediatric
patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric
Disorders, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and
WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the
name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not limited
to depression, suicidal ideation, suicide attempt, and completed suicide have been
reported in patients taking bupropion for smoking cessation. Some cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal
ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be
observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation,
depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide.
These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide
have been reported in some patients attempting to quit smoking while taking ZYBAN in the
postmarketing experience. When symptoms were reported, most were during treatment with
ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have
occurred in patients with and without pre-existing psychiatric disease; some have experienced
worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as
schizophrenia, bipolar disorder, and major depressive disorder did not participate in the
premarketing studies of ZYBAN.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-644/S-039
NDA 18-644/S-040
NDA 20-358/S-046
NDA 20-358/S-047
Page 34
Advise patients and caregivers that the patient using bupropion for smoking
cessation should stop taking bupropion and contact a healthcare provider
immediately if agitation, hostility, depressed mood, or changes in thinking or
behavior that are not typical for the patient are observed, or if the patient develops
suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of
symptoms after discontinuation of ZYBAN was reported, although in some cases the
symptoms persisted; therefore, ongoing monitoring and supportive care should be provided
until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the
benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence
from smoking for as long as 6 months compared to treatment with placebo. The health
benefits of quitting smoking are immediate and substantial. (See WARNINGS:
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment and
PRECAUTIONS: Information for Patients.)
DESCRIPTION
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class,
is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to
phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
structural formula is: chemical structure
WELLBUTRIN SR Tablets are supplied for oral administration as 100-mg (blue), 150-mg
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol,
polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the 100-mg
tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2 Lake and
FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
CLINICAL PHARMACOLOGY
Pharmacodynamics: Bupropion is a relatively weak inhibitor of the neuronal uptake of
norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of
serotonin. While the mechanism of action of bupropion, as with other antidepressants, is unknown,
it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
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Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and
pharmacokinetics of the individual enantiomers have not been studied. The mean elimination
half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma
concentrations of bupropion are reached within 8 days. In a study comparing chronic dosing with
WELLBUTRIN SR Tablets 150 mg twice daily to the immediate-release formulation of bupropion
at 100 mg 3 times daily, peak plasma concentrations of bupropion at steady state for
WELLBUTRIN SR Tablets were approximately 85% of those achieved with the immediate-release
formulation. There was equivalence for bupropion AUCs, as well as equivalence for both peak
plasma concentration and AUCs for all 3 of the detectable bupropion metabolites. Thus, at steady
state, WELLBUTRIN SR Tablets, given twice daily, and the immediate-release formulation of
bupropion, given 3 times daily, are essentially bioequivalent for both bupropion and the 3
quantitatively important metabolites.
Absorption: Following oral administration of WELLBUTRIN SR Tablets to healthy
volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. Food increased
Cmax and AUC of bupropion by 11% and 17%, respectively, indicating that there is no clinically
significant food effect.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have
been shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl
group of bupropion, and the amino-alcohol isomers threohydrobupropion and
erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings
suggest that cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation
of hydroxybupropion, while cytochrome P450 isoenzymes are not involved in the formation of
threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine
conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The
potency and toxicity of the metabolites relative to bupropion have not been fully characterized.
However, it has been demonstrated in an antidepressant screening test in mice that
hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and
erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance
because the plasma concentrations of the metabolites are as high or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug
interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6
(CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6
(CYP2D6), there is the potential for drug-drug interactions when bupropion is coadministered with
drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
approximately 6 hours after administration of WELLBUTRIN SR Tablets. Peak plasma
concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug at
steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its
AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the
erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
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hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37
(±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
respectively.
Bupropion and its metabolites exhibit linear
kinetics following chronic administration of 300 to 450 mg/day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with
the extensive metabolism of bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected
to influence the degree and extent of accumulation of the active metabolites of bupropion. The
elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic
function because they are moderately polar compounds and are likely to undergo further
metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
patients with mild-to-severe cirrhosis. The first study showed that the half-life of
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for
bupropion and the other metabolites in the 2 patient groups were minimal.
The second study showed no statistically significant differences in the pharmacokinetics of
bupropion and its active metabolites in 9 patients with mild-to-moderate hepatic cirrhosis compared
to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic
parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in patients with
mild-to-moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the
bupropion Cmax and AUC were substantially increased (mean difference: by approximately 70%
and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the
mean bupropion half-life was also longer (29 hours in patients with severe hepatic cirrhosis vs. 19
hours in healthy subjects). For the metabolite hydroxybupropion, the mean Cmax was approximately
69% lower. For the combined amino-alcohol isomers threohydrobupropion and
erythrohydrobupropion, the mean Cmax was approximately 31% lower. The mean AUC increased
by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The
median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for
threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and
threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe
hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and
DOSAGE AND ADMINISTRATION).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
renal impairment. An inter-study comparison between normal subjects and patients with end-stage
renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2
groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8
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fold increase, respectively, in AUC for patients with end-stage renal failure. A second study,
comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ±
10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release bupropion was
approximately 2-fold higher in patients with impaired renal function while levels of the
hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2
groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced
by impaired renal function (see PRECAUTIONS: Renal Impairment).
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in
14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on
x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed,
compared to healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
been fully characterized, but an exploration of steady-state bupropion concentrations from several
depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times
daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of
bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion
and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest
there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic
study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation
of bupropion and its metabolites (see PRECAUTIONS: Geriatric Use).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were
nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no
statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its
active metabolites between smokers and nonsmokers.
CLINICAL TRIALS
The efficacy of the immediate-release formulation of bupropion as a treatment for
depression was established in two 4-week, placebo-controlled trials in adult inpatients with
depression and in one 6-week, placebo-controlled trial in adult outpatients with depression. In the
first study, patients were titrated in a bupropion dose range of 300 to 600 mg/day on a 3 times daily
schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial demonstrated
the effectiveness of the immediate-release formulation of bupropion on the Hamilton Depression
Rating Scale (HDRS) total score, the depressed mood item (item 1) from that scale, and the Clinical
Global Impressions (CGI) severity score. A second study included 2 fixed doses of the
immediate-release formulation of bupropion (300 and 450 mg/day) and placebo. This trial
demonstrated the effectiveness of the immediate-release formulation of bupropion, but only at the
450-mg/day dose; the results were positive for the HDRS total score and the CGI severity score,
but not for HDRS item 1. In the third study, outpatients received 300 mg/day of the
immediate-release formulation of bupropion. This study demonstrated the effectiveness of the
immediate-release formulation of bupropion on the HDRS total score, HDRS item 1, the
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Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI improvement
score.
Although there are not as yet independent
trials demonstrating the antidepressant effectiveness of the sustained-release formulation of
bupropion, studies have demonstrated the bioequivalence of the immediate-release and
sustained-release forms of bupropion under steady-state conditions, i.e., bupropion
sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the
immediate-release formulation of bupropion, with regard to both rate and extent of absorption, for
parent drug and metabolites.
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder,
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
twice daily) were randomized to continuation of their same WELLBUTRIN SR dose or placebo,
for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI
Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks.
Relapse during the double-blind phase was defined as the investigator’s judgment that drug
treatment was needed for worsening depressive symptoms. Patients receiving continued
WELLBUTRIN SR treatment experienced significantly lower relapse rates over the subsequent
44 weeks compared to those receiving placebo.
INDICATIONS AND USAGE
WELLBUTRIN SR is indicated for the treatment of major depressive disorder.
The efficacy of bupropion in the treatment of a major depressive episode was established in
two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of depressed
outpatients whose diagnoses corresponded most closely to the Major Depression category of the
APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY).
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss
of interest or pleasure; in addition, at least 5 of the following symptoms have been present during
the same 2-week period and represent a change from previous functioning: depressed mood,
markedly diminished interest or pleasure in usual activities, significant change in weight and/or
appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings
of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal
ideation.
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial (see
CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use
WELLBUTRIN SR for extended periods should periodically reevaluate the long-term usefulness of
the drug for the individual patient.
CONTRAINDICATIONS
WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
WELLBUTRIN SR is contraindicated in patients treated with ZYBAN (bupropion
hydrochloride) Sustained-Release Tablets; WELLBUTRIN (bupropion hydrochloride), the
immediate-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended
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release formulation; or any other medications that contain bupropion because the incidence of
seizure is dose dependent.
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of
bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for
bulimia with the immediate-release formulation of bupropion.
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
alcohol or sedatives (including benzodiazepines).
The concurrent administration of WELLBUTRIN SR Tablets and a monoamine oxidase
(MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an
MAO inhibitor and initiation of treatment with WELLBUTRIN SR Tablets.
WELLBUTRIN SR is contraindicated in patients who have shown an allergic response to
bupropion or the other ingredients that make up WELLBUTRIN SR Tablets.
WARNINGS
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients with
major depressive disorder (MDD), both adult and pediatric, may experience worsening of their
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes
in behavior, whether or not they are taking antidepressant medications, and this risk may persist
until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There
has been a long-standing concern, however, that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early phases
of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs
and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality)
in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295
short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
increase in the younger patients for almost all drugs studied. There were differences in absolute risk
of suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1,000 patients treated) are provided in Table 1.
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Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug therapy, or at times of
dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major depressive
disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal
link between the emergence of such symptoms and either the worsening of depression and/or the
emergence of suicidal impulses has not been established, there is concern that such symptoms may
represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression or
suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability, unusual
changes in behavior, and the other symptoms described above, as well as the emergence of
suicidality, and to report such symptoms immediately to healthcare providers. Such
monitoring should include daily observation by families and caregivers. Prescriptions for
WELLBUTRIN SR should be written for the smallest quantity of tablets consistent with good
patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are not approved for smoking
cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious
neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation
(see BOXED WARNING, ADVERSE REACTIONS). These have included changes in mood
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(including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal
ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation,
suicide attempt, and completed suicide. Some reported cases may have been complicated
by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed
mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal
ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking
bupropion who continued to smoke. When symptoms were reported, most were during
bupropion treatment, but some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without pre-existing psychiatric
disease; some have experienced worsening of their psychiatric illnesses. All patients being
treated with bupropion as part of smoking cessation treatment should be observed for
neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder,
and major depressive disorder did not participate in the pre-marketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking
cessation should stop taking bupropion and contact a healthcare provider
immediately if agitation, depressed mood, or changes in behavior or thinking that
are not typical for the patient are observed, or if the patient develops suicidal
ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after
discontinuation of ZYBAN was reported, although in some cases the symptoms persisted,
therefore, ongoing monitoring and supportive care should be provided until symptoms
resolve.
The risks of using bupropion for smoking cessation should be weighed against the
benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence
from smoking for as long as six months compared to treatment with placebo. The health
benefits of quitting smoking are immediate and substantial.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled trials)
that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately screened
to determine if they are at risk for bipolar disorder; such screening should include a detailed
psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that WELLBUTRIN SR is not approved for use in treating bipolar depression.
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN SR
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation
treatment, and that WELLBUTRIN SR should not be used in combination with ZYBAN, or any
other medications that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride), the
immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the extended-
release formulation.
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Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures is
also related to patient factors, clinical situations, and concomitant medications, which must
be considered in selection of patients for therapy with WELLBUTRIN SR.
WELLBUTRIN SR should be discontinued and not restarted in patients who experience a
seizure while on treatment.
• Dose: At doses of WELLBUTRIN SR up to a dose of 300 mg/day, the incidence of seizure
is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the
maximum recommended dose of 400 mg/day.
Data for the immediate-release formulation of bupropion revealed a seizure
incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in
patients treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of
this dose range is close to the currently recommended maximum dose of 400 mg/day for
WELLBUTRIN SR Tablets. This seizure incidence (0.4%) may exceed that of other
marketed antidepressants and WELLBUTRIN SR Tablets up to 300 mg/day by as much
as 4-fold. This relative risk is only an approximate estimate because no direct comparative
studies have been conducted.
Additional data accumulated for the immediate-release formulation of
bupropion suggested that the estimated seizure incidence increases almost tenfold between
450 and 600 mg/day, which is twice the usual adult dose and one and one-half the
maximum recommended daily dose (400 mg) of WELLBUTRIN SR Tablets. This
disproportionate increase in seizure incidence with dose incrementation calls for caution
in dosing.
Data for WELLBUTRIN SR Tablets revealed a seizure incidence of
approximately 0.1% (i.e., 3 of 3,100 patients followed prospectively) in patients treated at
doses in a range of 100 to 300 mg/day. It is not possible to know if the lower seizure
incidence observed in this study involving the sustained-release formulation of bupropion
resulted from the different formulation or the lower dose used. However, as noted above,
the immediate-release and sustained-release formulations are bioequivalent with regard
to both rate and extent of absorption during steady state (the most pertinent condition to
estimating seizure incidence), since most observed seizures occur under steady-state
conditions.
• Patient factors: Predisposing factors that may increase the risk of seizure with bupropion
use include history of head trauma or prior seizure, central nervous system (CNS) tumor,
the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure
threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include,
among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction
to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and
diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
theophylline, systemic steroids) are known to lower seizure threshold.
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Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
clinical experience gained during the development of bupropion suggests that the risk of
seizure may be minimized if
• the total daily dose of WELLBUTRIN SR Tablets does not exceed 400 mg,
• the daily dose is administered twice daily, and
• the rate of incrementation of dose is gradual.
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion
and/or its metabolites.
WELLBUTRIN SR should be administered with extreme caution to patients with a history
of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with
other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.)
that lower seizure threshold.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
likely to occur in such patients to a greater extent than usual. The dose should not exceed
100 mg every day or 150 mg every other day in these patients (see CLINICAL
PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was
an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs
receiving large doses of bupropion chronically, various histologic changes were seen in the liver,
and laboratory tests suggesting mild hepatocellular injury were noted.
PRECAUTIONS
General: Agitation and Insomnia: Patients in placebo-controlled trials with
WELLBUTRIN SR Tablets experienced agitation, anxiety, and insomnia as shown in Table 2.
Table 2. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Agitation
Anxiety
Insomnia
3%
5%
11%
9%
6%
16%
2%
3%
6%
In clinical studies, these symptoms were sometimes of sufficient magnitude to require
treatment with sedative/hypnotic drugs.
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6%
of patients treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 0.8%
of patients treated with placebo.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
patients treated with an immediate-release formulation of bupropion or with WELLBUTRIN SR
Tablets have been reported to show a variety of neuropsychiatric signs and symptoms, including
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Page 44
delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic
episodes in bipolar disorder patients during the depressed phase of their illness and may activate
latent psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.
Altered Appetite and Weight: In placebo-controlled studies, patients experienced
weight gain or weight loss as shown in Table 3.
Table 3. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
Lost >5 lbs
3%
14%
2%
19%
4%
6%
In studies conducted with the immediate-release formulation of bupropion, 35% of patients
receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the
immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s
depressive illness, the anorectic and/or weight-reducing potential of WELLBUTRIN SR Tablets
should be considered.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms
such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been
reported in clinical trials with bupropion. In addition, there have been rare spontaneous
postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock
associated with bupropion. A patient should stop taking WELLBUTRIN SR and consult a doctor if
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest
pain, edema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
hypersensitivity have been reported in association with bupropion. These symptoms may resemble
serum sickness.
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe,
requiring acute treatment, has been reported in patients receiving bupropion alone and in
combination with nicotine replacement therapy. These events have been observed in both patients
with and without evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence
of treatment-emergent hypertension in patients treated with the combination of sustained-release
bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-
release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and
3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The
majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated
with the combination of ZYBAN and NTS and 1 patient (0.4%) treated with NTS had study
medication discontinued due to hypertension compared to none of the patients treated with ZYBAN
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or placebo. Monitoring of blood pressure is recommended in patients who receive the combination
of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of WELLBUTRIN SR Tablets in
patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care
should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients
who had previously developed orthostatic hypotension while receiving tricyclic antidepressants,
and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive
heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the
study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation
of baseline hypertension.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in
patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is
required. WELLBUTRIN SR should be used with caution in patients with hepatic impairment
(including mild-to-moderate hepatic cirrhosis) and reduced frequency and/or dose should be
considered in patients with mild-to-moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse
effects that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
WARNINGS, and DOSAGE AND ADMINISTRATION).
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
patients with renal impairment. An inter-study comparison between normal subjects and patients
with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites
had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A
second study, comparing normal subjects and patients with moderate-to-severe renal impairment
(GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release
bupropion was approximately 2-fold higher in patients with impaired renal function while levels of
the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the
2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and subsequently excreted by the kidneys. WELLBUTRIN SR should be used with
caution in patients with renal impairment and a reduced frequency and/or dose should be
considered as bupropion and the metabolites of bupropion may accumulate in such patients to a
greater extent than usual. The patient should be closely monitored for possible adverse effects that
could indicate high drug or metabolite levels.
Information for Patients: Prescribers or other health professionals should inform patients, their
families, and their caregivers about the benefits and risks associated with treatment with
WELLBUTRIN SR and should counsel them in its appropriate use. A patient Medication Guide
about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and
Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information
Should I Know About WELLBUTRIN SR?” is available for WELLBUTRIN SR. The prescriber or
health professional should instruct patients, their families, and their caregivers to read the
Medication Guide and should assist them in understanding its contents. Patients should be given the
opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions
they may have. The complete text of the Medication Guide is reprinted at the end of this document.
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Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking WELLBUTRIN SR.
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders:
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of
anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,
akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior,
worsening of depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be advised to look
for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient’s prescriber or health professional, especially if they are
severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and behavior and indicate a
need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment: Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it
contains the same active ingredient as ZYBAN which is approved for this use. Patients should be
informed that quitting smoking, with or without ZYBAN, may be associated with nicotine
withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing
psychiatric illness. Furthermore, some patients have experienced changes in mood (including
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide
when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility,
depressed mood, or changes in thinking or behavior that are not typical for them, or if patients
develop suicidal ideation or behavior, they should be urged to report these symptoms to their
healthcare provider immediately.
Bupropion-Containing Products: Patients should be made aware that
WELLBUTRIN SR contains the same active ingredient found in ZYBAN, used as an aid to
smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination with
ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN,
the immediate-release formulation and WELLBUTRIN XL, the extended-release formulation).
As dose is increased during initial titration to doses above 150 mg/day, patients should be
instructed to take WELLBUTRIN SR Tablets in 2 divided doses, preferably with at least 8 hours
between successive doses, to minimize the risk of seizures.
Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if
they experience a seizure while on treatment.
Patients should be told that any CNS-active drug like WELLBUTRIN SR Tablets may
impair their ability to perform tasks requiring judgment or motor and cognitive skills.
Consequently, until they are reasonably certain that WELLBUTRIN SR Tablets do not adversely
affect their performance, they should refrain from driving an automobile or operating complex,
hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or
sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported
lower alcohol tolerance during treatment with WELLBUTRIN SR. Patients should be advised that
the consumption of alcohol should be minimized or avoided.
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Patients should be advised to inform their physicians if they are taking or plan to take any
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR Tablets
and other drugs may affect each other’s metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to swallow WELLBUTRIN SR Tablets whole so that the release
rate is not altered. Do not chew, divide, or crush tablets.
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
following concomitant administration with other drugs or, alternatively, the effect of concomitant
administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may
affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction
between WELLBUTRIN SR and drugs that are substrates or inhibitors of the CYP2B6 isoenzyme
(e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, in vitro studies suggest that
paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz
inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this
finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the
cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the
pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male
volunteers. Following oral administration of two 150-mg WELLBUTRIN SR Tablets with and
without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were
unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the
combined moieties of threohydrobupropion and erythrohydrobupropion.
While not systematically studied, certain drugs may induce the metabolism of bupropion
(e.g., carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single-dose
pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to
8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be the potential for clinically important alterations of blood levels of
coadministered drugs.
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including
most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics
are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a
study of 15 male subjects (aged 19 to 35 years) who were extensive metabolizers of the CYP2D6
isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of
50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
has not been formally studied.
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Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-
blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be
approached with caution and should be initiated at the lower end of the dose range of the
concomitant medication. If bupropion is added to the treatment regimen of a patient already
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication
should be considered, particularly for those concomitant medications with a narrow therapeutic
index.
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of WELLBUTRIN SR Tablets to patients receiving either levodopa or amantadine
concurrently should be undertaken with caution, using small initial doses and gradual dose
increases.
Drugs That Lower Seizure Threshold: Concurrent administration of
WELLBUTRIN SR Tablets and agents (e.g., antipsychotics, other antidepressants, theophylline,
systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution
(see WARNINGS). Low initial dosing and gradual dose increases should be employed.
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
Alcohol: In postmarketing experience, there have been rare reports of adverse
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during
treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with
WELLBUTRIN SR should be minimized or avoided (also see CONTRAINDICATIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These doses
are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively,
on a mg/m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver
at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m2 basis); lower
doses were not tested. The question of whether or not such lesions may be precursors of neoplasms
of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no
increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains
in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in
vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
fertility.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis), during the period of
organogenesis. No clear evidence of teratogenic activity was found in either species; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed
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at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and
greater. Decreased fetal weights were seen at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
and lactation, there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women. This retrospective, managed-care
database study assessed the risk of congenital malformations overall and cardiovascular
malformations specifically, following exposure to bupropion in the first trimester compared to the
risk of these malformations following exposure to other antidepressants in the first trimester and
bupropion outside of the first trimester. This study included 7,005 infants with antidepressant
exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The
study showed no greater risk for congenital malformations overall or cardiovascular malformations
specifically, following first trimester bupropion exposure compared to exposure to all other
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of this
study have not been corroborated. WELLBUTRIN SR should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of WELLBUTRIN SR Tablets on labor and delivery in humans
is unknown.
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
milk. Because of the potential for serious adverse reactions in nursing infants from
WELLBUTRIN SR Tablets, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see
BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric
Disorders). Anyone considering the use of WELLBUTRIN SR in a child or adolescent must
balance the potential risks with the clinical need.
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
clinical trials using the immediate-release formulation of bupropion (depression studies). No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
metabolites in elderly subjects was similar to that of younger subjects; however, another
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk
for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to monitor renal
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
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ADVERSE REACTIONS (See also WARNINGS and PRECAUTIONS.)
The information included under the Incidence in Controlled Trials subsection of ADVERSE
REACTIONS is based primarily on data from controlled clinical trials with WELLBUTRIN SR
Tablets. Information on additional adverse events associated with the sustained-release formulation
of bupropion in smoking cessation trials, as well as the immediate-release formulation of
bupropion, is included in a separate section (see Other Events Observed During the Clinical
Development and Postmarketing Experience of Bupropion).
Incidence in Controlled Trials With WELLBUTRIN SR: Adverse Events Associated
With Discontinuation of Treatment Among Patients Treated With WELLBUTRIN SR
Tablets: In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and
400 mg/day, respectively, of WELLBUTRIN SR Tablets and 4% of patients treated with placebo
discontinued treatment due to adverse events. The specific adverse events in these trials that led to
discontinuation in at least 1% of patients treated with either 300 or 400 mg/day of
WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed in Table 4.
Table 4. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Rash
Nausea
Agitation
Migraine
2.4%
0.8%
0.3%
0.0%
0.9%
1.8%
1.8%
1.8%
0.0%
0.3%
0.3%
0.3%
Adverse Events Occurring at an Incidence of 1% or More Among Patients
Treated With WELLBUTRIN SR Tablets: Table 5 enumerates treatment-emergent adverse
events that occurred among patients treated with 300 and 400 mg/day of WELLBUTRIN SR
Tablets and with placebo in placebo-controlled trials. Events that occurred in either the 300- or
400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo group
are included. Reported adverse events were classified using a COSTART-based Dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug
are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting,
physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of
untoward events in the course of usual medical practice where patient characteristics and other
factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be
compared with those obtained from other clinical studies involving related drug products as each
group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
and/or clinical importance of the events. A better perspective on the serious adverse events
associated with the use of WELLBUTRIN SR Tablets is provided in the WARNINGS and
PRECAUTIONS sections.
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Table 5. Treatment-Emergent Adverse Events in Placebo-Controlled Trialsa
Body System/
Adverse Event
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous system
stimulation
2%
1%
1%
Respiratory
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Pharyngitis
Sinusitis
Increased cough
3%
3%
1%
11%
1%
2%
2%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Blurred vision or
diplopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal
hemorrhageb
0%
2%
—
Urinary tract infection
1%
0%
—
a Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day of
WELLBUTRIN SR Tablets, but equally or more frequently in the placebo group, were:
abnormal dreams, accidental injury, acne, appetite increased, back pain, bronchitis,
dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory
disorder, rhinitis, and tooth disorder.
b Incidence based on the number of female patients.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
Incidence of Commonly Observed Adverse Events in Controlled Clinical
Trials: Adverse events from Table 5 occurring in at least 5% of patients treated with
WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed below for the 300-
and 400-mg/day dose groups.
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus,
and tremor.
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness,
dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
frequency.
Other Events Observed During the Clinical Development and Postmarketing
Experience of Bupropion: In addition to the adverse events noted above, the following events
have been reported in clinical trials and postmarketing experience with the sustained-release
formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical
trials and postmarketing clinical experience with the immediate-release formulation of bupropion.
Adverse events for which frequencies are provided below occurred in clinical trials with the
sustained-release formulation of bupropion. The frequencies represent the proportion of patients
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who experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled
studies for depression (n = 987) or smoking cessation (n = 1,013), or patients who experienced an
adverse event requiring discontinuation of treatment in an open-label surveillance study with
WELLBUTRIN SR Tablets (n = 3,100). All treatment-emergent adverse events are included except
those listed in Tables 2 through 5, those events listed in other safety-related sections, those adverse
events subsumed under COSTART terms that are either overly general or excessively specific so as
to be uninformative, those events not reasonably associated with the use of the drug, and those
events that were not serious and occurred in fewer than 2 patients. Events of major clinical
importance are described in the WARNINGS and PRECAUTIONS sections of the labeling.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions of frequency: Frequent adverse events are defined as those
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
Adverse events for which frequencies are not provided occurred in clinical trials or
postmarketing experience with bupropion. Only those adverse events not previously listed for
sustained-release bupropion are included. The extent to which these events may be associated with
WELLBUTRIN SR is unknown.
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and
photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash
and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum
sickness (see PRECAUTIONS).
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
vasodilation. Rare was syncope. Also observed were complete atrioventricular block, extrasystoles,
hypotension, hypertension (in some cases severe, see PRECAUTIONS), myocardial infarction,
phlebitis, and pulmonary embolism.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of
tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage,
hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
inappropriate antidiuretic hormone.
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT
and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed
when bupropion was coadministered with warfarin.
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed
was glycosuria.
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle
rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Infrequent were abnormal coordination, decreased libido,
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also
observed were abnormal electroencephalogram (EEG), akinesia, aggression, aphasia, coma,
completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal
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syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy,
paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative
dermatitis, and hirsutism.
Special Senses: Infrequent were accommodation abnormality and dry eye. Also
observed were deafness, diplopia, increased intraocular pressure, and mydriasis.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed
were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful
erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Bupropion is not a controlled substance.
Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted in
normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients
showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
bupropion produced mild amphetamine-like activity as compared to placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score
intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales
measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of
drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing to
amphetamine or stimulant abusers. However, higher doses that could not be tested because of the
risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Animals: Studies in rodents and primates have shown that bupropion exhibits some
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of responding
in several schedule-controlled behavior paradigms. In primate models to assess the positive
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
OVERDOSAGE
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
reported. Seizure was reported in approximately one-third of all cases. Other serious reactions
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or
arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
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uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in
these patients.
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation. Monitor
cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours post-
ingestion. General supportive and symptomatic measures are also recommended. Induction of
emesis is not recommended.
Activated charcoal should be administered. There is no experience with the use of forced
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
overdoses. No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with WELLBUTRIN SR, hospitalization following
suspected overdose should be considered. Based on studies in animals, it is recommended that
seizures be treated with intravenous benzodiazepine administration and other supportive measures,
as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement. The
physician should consider contacting a poison control center for additional information on the
treatment of any overdose. Telephone numbers for certified poison control centers are listed in the
Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
General Dosing Considerations: It is particularly important to administer WELLBUTRIN SR
Tablets in a manner most likely to minimize the risk of seizure (see WARNINGS). Gradual
escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen
during the initial days of treatment, are to be minimized. If necessary, these effects may be
managed by temporary reduction of dose or the short-term administration of an intermediate to
long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of
treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward
effects supervene, dose escalation should be stopped. WELLBUTRIN SR should be swallowed
whole and not crushed, divided, or chewed.
Initial Treatment: The usual adult target dose for WELLBUTRIN SR Tablets is 300 mg/day,
given as 150 mg twice daily. Dosing with WELLBUTRIN SR Tablets should begin at 150 mg/day
given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, an
increase to the 300-mg/day target dose, given as 150 mg twice daily, may be made as early as day 4
of dosing. There should be an interval of at least 8 hours between successive doses.
Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full
antidepressant effect of WELLBUTRIN SR Tablets may not be evident until 4 weeks of treatment
or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may
be considered for patients in whom no clinical improvement is noted after several weeks of
treatment at 300 mg/day.
Maintenance Treatment: It is generally agreed that acute episodes of depression require several
months or longer of sustained pharmacological therapy beyond response to the acute episode. In a
study in which patients with major depressive disorder, recurrent type, who had responded during
8 weeks of acute treatment with WELLBUTRIN SR were assigned randomly to placebo or to the
same dose of WELLBUTRIN SR (150 mg twice daily) during 44 weeks of maintenance treatment
as they had received during the acute stabilization phase, longer-term efficacy was demonstrated
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(see CLINICAL TRIALS under CLINICAL PHARMACOLOGY). Based on these limited data, it
is unknown whether or not the dose of WELLBUTRIN SR needed for maintenance treatment is
identical to the dose needed to achieve an initial response. Patients should be periodically
reassessed to determine the need for maintenance treatment and the appropriate dose for such
treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN SR
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not
exceed 100 mg every day or 150 mg every other day in these patients. WELLBUTRIN SR should
be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic
cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild-to
moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and
PRECAUTIONS).
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN SR
should be used with caution in patients with renal impairment and a reduced frequency and/or dose
should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are
blue, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
(NDC 0173-0947-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
purple, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150" in bottles of 60
(NDC 0173-0135-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are
light pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of
60 (NDC 0173-0722-00) tablets.
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in
a tight, light-resistant container as defined in the USP.
MEDICATION GUIDE
WELLBUTRIN SR® (WELL byu-trin)
(bupropion hydrochloride) Sustained-Release Tablets
Read this Medication Guide carefully before you start using WELLBUTRIN SR and each time you
get a refill. There may be new information. This information does not take the place of talking with
your doctor about your medical condition or your treatment. If you have any questions about
WELLBUTRIN SR, ask your doctor or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section
is about the risk of suicidal thoughts and actions with antidepressant medicines; the second
section is about the risk of changes in thinking and behavior, depression and suicidal
thoughts or actions with medicines used to quit smoking; and the third section is entitled
“What Other Important Information Should I Know About WELLBUTRIN SR?”
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Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of suicidal thoughts and actions
with antidepressant medicines. Talk to your, or your family member’s, healthcare
provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
4. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
5. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
6. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family
member?
Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or
feelings. This is very important when an antidepressant medicine is started or when the dose
is changed.
Call the healthcare provider right away to report new or sudden changes in mood, behavior,
thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider
between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following
symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• trouble sleeping (insomnia)
• attempts to commit suicide
• new or worse irritability
• new or worse depression
• acting aggressive, being angry, or violent
• new or worse anxiety
• acting on dangerous impulses
• feeling very agitated or restless
• an extreme increase in activity and talking (mania)
• panic attacks
• other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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• Never stop an antidepressant medicine without first talking to a healthcare provider.
Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important
to discuss all the risks of treating depression and also the risks of not treating it. Patients and
their families or other caregivers should discuss all treatment choices with the healthcare
provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that
you or your family member takes. Keep a list of all medicines to show the healthcare provider.
Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child’s healthcare provider for more information.
WELLBUTRIN SR has not been studied in children under the age of 18 and is not approved for use
in children and teenagers.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior,
Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking and
behavior, depression and suicidal thoughts or actions with drugs used to quit smoking.
Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the same active
ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or
actions while taking bupropion to help them quit smoking. These symptoms can develop during
treatment with bupropion or after stopping treatment with bupropion.
If you, your family member, or your caregiver notice agitation, hostility, depression, or
changes in thinking or behavior that are not typical for you, or you have any of the
following symptoms, stop taking bupropion and call your healthcare provider right away:
• thoughts about suicide or dying
• an extreme increase in activity and talking (mania)
• attempts to commit suicide
• abnormal thoughts or sensations
• new or worse depression
• seeing or hearing things that are not there
• new or worse anxiety
(hallucinations)
• panic attacks
• feeling people are against you (paranoia)
• feeling very agitated or restless
• feeling confused
• acting aggressive, being angry, or violent
• other unusual changes in behavior or mood
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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• acting on dangerous impulses
When you try to quit smoking, with or without bupropion, you may have symptoms that may be
due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability,
frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and
increased appetite or weight gain. Some people have even experienced suicidal thoughts when
trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of
mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had depression or
other mental illnesses. You should also tell your doctor about any symptoms you had
during other times you tried to quit smoking, with or without bupropion.
What Other Important Information Should I Know About WELLBUTRIN SR?
Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN SR,
especially in people:
• with certain medical problems.
• who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN SR. For more
information, see the sections “Who should not take WELLBUTRIN SR?” and “What should I
tell my doctor before using WELLBUTRIN SR?” Tell your doctor about all of your medical
conditions and all the medicines you take. Do not take any other medicines while you are
using WELLBUTRIN SR unless your doctor has said it is okay to take them.
If you have a seizure while taking WELLBUTRIN SR, stop taking the tablets and call
your doctor right away. Do not take WELLBUTRIN SR again if you have a seizure.
• High blood pressure (hypertension). Some people get high blood pressure, that can be
severe, while taking WELLBUTRIN SR. The chance of high blood pressure may be higher if
you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking.
• Severe allergic reactions. Some people have severe allergic reaction to
WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your doctor right away if
you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be
signs of a serious allergic reaction.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
taking WELLBUTRIN SR, including delusions (believe you are someone else), hallucinations
(seeing or hearing things that are not there), paranoia (feeling that people are against you), or
feeling confused. If this happens to you, call your doctor.
What is WELLBUTRIN SR?
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type of depression
called major depressive disorder.
Who should not take WELLBUTRIN SR?
Do not take WELLBUTRIN SR if you
• have or had a seizure disorder or epilepsy.
• are taking ZYBAN® (used to help people stop smoking) or any other medicines that
contain bupropion hydrochloride, such as WELLBUTRIN® Tablets or WELLBUTRIN
XL® Extended-Release Tablets. Bupropion is the same active ingredient that is in
WELLBUTRIN SR.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make
you sleepy) or benzodiazepines and you stop using them all of a sudden.
• have taken within the last 14 days medicine for depression called a monoamine oxidase
inhibitor (MAOI), such as NARDIL®*(phenelzine sulfate), PARNATE®(tranylcypromine
sulfate), or MARPLAN®*(isocarboxazid).
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of the inactive
ingredients. See the end of this leaflet for a complete list of ingredients in WELLBUTRIN SR.
What should I tell my doctor before using WELLBUTRIN SR?
Tell your doctor if you have ever had depression, suicidal thoughts or actions, or other mental
health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions.”
a. Tell your doctor about your other medical conditions including if you:
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN SR can
harm your unborn baby.
• are breastfeeding. WELLBUTRIN SR passes through your milk. It is not known if
WELLBUTRIN SR can harm your baby.
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
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• have an eating disorder such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
• drink a lot of alcohol.
• abuse prescription medicines or street drugs.
• Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
chances of having seizures or other serious side effects if you take them while you are using
WELLBUTRIN SR.
How should I take WELLBUTRIN SR?
• Take WELLBUTRIN SR exactly as prescribed by your doctor.
• Do not chew, cut, or crush WELLBUTRIN SR Tablets. You must swallow the tablets
whole. Tell your doctor if you cannot swallow medicine tablets.
• Take WELLBUTRIN SR at the same time each day.
• Take your doses of WELLBUTRIN SR at least 8 hours apart.
• You may take WELLBUTRIN SR with or without food.
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and take
your next tablet at the regular time. This is very important. Too much WELLBUTRIN SR can
increase your chance of having a seizure.
• If you take too much WELLBUTRIN SR, or overdose, call your local emergency room or
poison control center right away.
• Do not take any other medicines while using WELLBUTRIN SR unless your doctor has
told you it is okay.
• It may take several weeks for you to feel that WELLBUTRIN SR is working. Once you feel
better, it is important to keep taking WELLBUTRIN SR exactly as directed by your doctor.
Call your doctor if you do not feel WELLBUTRIN SR is working for you.
• Do not change your dose or stop taking WELLBUTRIN SR without talking with your doctor
first.
What should I avoid while taking WELLBUTRIN SR?
• Do not drink a lot of alcohol while taking WELLBUTRIN SR. If you usually drink a lot of
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking alcohol,
you may increase your chance of having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR affects you.
WELLBUTRIN SR can impair your ability to perform these tasks.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-644/S-039
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What are possible side effects of WELLBUTRIN SR?
WELLBUTRIN SR can cause serious side effects. Read this entire Medication Guide for more
information about these serious side effects.
The most common side effects of WELLBUTRIN SR are loss of appetite, dry mouth, skin rash,
sweating, ringing in the ears, shakiness, stomach pain, agitation, anxiety, dizziness, trouble
sleeping, muscle pain, nausea, fast heartbeat, sore throat, and urinating more often.
If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your
medicine too close to bedtime.
These are not all the side effects of WELLBUTRIN SR. For a complete list, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store WELLBUTRIN SR?
• Store WELLBUTRIN SR at room temperature. Store out of direct sunlight. Keep
WELLBUTRIN SR in its tightly closed bottle.
• WELLBUTRIN SR tablets may have an odor.
General Information about WELLBUTRIN SR.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do
not use WELLBUTRIN SR for a condition for which it was not prescribed. Do not give
WELLBUTRIN SR to other people, even if they have the same symptoms you have. It may harm
them. Keep WELLBUTRIN SR out of the reach of children.
This Medication Guide summarizes important information about WELLBUTRIN SR. For more
information, talk with your doctor. You can ask your doctor or pharmacist for information about
WELLBUTRIN SR that is written for health professionals.
What are the ingredients in WELLBUTRIN SR?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. In addition,
the 100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake. The
tablets are printed with edible black ink.
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RX Only
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WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, ZYBAN, and PARNATE are registered
trademarks of GlaxoSmithKline.
*The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
June 2009
WLS:5MG GSK logo
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
or DSM Pharmaceuticals, Inc.
Greenville, NC 27834
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©2009, GlaxoSmithKline. All rights reserved.
June 2009
WLS:4PI
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custom-source
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020358s046s047lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 46}
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PRESCRIBING INFORMATION
WELLBUTRIN SR®
(bupropion hydrochloride)
Sustained-Release Tablets
WARNING
Suicidality and Antidepressant Drugs
Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared
to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone
considering the use of WELLBUTRIN SR or any other antidepressant in a child, adolescent, or
young adult must balance this risk with the clinical need. Short-term studies did not show an
increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age
24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
older. Depression and certain other psychiatric disorders are themselves associated with increases
in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be
monitored appropriately and observed closely for clinical worsening, suicidality, or unusual
changes in behavior. Families and caregivers should be advised of the need for close observation
and communication with the prescriber. WELLBUTRIN SR is not approved for use in pediatric
patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric
Disorders, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and
WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the
name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not limited
to depression, suicidal ideation, suicide attempt, and completed suicide have been
reported in patients taking bupropion for smoking cessation. Some cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal
ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be
observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation,
depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide.
These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide
have been reported in some patients attempting to quit smoking while taking ZYBAN in the
postmarketing experience. When symptoms were reported, most were during treatment with
ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have
occurred in patients with and without pre-existing psychiatric disease; some have experienced
worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as
schizophrenia, bipolar disorder, and major depressive disorder did not participate in the
premarketing studies of ZYBAN.
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Advise patients and caregivers that the patient using bupropion for smoking
cessation should stop taking bupropion and contact a healthcare provider
immediately if agitation, hostility, depressed mood, or changes in thinking or
behavior that are not typical for the patient are observed, or if the patient develops
suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of
symptoms after discontinuation of ZYBAN was reported, although in some cases the
symptoms persisted; therefore, ongoing monitoring and supportive care should be provided
until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the
benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence
from smoking for as long as 6 months compared to treatment with placebo. The health
benefits of quitting smoking are immediate and substantial. (See WARNINGS:
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment and
PRECAUTIONS: Information for Patients.)
DESCRIPTION
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class,
is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to
phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
structural formula is: chemical structure
WELLBUTRIN SR Tablets are supplied for oral administration as 100-mg (blue), 150-mg
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol,
polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the 100-mg
tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2 Lake and
FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
CLINICAL PHARMACOLOGY
Pharmacodynamics: Bupropion is a relatively weak inhibitor of the neuronal uptake of
norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of
serotonin. While the mechanism of action of bupropion, as with other antidepressants, is unknown,
it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
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Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and
pharmacokinetics of the individual enantiomers have not been studied. The mean elimination
half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma
concentrations of bupropion are reached within 8 days. In a study comparing chronic dosing with
WELLBUTRIN SR Tablets 150 mg twice daily to the immediate-release formulation of bupropion
at 100 mg 3 times daily, peak plasma concentrations of bupropion at steady state for
WELLBUTRIN SR Tablets were approximately 85% of those achieved with the immediate-release
formulation. There was equivalence for bupropion AUCs, as well as equivalence for both peak
plasma concentration and AUCs for all 3 of the detectable bupropion metabolites. Thus, at steady
state, WELLBUTRIN SR Tablets, given twice daily, and the immediate-release formulation of
bupropion, given 3 times daily, are essentially bioequivalent for both bupropion and the 3
quantitatively important metabolites.
Absorption: Following oral administration of WELLBUTRIN SR Tablets to healthy
volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. Food increased
Cmax and AUC of bupropion by 11% and 17%, respectively, indicating that there is no clinically
significant food effect.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have
been shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl
group of bupropion, and the amino-alcohol isomers threohydrobupropion and
erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings
suggest that cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation
of hydroxybupropion, while cytochrome P450 isoenzymes are not involved in the formation of
threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine
conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The
potency and toxicity of the metabolites relative to bupropion have not been fully characterized.
However, it has been demonstrated in an antidepressant screening test in mice that
hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and
erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance
because the plasma concentrations of the metabolites are as high or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug
interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6
(CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6
(CYP2D6), there is the potential for drug-drug interactions when bupropion is coadministered with
drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
approximately 6 hours after administration of WELLBUTRIN SR Tablets. Peak plasma
concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug at
steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its
AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the
erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
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hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37
(±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
respectively.
Bupropion and its metabolites exhibit linear
kinetics following chronic administration of 300 to 450 mg/day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with
the extensive metabolism of bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected
to influence the degree and extent of accumulation of the active metabolites of bupropion. The
elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic
function because they are moderately polar compounds and are likely to undergo further
metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
patients with mild-to-severe cirrhosis. The first study showed that the half-life of
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for
bupropion and the other metabolites in the 2 patient groups were minimal.
The second study showed no statistically significant differences in the pharmacokinetics of
bupropion and its active metabolites in 9 patients with mild-to-moderate hepatic cirrhosis compared
to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic
parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in patients with
mild-to-moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the
bupropion Cmax and AUC were substantially increased (mean difference: by approximately 70%
and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the
mean bupropion half-life was also longer (29 hours in patients with severe hepatic cirrhosis vs. 19
hours in healthy subjects). For the metabolite hydroxybupropion, the mean Cmax was approximately
69% lower. For the combined amino-alcohol isomers threohydrobupropion and
erythrohydrobupropion, the mean Cmax was approximately 31% lower. The mean AUC increased
by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The
median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for
threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and
threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe
hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and
DOSAGE AND ADMINISTRATION).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
renal impairment. An inter-study comparison between normal subjects and patients with end-stage
renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2
groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8
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fold increase, respectively, in AUC for patients with end-stage renal failure. A second study,
comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ±
10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release bupropion was
approximately 2-fold higher in patients with impaired renal function while levels of the
hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2
groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced
by impaired renal function (see PRECAUTIONS: Renal Impairment).
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in
14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on
x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed,
compared to healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
been fully characterized, but an exploration of steady-state bupropion concentrations from several
depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times
daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of
bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion
and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest
there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic
study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation
of bupropion and its metabolites (see PRECAUTIONS: Geriatric Use).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were
nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no
statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its
active metabolites between smokers and nonsmokers.
CLINICAL TRIALS
The efficacy of the immediate-release formulation of bupropion as a treatment for
depression was established in two 4-week, placebo-controlled trials in adult inpatients with
depression and in one 6-week, placebo-controlled trial in adult outpatients with depression. In the
first study, patients were titrated in a bupropion dose range of 300 to 600 mg/day on a 3 times daily
schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial demonstrated
the effectiveness of the immediate-release formulation of bupropion on the Hamilton Depression
Rating Scale (HDRS) total score, the depressed mood item (item 1) from that scale, and the Clinical
Global Impressions (CGI) severity score. A second study included 2 fixed doses of the
immediate-release formulation of bupropion (300 and 450 mg/day) and placebo. This trial
demonstrated the effectiveness of the immediate-release formulation of bupropion, but only at the
450-mg/day dose; the results were positive for the HDRS total score and the CGI severity score,
but not for HDRS item 1. In the third study, outpatients received 300 mg/day of the
immediate-release formulation of bupropion. This study demonstrated the effectiveness of the
immediate-release formulation of bupropion on the HDRS total score, HDRS item 1, the
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Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI improvement
score.
Although there are not as yet independent
trials demonstrating the antidepressant effectiveness of the sustained-release formulation of
bupropion, studies have demonstrated the bioequivalence of the immediate-release and
sustained-release forms of bupropion under steady-state conditions, i.e., bupropion
sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the
immediate-release formulation of bupropion, with regard to both rate and extent of absorption, for
parent drug and metabolites.
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder,
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
twice daily) were randomized to continuation of their same WELLBUTRIN SR dose or placebo,
for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI
Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks.
Relapse during the double-blind phase was defined as the investigator’s judgment that drug
treatment was needed for worsening depressive symptoms. Patients receiving continued
WELLBUTRIN SR treatment experienced significantly lower relapse rates over the subsequent
44 weeks compared to those receiving placebo.
INDICATIONS AND USAGE
WELLBUTRIN SR is indicated for the treatment of major depressive disorder.
The efficacy of bupropion in the treatment of a major depressive episode was established in
two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of depressed
outpatients whose diagnoses corresponded most closely to the Major Depression category of the
APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY).
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss
of interest or pleasure; in addition, at least 5 of the following symptoms have been present during
the same 2-week period and represent a change from previous functioning: depressed mood,
markedly diminished interest or pleasure in usual activities, significant change in weight and/or
appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings
of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal
ideation.
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial (see
CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use
WELLBUTRIN SR for extended periods should periodically reevaluate the long-term usefulness of
the drug for the individual patient.
CONTRAINDICATIONS
WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
WELLBUTRIN SR is contraindicated in patients treated with ZYBAN (bupropion
hydrochloride) Sustained-Release Tablets; WELLBUTRIN (bupropion hydrochloride), the
immediate-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended
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release formulation; or any other medications that contain bupropion because the incidence of
seizure is dose dependent.
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of
bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for
bulimia with the immediate-release formulation of bupropion.
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
alcohol or sedatives (including benzodiazepines).
The concurrent administration of WELLBUTRIN SR Tablets and a monoamine oxidase
(MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an
MAO inhibitor and initiation of treatment with WELLBUTRIN SR Tablets.
WELLBUTRIN SR is contraindicated in patients who have shown an allergic response to
bupropion or the other ingredients that make up WELLBUTRIN SR Tablets.
WARNINGS
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients with
major depressive disorder (MDD), both adult and pediatric, may experience worsening of their
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes
in behavior, whether or not they are taking antidepressant medications, and this risk may persist
until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There
has been a long-standing concern, however, that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early phases
of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs
and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality)
in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295
short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
increase in the younger patients for almost all drugs studied. There were differences in absolute risk
of suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1,000 patients treated) are provided in Table 1.
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Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug therapy, or at times of
dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major depressive
disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal
link between the emergence of such symptoms and either the worsening of depression and/or the
emergence of suicidal impulses has not been established, there is concern that such symptoms may
represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression or
suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability, unusual
changes in behavior, and the other symptoms described above, as well as the emergence of
suicidality, and to report such symptoms immediately to healthcare providers. Such
monitoring should include daily observation by families and caregivers. Prescriptions for
WELLBUTRIN SR should be written for the smallest quantity of tablets consistent with good
patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are not approved for smoking
cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious
neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation
(see BOXED WARNING, ADVERSE REACTIONS). These have included changes in mood
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(including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal
ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation,
suicide attempt, and completed suicide. Some reported cases may have been complicated
by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed
mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal
ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking
bupropion who continued to smoke. When symptoms were reported, most were during
bupropion treatment, but some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without pre-existing psychiatric
disease; some have experienced worsening of their psychiatric illnesses. All patients being
treated with bupropion as part of smoking cessation treatment should be observed for
neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder,
and major depressive disorder did not participate in the pre-marketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking
cessation should stop taking bupropion and contact a healthcare provider
immediately if agitation, depressed mood, or changes in behavior or thinking that
are not typical for the patient are observed, or if the patient develops suicidal
ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after
discontinuation of ZYBAN was reported, although in some cases the symptoms persisted,
therefore, ongoing monitoring and supportive care should be provided until symptoms
resolve.
The risks of using bupropion for smoking cessation should be weighed against the
benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence
from smoking for as long as six months compared to treatment with placebo. The health
benefits of quitting smoking are immediate and substantial.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled trials)
that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately screened
to determine if they are at risk for bipolar disorder; such screening should include a detailed
psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that WELLBUTRIN SR is not approved for use in treating bipolar depression.
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN SR
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation
treatment, and that WELLBUTRIN SR should not be used in combination with ZYBAN, or any
other medications that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride), the
immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the extended-
release formulation.
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Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures is
also related to patient factors, clinical situations, and concomitant medications, which must
be considered in selection of patients for therapy with WELLBUTRIN SR.
WELLBUTRIN SR should be discontinued and not restarted in patients who experience a
seizure while on treatment.
• Dose: At doses of WELLBUTRIN SR up to a dose of 300 mg/day, the incidence of seizure
is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the
maximum recommended dose of 400 mg/day.
Data for the immediate-release formulation of bupropion revealed a seizure
incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in
patients treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of
this dose range is close to the currently recommended maximum dose of 400 mg/day for
WELLBUTRIN SR Tablets. This seizure incidence (0.4%) may exceed that of other
marketed antidepressants and WELLBUTRIN SR Tablets up to 300 mg/day by as much
as 4-fold. This relative risk is only an approximate estimate because no direct comparative
studies have been conducted.
Additional data accumulated for the immediate-release formulation of
bupropion suggested that the estimated seizure incidence increases almost tenfold between
450 and 600 mg/day, which is twice the usual adult dose and one and one-half the
maximum recommended daily dose (400 mg) of WELLBUTRIN SR Tablets. This
disproportionate increase in seizure incidence with dose incrementation calls for caution
in dosing.
Data for WELLBUTRIN SR Tablets revealed a seizure incidence of
approximately 0.1% (i.e., 3 of 3,100 patients followed prospectively) in patients treated at
doses in a range of 100 to 300 mg/day. It is not possible to know if the lower seizure
incidence observed in this study involving the sustained-release formulation of bupropion
resulted from the different formulation or the lower dose used. However, as noted above,
the immediate-release and sustained-release formulations are bioequivalent with regard
to both rate and extent of absorption during steady state (the most pertinent condition to
estimating seizure incidence), since most observed seizures occur under steady-state
conditions.
• Patient factors: Predisposing factors that may increase the risk of seizure with bupropion
use include history of head trauma or prior seizure, central nervous system (CNS) tumor,
the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure
threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include,
among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction
to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and
diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
theophylline, systemic steroids) are known to lower seizure threshold.
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Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
clinical experience gained during the development of bupropion suggests that the risk of
seizure may be minimized if
• the total daily dose of WELLBUTRIN SR Tablets does not exceed 400 mg,
• the daily dose is administered twice daily, and
• the rate of incrementation of dose is gradual.
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion
and/or its metabolites.
WELLBUTRIN SR should be administered with extreme caution to patients with a history
of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with
other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.)
that lower seizure threshold.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
likely to occur in such patients to a greater extent than usual. The dose should not exceed
100 mg every day or 150 mg every other day in these patients (see CLINICAL
PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was
an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs
receiving large doses of bupropion chronically, various histologic changes were seen in the liver,
and laboratory tests suggesting mild hepatocellular injury were noted.
PRECAUTIONS
General: Agitation and Insomnia: Patients in placebo-controlled trials with
WELLBUTRIN SR Tablets experienced agitation, anxiety, and insomnia as shown in Table 2.
Table 2. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Agitation
Anxiety
Insomnia
3%
5%
11%
9%
6%
16%
2%
3%
6%
In clinical studies, these symptoms were sometimes of sufficient magnitude to require
treatment with sedative/hypnotic drugs.
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6%
of patients treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 0.8%
of patients treated with placebo.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
patients treated with an immediate-release formulation of bupropion or with WELLBUTRIN SR
Tablets have been reported to show a variety of neuropsychiatric signs and symptoms, including
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delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic
episodes in bipolar disorder patients during the depressed phase of their illness and may activate
latent psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.
Altered Appetite and Weight: In placebo-controlled studies, patients experienced
weight gain or weight loss as shown in Table 3.
Table 3. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
Lost >5 lbs
3%
14%
2%
19%
4%
6%
In studies conducted with the immediate-release formulation of bupropion, 35% of patients
receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the
immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s
depressive illness, the anorectic and/or weight-reducing potential of WELLBUTRIN SR Tablets
should be considered.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms
such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been
reported in clinical trials with bupropion. In addition, there have been rare spontaneous
postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock
associated with bupropion. A patient should stop taking WELLBUTRIN SR and consult a doctor if
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest
pain, edema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
hypersensitivity have been reported in association with bupropion. These symptoms may resemble
serum sickness.
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe,
requiring acute treatment, has been reported in patients receiving bupropion alone and in
combination with nicotine replacement therapy. These events have been observed in both patients
with and without evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence
of treatment-emergent hypertension in patients treated with the combination of sustained-release
bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-
release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and
3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The
majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated
with the combination of ZYBAN and NTS and 1 patient (0.4%) treated with NTS had study
medication discontinued due to hypertension compared to none of the patients treated with ZYBAN
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or placebo. Monitoring of blood pressure is recommended in patients who receive the combination
of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of WELLBUTRIN SR Tablets in
patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care
should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients
who had previously developed orthostatic hypotension while receiving tricyclic antidepressants,
and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive
heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the
study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation
of baseline hypertension.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in
patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is
required. WELLBUTRIN SR should be used with caution in patients with hepatic impairment
(including mild-to-moderate hepatic cirrhosis) and reduced frequency and/or dose should be
considered in patients with mild-to-moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse
effects that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
WARNINGS, and DOSAGE AND ADMINISTRATION).
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
patients with renal impairment. An inter-study comparison between normal subjects and patients
with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites
had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A
second study, comparing normal subjects and patients with moderate-to-severe renal impairment
(GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release
bupropion was approximately 2-fold higher in patients with impaired renal function while levels of
the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the
2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and subsequently excreted by the kidneys. WELLBUTRIN SR should be used with
caution in patients with renal impairment and a reduced frequency and/or dose should be
considered as bupropion and the metabolites of bupropion may accumulate in such patients to a
greater extent than usual. The patient should be closely monitored for possible adverse effects that
could indicate high drug or metabolite levels.
Information for Patients: Prescribers or other health professionals should inform patients, their
families, and their caregivers about the benefits and risks associated with treatment with
WELLBUTRIN SR and should counsel them in its appropriate use. A patient Medication Guide
about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and
Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information
Should I Know About WELLBUTRIN SR?” is available for WELLBUTRIN SR. The prescriber or
health professional should instruct patients, their families, and their caregivers to read the
Medication Guide and should assist them in understanding its contents. Patients should be given the
opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions
they may have. The complete text of the Medication Guide is reprinted at the end of this document.
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Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking WELLBUTRIN SR.
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders:
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of
anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,
akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior,
worsening of depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be advised to look
for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient’s prescriber or health professional, especially if they are
severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and behavior and indicate a
need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment: Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it
contains the same active ingredient as ZYBAN which is approved for this use. Patients should be
informed that quitting smoking, with or without ZYBAN, may be associated with nicotine
withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing
psychiatric illness. Furthermore, some patients have experienced changes in mood (including
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide
when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility,
depressed mood, or changes in thinking or behavior that are not typical for them, or if patients
develop suicidal ideation or behavior, they should be urged to report these symptoms to their
healthcare provider immediately.
Bupropion-Containing Products: Patients should be made aware that
WELLBUTRIN SR contains the same active ingredient found in ZYBAN, used as an aid to
smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination with
ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN,
the immediate-release formulation and WELLBUTRIN XL, the extended-release formulation).
As dose is increased during initial titration to doses above 150 mg/day, patients should be
instructed to take WELLBUTRIN SR Tablets in 2 divided doses, preferably with at least 8 hours
between successive doses, to minimize the risk of seizures.
Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if
they experience a seizure while on treatment.
Patients should be told that any CNS-active drug like WELLBUTRIN SR Tablets may
impair their ability to perform tasks requiring judgment or motor and cognitive skills.
Consequently, until they are reasonably certain that WELLBUTRIN SR Tablets do not adversely
affect their performance, they should refrain from driving an automobile or operating complex,
hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or
sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported
lower alcohol tolerance during treatment with WELLBUTRIN SR. Patients should be advised that
the consumption of alcohol should be minimized or avoided.
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Patients should be advised to inform their physicians if they are taking or plan to take any
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR Tablets
and other drugs may affect each other’s metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to swallow WELLBUTRIN SR Tablets whole so that the release
rate is not altered. Do not chew, divide, or crush tablets.
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
following concomitant administration with other drugs or, alternatively, the effect of concomitant
administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may
affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction
between WELLBUTRIN SR and drugs that are substrates or inhibitors of the CYP2B6 isoenzyme
(e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, in vitro studies suggest that
paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz
inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this
finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the
cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the
pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male
volunteers. Following oral administration of two 150-mg WELLBUTRIN SR Tablets with and
without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were
unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the
combined moieties of threohydrobupropion and erythrohydrobupropion.
While not systematically studied, certain drugs may induce the metabolism of bupropion
(e.g., carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single-dose
pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to
8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be the potential for clinically important alterations of blood levels of
coadministered drugs.
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including
most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics
are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a
study of 15 male subjects (aged 19 to 35 years) who were extensive metabolizers of the CYP2D6
isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of
50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
has not been formally studied.
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Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-
blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be
approached with caution and should be initiated at the lower end of the dose range of the
concomitant medication. If bupropion is added to the treatment regimen of a patient already
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication
should be considered, particularly for those concomitant medications with a narrow therapeutic
index.
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of WELLBUTRIN SR Tablets to patients receiving either levodopa or amantadine
concurrently should be undertaken with caution, using small initial doses and gradual dose
increases.
Drugs That Lower Seizure Threshold: Concurrent administration of
WELLBUTRIN SR Tablets and agents (e.g., antipsychotics, other antidepressants, theophylline,
systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution
(see WARNINGS). Low initial dosing and gradual dose increases should be employed.
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
Alcohol: In postmarketing experience, there have been rare reports of adverse
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during
treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with
WELLBUTRIN SR should be minimized or avoided (also see CONTRAINDICATIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These doses
are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively,
on a mg/m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver
at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m2 basis); lower
doses were not tested. The question of whether or not such lesions may be precursors of neoplasms
of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no
increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains
in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in
vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
fertility.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis), during the period of
organogenesis. No clear evidence of teratogenic activity was found in either species; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed
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at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and
greater. Decreased fetal weights were seen at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
and lactation, there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women. This retrospective, managed-care
database study assessed the risk of congenital malformations overall and cardiovascular
malformations specifically, following exposure to bupropion in the first trimester compared to the
risk of these malformations following exposure to other antidepressants in the first trimester and
bupropion outside of the first trimester. This study included 7,005 infants with antidepressant
exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The
study showed no greater risk for congenital malformations overall or cardiovascular malformations
specifically, following first trimester bupropion exposure compared to exposure to all other
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of this
study have not been corroborated. WELLBUTRIN SR should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of WELLBUTRIN SR Tablets on labor and delivery in humans
is unknown.
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
milk. Because of the potential for serious adverse reactions in nursing infants from
WELLBUTRIN SR Tablets, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see
BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric
Disorders). Anyone considering the use of WELLBUTRIN SR in a child or adolescent must
balance the potential risks with the clinical need.
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
clinical trials using the immediate-release formulation of bupropion (depression studies). No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
metabolites in elderly subjects was similar to that of younger subjects; however, another
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk
for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to monitor renal
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
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ADVERSE REACTIONS (See also WARNINGS and PRECAUTIONS.)
The information included under the Incidence in Controlled Trials subsection of ADVERSE
REACTIONS is based primarily on data from controlled clinical trials with WELLBUTRIN SR
Tablets. Information on additional adverse events associated with the sustained-release formulation
of bupropion in smoking cessation trials, as well as the immediate-release formulation of
bupropion, is included in a separate section (see Other Events Observed During the Clinical
Development and Postmarketing Experience of Bupropion).
Incidence in Controlled Trials With WELLBUTRIN SR: Adverse Events Associated
With Discontinuation of Treatment Among Patients Treated With WELLBUTRIN SR
Tablets: In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and
400 mg/day, respectively, of WELLBUTRIN SR Tablets and 4% of patients treated with placebo
discontinued treatment due to adverse events. The specific adverse events in these trials that led to
discontinuation in at least 1% of patients treated with either 300 or 400 mg/day of
WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed in Table 4.
Table 4. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Rash
Nausea
Agitation
Migraine
2.4%
0.8%
0.3%
0.0%
0.9%
1.8%
1.8%
1.8%
0.0%
0.3%
0.3%
0.3%
Adverse Events Occurring at an Incidence of 1% or More Among Patients
Treated With WELLBUTRIN SR Tablets: Table 5 enumerates treatment-emergent adverse
events that occurred among patients treated with 300 and 400 mg/day of WELLBUTRIN SR
Tablets and with placebo in placebo-controlled trials. Events that occurred in either the 300- or
400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo group
are included. Reported adverse events were classified using a COSTART-based Dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug
are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting,
physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of
untoward events in the course of usual medical practice where patient characteristics and other
factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be
compared with those obtained from other clinical studies involving related drug products as each
group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
and/or clinical importance of the events. A better perspective on the serious adverse events
associated with the use of WELLBUTRIN SR Tablets is provided in the WARNINGS and
PRECAUTIONS sections.
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Table 5. Treatment-Emergent Adverse Events in Placebo-Controlled Trialsa
Body System/
Adverse Event
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous system
stimulation
2%
1%
1%
Respiratory
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Pharyngitis
Sinusitis
Increased cough
3%
3%
1%
11%
1%
2%
2%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Blurred vision or
diplopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal
hemorrhageb
0%
2%
—
Urinary tract infection
1%
0%
—
a Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day of
WELLBUTRIN SR Tablets, but equally or more frequently in the placebo group, were:
abnormal dreams, accidental injury, acne, appetite increased, back pain, bronchitis,
dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory
disorder, rhinitis, and tooth disorder.
b Incidence based on the number of female patients.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
Incidence of Commonly Observed Adverse Events in Controlled Clinical
Trials: Adverse events from Table 5 occurring in at least 5% of patients treated with
WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed below for the 300-
and 400-mg/day dose groups.
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus,
and tremor.
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness,
dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
frequency.
Other Events Observed During the Clinical Development and Postmarketing
Experience of Bupropion: In addition to the adverse events noted above, the following events
have been reported in clinical trials and postmarketing experience with the sustained-release
formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical
trials and postmarketing clinical experience with the immediate-release formulation of bupropion.
Adverse events for which frequencies are provided below occurred in clinical trials with the
sustained-release formulation of bupropion. The frequencies represent the proportion of patients
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who experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled
studies for depression (n = 987) or smoking cessation (n = 1,013), or patients who experienced an
adverse event requiring discontinuation of treatment in an open-label surveillance study with
WELLBUTRIN SR Tablets (n = 3,100). All treatment-emergent adverse events are included except
those listed in Tables 2 through 5, those events listed in other safety-related sections, those adverse
events subsumed under COSTART terms that are either overly general or excessively specific so as
to be uninformative, those events not reasonably associated with the use of the drug, and those
events that were not serious and occurred in fewer than 2 patients. Events of major clinical
importance are described in the WARNINGS and PRECAUTIONS sections of the labeling.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions of frequency: Frequent adverse events are defined as those
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
Adverse events for which frequencies are not provided occurred in clinical trials or
postmarketing experience with bupropion. Only those adverse events not previously listed for
sustained-release bupropion are included. The extent to which these events may be associated with
WELLBUTRIN SR is unknown.
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and
photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash
and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum
sickness (see PRECAUTIONS).
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
vasodilation. Rare was syncope. Also observed were complete atrioventricular block, extrasystoles,
hypotension, hypertension (in some cases severe, see PRECAUTIONS), myocardial infarction,
phlebitis, and pulmonary embolism.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of
tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage,
hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
inappropriate antidiuretic hormone.
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT
and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed
when bupropion was coadministered with warfarin.
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed
was glycosuria.
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle
rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Infrequent were abnormal coordination, decreased libido,
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also
observed were abnormal electroencephalogram (EEG), akinesia, aggression, aphasia, coma,
completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal
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syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy,
paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative
dermatitis, and hirsutism.
Special Senses: Infrequent were accommodation abnormality and dry eye. Also
observed were deafness, diplopia, increased intraocular pressure, and mydriasis.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed
were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful
erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Bupropion is not a controlled substance.
Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted in
normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients
showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
bupropion produced mild amphetamine-like activity as compared to placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score
intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales
measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of
drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing to
amphetamine or stimulant abusers. However, higher doses that could not be tested because of the
risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Animals: Studies in rodents and primates have shown that bupropion exhibits some
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of responding
in several schedule-controlled behavior paradigms. In primate models to assess the positive
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
OVERDOSAGE
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
reported. Seizure was reported in approximately one-third of all cases. Other serious reactions
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or
arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
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uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in
these patients.
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation. Monitor
cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours post-
ingestion. General supportive and symptomatic measures are also recommended. Induction of
emesis is not recommended.
Activated charcoal should be administered. There is no experience with the use of forced
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
overdoses. No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with WELLBUTRIN SR, hospitalization following
suspected overdose should be considered. Based on studies in animals, it is recommended that
seizures be treated with intravenous benzodiazepine administration and other supportive measures,
as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement. The
physician should consider contacting a poison control center for additional information on the
treatment of any overdose. Telephone numbers for certified poison control centers are listed in the
Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
General Dosing Considerations: It is particularly important to administer WELLBUTRIN SR
Tablets in a manner most likely to minimize the risk of seizure (see WARNINGS). Gradual
escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen
during the initial days of treatment, are to be minimized. If necessary, these effects may be
managed by temporary reduction of dose or the short-term administration of an intermediate to
long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of
treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward
effects supervene, dose escalation should be stopped. WELLBUTRIN SR should be swallowed
whole and not crushed, divided, or chewed.
Initial Treatment: The usual adult target dose for WELLBUTRIN SR Tablets is 300 mg/day,
given as 150 mg twice daily. Dosing with WELLBUTRIN SR Tablets should begin at 150 mg/day
given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, an
increase to the 300-mg/day target dose, given as 150 mg twice daily, may be made as early as day 4
of dosing. There should be an interval of at least 8 hours between successive doses.
Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full
antidepressant effect of WELLBUTRIN SR Tablets may not be evident until 4 weeks of treatment
or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may
be considered for patients in whom no clinical improvement is noted after several weeks of
treatment at 300 mg/day.
Maintenance Treatment: It is generally agreed that acute episodes of depression require several
months or longer of sustained pharmacological therapy beyond response to the acute episode. In a
study in which patients with major depressive disorder, recurrent type, who had responded during
8 weeks of acute treatment with WELLBUTRIN SR were assigned randomly to placebo or to the
same dose of WELLBUTRIN SR (150 mg twice daily) during 44 weeks of maintenance treatment
as they had received during the acute stabilization phase, longer-term efficacy was demonstrated
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(see CLINICAL TRIALS under CLINICAL PHARMACOLOGY). Based on these limited data, it
is unknown whether or not the dose of WELLBUTRIN SR needed for maintenance treatment is
identical to the dose needed to achieve an initial response. Patients should be periodically
reassessed to determine the need for maintenance treatment and the appropriate dose for such
treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN SR
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not
exceed 100 mg every day or 150 mg every other day in these patients. WELLBUTRIN SR should
be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic
cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild-to
moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and
PRECAUTIONS).
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN SR
should be used with caution in patients with renal impairment and a reduced frequency and/or dose
should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are
blue, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
(NDC 0173-0947-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
purple, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150" in bottles of 60
(NDC 0173-0135-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are
light pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of
60 (NDC 0173-0722-00) tablets.
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in
a tight, light-resistant container as defined in the USP.
MEDICATION GUIDE
WELLBUTRIN SR® (WELL byu-trin)
(bupropion hydrochloride) Sustained-Release Tablets
Read this Medication Guide carefully before you start using WELLBUTRIN SR and each time you
get a refill. There may be new information. This information does not take the place of talking with
your doctor about your medical condition or your treatment. If you have any questions about
WELLBUTRIN SR, ask your doctor or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section
is about the risk of suicidal thoughts and actions with antidepressant medicines; the second
section is about the risk of changes in thinking and behavior, depression and suicidal
thoughts or actions with medicines used to quit smoking; and the third section is entitled
“What Other Important Information Should I Know About WELLBUTRIN SR?”
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Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of suicidal thoughts and actions
with antidepressant medicines. Talk to your, or your family member’s, healthcare
provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
4. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
5. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
6. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family
member?
Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or
feelings. This is very important when an antidepressant medicine is started or when the dose
is changed.
Call the healthcare provider right away to report new or sudden changes in mood, behavior,
thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider
between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following
symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• trouble sleeping (insomnia)
• attempts to commit suicide
• new or worse irritability
• new or worse depression
• acting aggressive, being angry, or violent
• new or worse anxiety
• acting on dangerous impulses
• feeling very agitated or restless
• an extreme increase in activity and talking (mania)
• panic attacks
• other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
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• Never stop an antidepressant medicine without first talking to a healthcare provider.
Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important
to discuss all the risks of treating depression and also the risks of not treating it. Patients and
their families or other caregivers should discuss all treatment choices with the healthcare
provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that
you or your family member takes. Keep a list of all medicines to show the healthcare provider.
Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child’s healthcare provider for more information.
WELLBUTRIN SR has not been studied in children under the age of 18 and is not approved for use
in children and teenagers.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior,
Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking and
behavior, depression and suicidal thoughts or actions with drugs used to quit smoking.
Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the same active
ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or
actions while taking bupropion to help them quit smoking. These symptoms can develop during
treatment with bupropion or after stopping treatment with bupropion.
If you, your family member, or your caregiver notice agitation, hostility, depression, or
changes in thinking or behavior that are not typical for you, or you have any of the
following symptoms, stop taking bupropion and call your healthcare provider right away:
• thoughts about suicide or dying
• an extreme increase in activity and talking (mania)
• attempts to commit suicide
• abnormal thoughts or sensations
• new or worse depression
• seeing or hearing things that are not there
• new or worse anxiety
(hallucinations)
• panic attacks
• feeling people are against you (paranoia)
• feeling very agitated or restless
• feeling confused
• acting aggressive, being angry, or violent
• other unusual changes in behavior or mood
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• acting on dangerous impulses
When you try to quit smoking, with or without bupropion, you may have symptoms that may be
due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability,
frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and
increased appetite or weight gain. Some people have even experienced suicidal thoughts when
trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of
mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had depression or
other mental illnesses. You should also tell your doctor about any symptoms you had
during other times you tried to quit smoking, with or without bupropion.
What Other Important Information Should I Know About WELLBUTRIN SR?
Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN SR,
especially in people:
• with certain medical problems.
• who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN SR. For more
information, see the sections “Who should not take WELLBUTRIN SR?” and “What should I
tell my doctor before using WELLBUTRIN SR?” Tell your doctor about all of your medical
conditions and all the medicines you take. Do not take any other medicines while you are
using WELLBUTRIN SR unless your doctor has said it is okay to take them.
If you have a seizure while taking WELLBUTRIN SR, stop taking the tablets and call
your doctor right away. Do not take WELLBUTRIN SR again if you have a seizure.
• High blood pressure (hypertension). Some people get high blood pressure, that can be
severe, while taking WELLBUTRIN SR. The chance of high blood pressure may be higher if
you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking.
• Severe allergic reactions. Some people have severe allergic reaction to
WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your doctor right away if
you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around
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the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be
signs of a serious allergic reaction.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
taking WELLBUTRIN SR, including delusions (believe you are someone else), hallucinations
(seeing or hearing things that are not there), paranoia (feeling that people are against you), or
feeling confused. If this happens to you, call your doctor.
What is WELLBUTRIN SR?
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type of depression
called major depressive disorder.
Who should not take WELLBUTRIN SR?
Do not take WELLBUTRIN SR if you
• have or had a seizure disorder or epilepsy.
• are taking ZYBAN® (used to help people stop smoking) or any other medicines that
contain bupropion hydrochloride, such as WELLBUTRIN® Tablets or WELLBUTRIN
XL® Extended-Release Tablets. Bupropion is the same active ingredient that is in
WELLBUTRIN SR.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make
you sleepy) or benzodiazepines and you stop using them all of a sudden.
• have taken within the last 14 days medicine for depression called a monoamine oxidase
inhibitor (MAOI), such as NARDIL®*(phenelzine sulfate), PARNATE®(tranylcypromine
sulfate), or MARPLAN®*(isocarboxazid).
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of the inactive
ingredients. See the end of this leaflet for a complete list of ingredients in WELLBUTRIN SR.
What should I tell my doctor before using WELLBUTRIN SR?
Tell your doctor if you have ever had depression, suicidal thoughts or actions, or other mental
health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions.”
a. Tell your doctor about your other medical conditions including if you:
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN SR can
harm your unborn baby.
• are breastfeeding. WELLBUTRIN SR passes through your milk. It is not known if
WELLBUTRIN SR can harm your baby.
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-644/S-039
NDA 18-644/S-040
NDA 20-358/S-046
NDA 20-358/S-047
Page 61
• have an eating disorder such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
• drink a lot of alcohol.
• abuse prescription medicines or street drugs.
• Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
chances of having seizures or other serious side effects if you take them while you are using
WELLBUTRIN SR.
How should I take WELLBUTRIN SR?
• Take WELLBUTRIN SR exactly as prescribed by your doctor.
• Do not chew, cut, or crush WELLBUTRIN SR Tablets. You must swallow the tablets
whole. Tell your doctor if you cannot swallow medicine tablets.
• Take WELLBUTRIN SR at the same time each day.
• Take your doses of WELLBUTRIN SR at least 8 hours apart.
• You may take WELLBUTRIN SR with or without food.
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and take
your next tablet at the regular time. This is very important. Too much WELLBUTRIN SR can
increase your chance of having a seizure.
• If you take too much WELLBUTRIN SR, or overdose, call your local emergency room or
poison control center right away.
• Do not take any other medicines while using WELLBUTRIN SR unless your doctor has
told you it is okay.
• It may take several weeks for you to feel that WELLBUTRIN SR is working. Once you feel
better, it is important to keep taking WELLBUTRIN SR exactly as directed by your doctor.
Call your doctor if you do not feel WELLBUTRIN SR is working for you.
• Do not change your dose or stop taking WELLBUTRIN SR without talking with your doctor
first.
What should I avoid while taking WELLBUTRIN SR?
• Do not drink a lot of alcohol while taking WELLBUTRIN SR. If you usually drink a lot of
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking alcohol,
you may increase your chance of having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR affects you.
WELLBUTRIN SR can impair your ability to perform these tasks.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-644/S-039
NDA 18-644/S-040
NDA 20-358/S-046
NDA 20-358/S-047
Page 62
What are possible side effects of WELLBUTRIN SR?
WELLBUTRIN SR can cause serious side effects. Read this entire Medication Guide for more
information about these serious side effects.
The most common side effects of WELLBUTRIN SR are loss of appetite, dry mouth, skin rash,
sweating, ringing in the ears, shakiness, stomach pain, agitation, anxiety, dizziness, trouble
sleeping, muscle pain, nausea, fast heartbeat, sore throat, and urinating more often.
If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your
medicine too close to bedtime.
These are not all the side effects of WELLBUTRIN SR. For a complete list, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store WELLBUTRIN SR?
• Store WELLBUTRIN SR at room temperature. Store out of direct sunlight. Keep
WELLBUTRIN SR in its tightly closed bottle.
• WELLBUTRIN SR tablets may have an odor.
General Information about WELLBUTRIN SR.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do
not use WELLBUTRIN SR for a condition for which it was not prescribed. Do not give
WELLBUTRIN SR to other people, even if they have the same symptoms you have. It may harm
them. Keep WELLBUTRIN SR out of the reach of children.
This Medication Guide summarizes important information about WELLBUTRIN SR. For more
information, talk with your doctor. You can ask your doctor or pharmacist for information about
WELLBUTRIN SR that is written for health professionals.
What are the ingredients in WELLBUTRIN SR?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. In addition,
the 100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake. The
tablets are printed with edible black ink.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RX Only
NDA 18-644/S-039
NDA 18-644/S-040
NDA 20-358/S-046
NDA 20-358/S-047
Page 63
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, ZYBAN, and PARNATE are registered
trademarks of GlaxoSmithKline.
*The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
June 2009
WLS:5MG GSK logo
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
or DSM Pharmaceuticals, Inc.
Greenville, NC 27834
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-644/S-039
NDA 18-644/S-040
NDA 20-358/S-046
NDA 20-358/S-047
Page 64
©2009, GlaxoSmithKline. All rights reserved.
June 2009
WLS:4PI
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:31.005292
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020358s046s047lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 47}
|
12,473
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
WELLBUTRIN SR safely and effectively. See full prescribing
information for WELLBUTRIN SR.
WELLBUTRIN SR (bupropion hydrochloride) Sustained-Release
Tablets, for oral use
Initial U.S. Approval: 1985
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
See full prescribing information for complete boxed warning.
• Increased risk of suicidal thinking and behavior in children,
adolescents and young adults taking antidepressants. (5.1)
• Monitor for worsening and emergence of suicidal thoughts and
behaviors. (5.1)
• Serious neuropsychiatric events have been reported in patients
taking bupropion for smoking cessation. (5.2)
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.4, 2.5)
03/2013
Contraindications (4)
03/2013
----------------------------INDICATIONS AND USAGE ---------------------------
• WELLBUTRIN SR is an aminoketone antidepressant, indicated for the
treatment of major depressive disorder (MDD). (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
•
Starting Dose: 150 mg per day (2.1)
•
General: Increase dose gradually to reduce seizure risk. (2.1, 5.3)
•
After 3 days, may increase the dose to 300 mg per day, given as 150 mg
twice daily at an interval of at least 8 hours. (2.1)
•
Usual target dose: 300 mg per day as 150 mg twice daily. (2.1)
•
Maximum dose: 400 mg per day, given as 200 mg twice daily, for
patients not responding to 300 mg per day. (2.1)
•
Periodically reassess the dose and need for maintenance treatment. (2.1)
• Moderate to severe hepatic impairment: 100 mg daily or 150 mg every
other day. (2.2, 8.7)
• Mild hepatic impairment: Consider reducing the dose and/or frequency of
dosing. (2.2, 8.7)
•
Renal Impairment: Consider reducing the dose and/or frequency. (2.3,
8.6)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets: 100 mg, 150 mg, 200 mg. (3)
-------------------------------CONTRAINDICATIONS ------------------------------
•
Seizure disorder. (4, 5.3)
•
Current or prior diagnosis of bulimia or anorexia nervosa. (4, 5.3)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates,
antiepileptic drugs. (4, 5.3)
•
Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to
treat psychiatric disorders with WELLBUTRIN SR or within 14 days of
stopping treatment with WELLBUTRIN SR. Do not use WELLBUTRIN
SR within 14 days of stopping an MAOI intended to treat psychiatric
disorders. In addition, do not start WELLBUTRIN SR in a patient who is
being treated with linezolid or intravenous methylene blue. (4, 7.6)
• Known hypersensitivity to bupropion or other ingredients of
WELLBUTRIN SR. (4, 5.7)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Seizure risk: The risk is dose-related. Can minimize risk by gradually
increasing the dose and limiting daily dose to 400 mg. Discontinue if
seizure occurs. (4, 5.3, 7.3)
• Hypertension: WELLBUTRIN SR can increase blood pressure. Monitor
blood pressure before initiating treatment and periodically during
treatment. (5.4)
•
Activation of mania/hypomania: Screen patients for bipolar disorder and
monitor for these symptoms. (5.5)
•
Psychosis and other neuropsychiatric reactions: Instruct patients to
contact a healthcare professional if such reactions occur. (5.6)
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions (incidence ≥5% and ≥2% more than placebo
rate) are: headache, dry mouth, nausea, insomnia, dizziness, pharyngitis,
constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitation,
myalgia, sweating, rash, and anorexia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• CYP2B6 inducers: Dose increase may be necessary if coadministered
with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz,
carbamazepine, phenobarbital, and phenytoin) based on clinical response,
but should not exceed the maximum recommended dose. (7.1)
• Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can
increase concentrations of: antidepressants (e.g., venlafaxine,
nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline),
antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers
(e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone,
flecainide). Consider dose reduction when using with bupropion. (7.2)
• Drugs that lower seizure threshold: Dose WELLBUTRIN SR with
caution. (5.3, 7.3)
• Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur
when used concomitantly with WELLBUTRIN SR. (7.4)
•
MAOIs: Increased risk of hypertensive reactions can occur when used
concomitantly with WELLBUTRIN SR. (7.6)
•
Drug-laboratory test interactions: WELLBUTRIN SR can cause false-
positive urine test results for amphetamines. (7.7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
•
Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: Month Year
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
2.2
Dose Adjustment in Patients With Hepatic Impairment
2.3 Dose Adjustment in Patients With Renal Impairment
2.4
Switching a Patient To or From a Monoamine Oxidase
Inhibitor (MAOI) Antidepressant
2.5
Use of WELLBUTRIN SR With Reversible MAOIs
Such as Linezolid or Methylene Blue
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children,
Adolescents, and Young Adults
5.2
Neuropsychiatric Symptoms and Suicide Risk in
Smoking Cessation Treatment
5.3
Seizure
5.4
Hypertension
5.5
Activation of Mania/Hypomania
5.6
Psychosis and Other Neuropsychiatric Reactions
5.7
Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN SR
7.2
Potential for WELLBUTRIN SR to Affect Other Drugs
7.3
Drugs That Lower Seizure Threshold
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
7.5
Use With Alcohol
7.6
MAO Inhibitors
7.7
Drug-Laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
1
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.5
Geriatric Use
11 DESCRIPTION
8.6
Renal Impairment
12 CLINICAL PHARMACOLOGY
8.7
Hepatic Impairment
12.1 Mechanism of Action
9
DRUG ABUSE AND DEPENDENCE
12.3 Pharmacokinetics
9.1
Controlled Substance
13 NONCLINICAL TOXICOLOGY
9.2
Abuse
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
10 OVERDOSAGE
14 CLINICAL STUDIES
10.1 Human Overdose Experience
16 HOW SUPPLIED/STORAGE AND HANDLING
10.2 Overdosage Management
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC
REACTIONS
SUICIDALITY AND ANTIDEPRESSANT DRUGS
Antidepressants increased the risk of suicidal thoughts and behavior in children,
adolescents, and young adults in short-term trials. These trials did not show an increase in
the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24;
there was a reduction in risk with antidepressant use in subjects aged 65 and older [see
Warnings and Precautions (5.1)].
In patients of all ages who are started on antidepressant therapy, monitor closely for
worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
caregivers of the need for close observation and communication with the prescriber [see
Warnings and Precautions (5.1)].
NEUROPSYCHIATRIC REACTIONS IN PATIENTS TAKING BUPROPION FOR
SMOKING CESSATION
Serious neuropsychiatric reactions have occurred in patients taking bupropion for
smoking cessation [see Warnings and Precautions (5.2)]. The majority of these reactions
occurred during bupropion treatment, but some occurred in the context of discontinuing
treatment. In many cases, a causal relationship to bupropion treatment is not certain,
because depressed mood may be a symptom of nicotine withdrawal. However, some of the
cases occurred in patients taking bupropion who continued to smoke. Although
WELLBUTRIN® SR is not approved for smoking cessation, observe all patients for
neuropsychiatric reactions. Instruct the patient to contact a healthcare provider if such
reactions occur [see Warnings and Precautions (5.2)].
1
INDICATIONS AND USAGE
WELLBUTRIN SR (bupropion hydrochloride) is indicated for the treatment of major
depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of bupropion in the treatment of a major depressive episode was established
in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult
subjects with MDD [see Clinical Studies (14)].
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
[see Clinical Studies (14)].
2
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
To minimize the risk of seizure, increase the dose gradually [see Warnings and
Precautions (5.3)]. WELLBUTRIN SR Tablets should be swallowed whole and not crushed,
divided, or chewed. WELLBUTRIN SR may be taken with or without food.
The usual adult target dose for WELLBUTRIN SR is 300 mg per day, given as 150 mg
twice daily. Initiate dosing with 150 mg per day given as a single daily dose in the morning.
After 3 days of dosing, the dose may be increased to the 300-mg-per-day target dose, given as
150 mg twice daily. There should be an interval of at least 8 hours between successive doses. A
maximum of 400 mg per day, given as 200 mg twice daily, may be considered for patients in
whom no clinical improvement is noted after several weeks of treatment at 300 mg per day. To
avoid high peak concentrations of bupropion and/or its metabolites, do not exceed 200 mg in any
single dose.
It is generally agreed that acute episodes of depression require several months or longer
of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether
the dose of WELLBUTRIN SR needed for maintenance treatment is identical to the dose that
provided an initial response. Periodically reassess the need for maintenance treatment and the
appropriate dose for such treatment.
2.2
Dose Adjustment in Patients With Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
maximum dose of WELLBUTRIN SR is 100 mg per day or 150 mg every other day. In patients
with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or
frequency of dosing [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
2.3 Dose Adjustment in Patients With Renal Impairment
Consider reducing the dose and/or frequency of WELLBUTRIN SR in patients with renal
impairment (Glomerular Filtration Rate <90 mL/min) [see Use in Specific Populations (8.6) and
Clinical Pharmacology (12.3)].
2.4
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI)
Antidepressant
At least 14 days should elapse between discontinuation of an MAOI intended to treat
depression and initiation of therapy with WELLBUTRIN SR. Conversely, at least 14 days
should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant
[see Contraindications (4) and Drug Interactions (7.6)].
2.5
Use of WELLBUTRIN SR With Reversible MAOIs Such as Linezolid or
Methylene Blue
Do not start WELLBUTRIN SR in a patient who is being treated with a reversible MAOI
such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of
hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric
condition, non-pharmacological interventions, including hospitalization, should be considered
[see Contraindications (4) and Drug Interactions (7.6)].
3
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In some cases, a patient already receiving therapy with WELLBUTRIN SR may require
urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential benefits of
linezolid or intravenous methylene blue treatment are judged to outweigh the risks of
hypertensive reactions in a particular patient, WELLBUTRIN SR should be stopped promptly,
and linezolid or intravenous methylene blue can be administered. The patient should be
monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene
blue, whichever comes first. Therapy with WELLBUTRIN SR may be resumed 24 hours after
the last dose of linezolid or intravenous methylene blue.
The risk of administering methylene blue by non-intravenous routes (such as oral tablets
or by local injection) or in intravenous doses much lower than 1 mg/kg with WELLBUTRIN SR
is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction
with such use [see Contraindications (4) and Drug Interactions (7.6)].
3
DOSAGE FORMS AND STRENGTHS
• 100 mg – blue, round, biconvex, film-coated, sustained-release tablets printed with
“WELLBUTRIN SR 100”.
• 150 mg – purple, round, biconvex, film-coated, sustained-release tablets printed with
“WELLBUTRIN SR 150”.
• 200 mg – light pink, round, biconvex, film-coated, sustained-release tablets printed with
“WELLBUTRIN SR 200”.
4
CONTRAINDICATIONS
• WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
• WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia
or anorexia nervosa as a higher incidence of seizures was observed in such patients treated
with the immediate-release formulation of bupropion [see Warnings and Precautions (5.3)].
• WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and
Precautions (5.3) and Drug Interactions (7.3)].
• The use of MAOIs (intended to treat psychiatric disorders) concomitantly with
WELLBUTRIN SR or within 14 days of discontinuing treatment with WELLBUTRIN SR is
contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN
SR is used concomitantly with MAOIs. The use of WELLBUTRIN SR within 14 days of
discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN SR
in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is
contraindicated [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.4),
and Drug Interactions (7.6)].
• WELLBUTRIN SR is contraindicated in patients with known hypersensitivity to bupropion
or other ingredients of WELLBUTRIN SR. Anaphylactoid/anaphylactic reactions and
Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.7)].
4
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young
Adults
Patients with MDD, both adult and pediatric, may experience worsening of their
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early
phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective
serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to
24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase
in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24;
there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
subjects. There was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger subjects for almost all drugs studied. There were differences in
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs. placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of cases of
suicidality per 1,000 subjects treated) are provided in Table 1.
Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled
Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1,000 Subjects Treated
Increases Compared With Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared With Placebo
25-64
1 fewer case
≥65
6 fewer cases
5
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality, and
unusual changes in behavior, especially during the initial few months of a course of drug
therapy, or at times of dose changes, either increases or decreases [see Boxed Warning].
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or
other indications, both psychiatric and nonpsychiatric, should be alerted about the need to
monitor patients for the emergence of agitation, irritability, unusual changes in behavior,
and the other symptoms described above, as well as the emergence of suicidality, and to
report such symptoms immediately to healthcare providers. Such monitoring should
include daily observation by families and caregivers. Prescriptions for WELLBUTRIN SR
should be written for the smallest quantity of tablets consistent with good patient
management, in order to reduce the risk of overdose.
5.2
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment
WELLBUTRIN SR is not approved for smoking cessation treatment; however, ZYBAN®
is approved for this use. Serious neuropsychiatric symptoms have been reported in patients
taking bupropion for smoking cessation. These have included changes in mood (including
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt,
and completed suicide [see Boxed Warning and Adverse Reactions (6.2)]. Observe patients for
the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional
if such reactions occur.
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In many of these cases, a causal relationship to bupropion treatment is not certain,
because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases
occurred in patients taking bupropion who continued to smoke.
5.3
Seizure
WELLBUTRIN SR can cause seizure. The risk of seizure is dose-related. The dose
should not exceed 400 mg per day. Increase the dose gradually. Discontinue WELLBUTRIN SR
and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant
medications that lower the seizure threshold. Consider these risks before initiating treatment with
WELLBUTRIN SR. WELLBUTRIN SR is contraindicated in patients with a seizure disorder,
current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation
of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4) and
Drug Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe
head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke;
concomitant use of other medications that lower the seizure threshold (e.g., other bupropion
products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids);
metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and
hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as
CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral
hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol,
benzodiazepines, sedative/hypnotics, or opiates.
Incidence of Seizure With Bupropion Use: When WELLBUTRIN SR is dosed up to
300 mg per day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to
approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.
The risk of seizure can be reduced if the dose of WELLBUTRIN SR does not exceed
400 mg per day, given as 200 mg twice daily, and the titration rate is gradual.
5.4
Hypertension
Treatment with WELLBUTRIN SR can result in elevated blood pressure and
hypertension. Assess blood pressure before initiating treatment with WELLBUTRIN SR, and
monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN
SR is used concomitantly with MAOIs or other drugs that increase dopaminergic or
noradrenergic activity [see Contraindications (4)].
Data from a comparative trial of the sustained-release formulation of bupropion HCl,
nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS,
and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent
hypertension in patients treated with the combination of sustained-release bupropion and NTS. In
this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS
had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with
sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had
evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of
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sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study
medication discontinued due to hypertension compared with none of the subjects treated with
sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in
patients who receive the combination of bupropion and nicotine replacement.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive
heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing
hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no
controlled trials assessing the safety of bupropion in patients with a recent history of myocardial
infarction or unstable cardiac disease.
5.5
Activation of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode.
The risk appears to be increased in patients with bipolar disorder or who have risk factors for
bipolar disorder. Prior to initiating WELLBUTRIN SR, screen patients for a history of bipolar
disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar
disorder, suicide, or depression). WELLBUTRIN SR is not approved for use in treating bipolar
depression.
5.6
Psychosis and Other Neuropsychiatric Reactions
Depressed patients treated with WELLBUTRIN SR have had a variety of
neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis,
concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of
bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal
of treatment. Instruct patients to contact a healthcare professional if such reactions occur.
5.7
Hypersensitivity Reactions
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion.
Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring
medical treatment. In addition, there have been rare, spontaneous postmarketing reports of
erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with
bupropion. Instruct patients to discontinue WELLBUTRIN SR and consult a healthcare provider
if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives,
chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like
symptoms suggestive of delayed hypersensitivity.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
• Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning and
Warnings and Precautions (5.1)]
• Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed
Warning and Warnings and Precautions (5.2)]
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• Seizure [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Activation of mania or hypomania [see Warnings and Precautions (5.5)]
• Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6)]
• Hypersensitivity reactions [see Warnings and Precautions (5.7)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Leading to Discontinuation of Treatment: In placebo-controlled
clinical trials, 4%, 9%, and 11% of the placebo, 300-mg-per-day, and 400-mg-per-day groups,
respectively, discontinued treatment due to adverse reactions. The specific adverse reactions
leading to discontinuation in at least 1% of the 300-mg-per-day or 400-mg-per-day groups and at
a rate at least twice the placebo rate are listed in Table 2.
Table 2. Treatment Discontinuations Due to Adverse Reactions in Placebo-Controlled
Trials
WELLBUTRIN SR
WELLBUTRIN SR
Placebo
300 mg/day
400 mg/day
Adverse Reaction
(n = 385)
(n = 376)
(n = 114)
Rash
0.0%
2.4%
0.9%
Nausea
0.3%
0.8%
1.8%
Agitation
0.3%
0.3%
1.8%
Migraine
0.3%
0.0%
1.8%
Commonly Observed Adverse Reactions: Adverse reactions from Table 3 occurring
in at least 5% of subjects treated with WELLBUTRIN SR and at a rate at least twice the placebo
rate are listed below for the 300- and 400-mg-per-day dose groups.
WELLBUTRIN SR 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus,
and tremor.
WELLBUTRIN SR 400 mg per day: Abdominal pain, agitation, anxiety, dizziness,
dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
frequency.
Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported
adverse reactions were classified using a COSTART-based Dictionary.
Table 3. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater
Frequency Than Placebo in Controlled Clinical Trials
Body System/
WELLBUTRIN SR
WELLBUTRIN SR
Placebo
Adverse Reaction
300 mg/day
400 mg/day
(n = 385)
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(n = 376)
(n = 114)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous system
2%
1%
1%
stimulation
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Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Blurred vision or
diplopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal hemorrhagea
0%
2%
—
Urinary tract infection
1%
0%
—
a Incidence based on the number of female subjects.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects.
Other Adverse Reactions Observed During the Clinical Development of
Bupropion: In addition to the adverse reactions noted above, the following adverse reactions
have been reported in clinical trials with the sustained-release formulation of bupropion in
depressed subjects and in nondepressed smokers, as well as in clinical trials with the
immediate-release formulation of bupropion.
Adverse reaction frequencies represent the proportion of subjects who experienced a
treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for
depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse
reaction requiring discontinuation of treatment in an open-label surveillance trial with
WELLBUTRIN SR (n = 3,100). All treatment-emergent adverse reactions are included except
those listed in Table 3, those listed in other safety-related sections of the prescribing information,
those subsumed under COSTART terms that are either overly general or excessively specific so
as to be uninformative, those not reasonably associated with the use of the drug, and those that
were not serious and occurred in fewer than 2 subjects.
Adverse reactions are further categorized by body system and listed in order of
decreasing frequency according to the following definitions of frequency: Frequent adverse
reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions
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are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than
1/1,000 subjects.
Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was
malaise.
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
vasodilation. Rare were syncope and myocardial infarction.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.
Hemic and Lymphatic: Infrequent was ecchymosis.
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
Musculoskeletal: Infrequent were leg cramps.
Nervous System: Infrequent were abnormal coordination, decreased libido,
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.
Respiratory: Rare was bronchospasm.
Special Senses: Infrequent were accommodation abnormality and dry eye.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder.
Changes in Body Weight: In placebo-controlled trials, subjects experienced weight
gain or weight loss as shown in Table 4.
Table 4. Incidence of Weight Gain and Weight Loss (≥5 lbs.) in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
Lost >5 lbs
3%
14%
2%
19%
4%
6%
In clinical trials conducted with the immediate-release formulation of bupropion, 35% of
subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated
with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of
a patient’s depressive illness, the anorectic and/or weight-reducing potential of
WELLBUTRIN SR should be considered.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
WELLBUTRIN SR and are not described elsewhere in the label. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Body (General): Arthralgia, myalgia, and fever with rash and other symptoms
suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see
Warnings and Precautions (5.7)].
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Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension,
hypertension (in some cases severe), phlebitis, and pulmonary embolism.
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis,
intestinal perforation, pancreatitis, and stomach ulcer.
Endocrine: Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic
hormone.
Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy,
pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with
hemorrhagic or thrombotic complications, were observed when bupropion was coadministered
with warfarin.
Metabolic and Nutritional: Glycosuria.
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia,
aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria,
extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction,
neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive
dyskinesia.
Respiratory: Pneumonia.
Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson
syndrome.
Special Senses: Deafness, increased intraocular pressure, and mydriasis.
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia,
menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
7
DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN SR
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the
potential exists for drug interactions between WELLBUTRIN SR and drugs that are inhibitors or
inducers of CYP2B6.
Inhibitors of CYP2B6: Ticlopidine and Clopidogrel: Concomitant treatment with these
drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on
clinical response, dosage adjustment of WELLBUTRIN SR may be necessary when
coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical
Pharmacology (12.3)].
Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment
with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of
WELLBUTRIN SR may be necessary when coadministered with ritonavir, lopinavir, or
efavirenz [see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended
dose.
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Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see
Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may
be necessary to increase the dose of bupropion, but the maximum recommended dose should not
be exceeded.
7.2
Potential for WELLBUTRIN SR to Affect Other Drugs
Drugs Metabolized by CYP2D6: Bupropion and its metabolites
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors.
Therefore, coadministration of WELLBUTRIN SR with drugs that are metabolized by CYP2D6
can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain
antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine,
and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g.,
metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used
concomitantly with WELLBUTRIN SR, it may be necessary to decrease the dose of these
CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen)
theoretically could have reduced efficacy when administered concomitantly with inhibitors of
CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN SR and such
drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].
7.3
Drugs That Lower Seizure Threshold
Use extreme caution when coadministering WELLBUTRIN SR with other drugs that
lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants,
theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually
[see Contraindications (4) and Warnings and Precautions (5.3)].
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has
been reported when bupropion was coadministered with levodopa or amantadine. Adverse
reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and
dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use
caution when administering WELLBUTRIN SR concomitantly with these drugs.
7.5
Use With Alcohol
In postmarketing experience, there have been rare reports of adverse neuropsychiatric
events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with
WELLBUTRIN SR. The consumption of alcohol during treatment with WELLBUTRIN SR
should be minimized or avoided.
7.6
MAO Inhibitors
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of
MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive
reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that
the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days
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should elapse between discontinuation of an MAOI intended to treat depression and initiation of
treatment with WELLBUTRIN SR. Conversely, at least 14 days should be allowed after
stopping WELLBUTRIN SR before starting an MAOI antidepressant [see Dosage and
Administration (2.4, 2.5) and Contraindications (4)].
7.7
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for amphetamines have been reported
in patients taking bupropion. This is due to lack of specificity of some screening tests. False-
positive test results may result even following discontinuation of bupropion therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion
from amphetamines.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary: Data from epidemiological studies of pregnant women exposed to
bupropion in the first trimester indicate no increased risk of congenital malformations overall.
All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major
malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity
was found in reproductive developmental studies conducted in rats and rabbits; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
observed at doses approximately equal to the maximum recommended human dose (MRHD) and
greater and decreased fetal weights were seen at doses twice the MRHD and greater.
WELLBUTRIN SR should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Clinical Considerations: Consider the risks of untreated depression when discontinuing
or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data: Data from the international bupropion Pregnancy Registry (675 first
trimester exposures) and a retrospective cohort study using the United Healthcare database
(1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after
bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular
malformations in pregnancies with exposure to bupropion in the first trimester from the
international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
maternal bupropion exposures), which is similar to the background rate of cardiovascular
malformations (approximately 1%). Data from the United Healthcare database and a case-control
study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular
malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an
increased risk for cardiovascular malformations overall after bupropion exposure during the first
trimester.
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Study findings on bupropion exposure during the first trimester and risk for left
ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions
regarding a possible association. The United Healthcare database lacked sufficient power to
evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk
for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular
septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible
association. The Slone Epidemiology Study found an increased risk for VSD following first
trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not
find increased risk for any other cardiovascular malformations studied (including LVOTO as
above). The NBDPS and United Healthcare database study did not find an association between
first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of
exposed cases, inconsistent findings among studies, and the potential for chance findings from
multiple comparisons in case control studies.
Animal Data: In studies conducted in rats and rabbits, bupropion was administered
orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis). No clear evidence of
teratogenic activity was found in either species; however, in rabbits, slightly increased incidences
of fetal malformations and skeletal variations were observed at the lowest dose tested (25
mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal
weights were observed at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
and lactation, there were no apparent adverse effects on offspring development.
8.3
Nursing Mothers
Bupropion and its metabolites are present in human milk. In a lactation study of 10
women, levels of orally dosed bupropion and its active metabolites were measured in expressed
milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion
and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when
WELLBUTRIN SR is administered to a nursing woman.
8.4
Pediatric Use
Safety and effectiveness in the pediatric population have not been established [see Boxed
Warning and Warnings and Precautions (5.1)].
8.5
Geriatric Use
Of the approximately 6,000 subjects who participated in clinical trials with bupropion
sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and
47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in
clinical trials using the immediate-release formulation of bupropion (depression trials). No
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overall differences in safety or effectiveness were observed between these subjects and younger
subjects. Reported clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients
with impaired renal function. Because elderly patients are more likely to have decreased renal
function, it may be necessary to consider this factor in dose selection; it may be useful to monitor
renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and
Clinical Pharmacology (12.3)].
8.6
Renal Impairment
Consider a reduced dose and/or dosing frequency of WELLBUTRIN SR in patients with
renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are
cleared renally and may accumulate in such patients to a greater extent than usual. Monitor
closely for adverse reactions that could indicate high bupropion or metabolite exposures [see
Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
maximum dose of WELLBUTRIN SR is 100 mg per day or 150 mg every other day. In patients
with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or
frequency of dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
Bupropion is not a controlled substance.
9.2
Abuse
Humans: Controlled clinical trials of bupropion (immediate-release formulation)
conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in
depressed subjects showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg
of bupropion produced mild amphetamine-like activity as compared with placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential
of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be significantly
reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be
tested because of the risk of seizure) might be modestly attractive to those who abuse CNS
stimulant drugs.
17
Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Animals: Studies in rodents and primates demonstrated that bupropion exhibits some
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding
in several schedule-controlled behavior paradigms. In primate models assessing the positive
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
10
OVERDOSAGE
10.1 Human Overdose Experience
Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was
reported in approximately one-third of all cases. Other serious reactions reported with overdoses
of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG
changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever,
muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been
reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
in these patients.
10.2 Overdosage Management
Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone
numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR).
Call 1-800-222-1222 or refer to www.poison.org.
There are no known antidotes for bupropion. In case of an overdose, provide supportive
care, including close medical supervision and monitoring. Consider the possibility of multiple
drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm
and vital signs. Induction of emesis is not recommended.
11
DESCRIPTION
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone
class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or
other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is
related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1
dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular
formula is C13 H18 ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly
soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral
mucosa. The structural formula is:
18
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
WELLBUTRIN SR is supplied for oral administration as 100-mg (blue), 150-mg
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the
100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The exact mechanism of the antidepressant action of bupropion is not known, but is
presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a
relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not
inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.
12.3 Pharmacokinetics
Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of
the individual enantiomers have not been studied. The mean elimination half-life (±SD) of
bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of
bupropion are reached within 8 days.
Absorption: The absolute bioavailability of WELLBUTRIN SR in humans has not been
determined because an intravenous formulation for human use is not available. However, it
appears likely that only a small proportion of any orally administered dose reaches the systemic
circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to
20%.
In humans, following oral administration of WELLBUTRIN SR, peak plasma
concentration (C max ) of bupropion is usually achieved within 3 hours.
In a trial comparing chronic dosing with WELLBUTRIN SR 150 mg twice daily to
bupropion immediate-release formulation 100 mg 3 times daily, the steady state C max for
bupropion after WELLBUTRIN SR administration was approximately 85% of those achieved
after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion
was equivalent for both formulations. Bioequivalence was also demonstrated for all three major
active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion)
for both Cmax and AUC. Thus, at steady state, WELLBUTRIN SR given twice daily, and the
19
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for
both bupropion and the 3 quantitatively important metabolites.
WELLBUTRIN SR can be taken with or without food. Bupropion Cmax and AUC
wasincreased by 11% to 35% and 16% to 19%, respectively, when WELLBUTRIN SR was
administered with food to healthy volunteers in three trials. The food effect is not considered
clinically significant.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins
at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion; whereas, the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are
active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of
bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion,
which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is
the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450
enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion
side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is
then excreted as the major urinary metabolite. The potency and toxicity of the metabolites
relative to bupropion have not been fully characterized. However, it has been demonstrated in an
antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion,
while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion.
This may be of clinical importance because the plasma concentrations of the metabolites are as
high as or higher than those of bupropion.
Following a single dose administration of WELLBUTRIN SR in humans, Cmax of
hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the
peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is
approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The
times to peak concentrations for the erythrohydrobupropion and threohydrobupropion
metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination
half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5
and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of
300 to 450 mg per day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87%
and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5%
of the oral dose was excreted as unchanged bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
be expected to influence the degree and extent of accumulation of the active metabolites of
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
20
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
renal or hepatic function because they are moderately polar compounds and are likely to undergo
further metabolism or conjugation in the liver prior to urinary excretion.
Renal Impairment: There is limited information on the pharmacokinetics of
bupropion in patients with renal impairment. An inter-trial comparison between normal subjects
and subjects with end-stage renal failure demonstrated that the parent drug C max and AUC values
were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage
renal failure. A second trial, comparing normal subjects and subjects with moderate-to-severe
renal impairment (GFR 30.9 ± 10.8 mL/min), showed that after a single 150-mg dose of
sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects
with impaired renal function, while levels of the hydroxybupropion and
threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is
extensively metabolized in the liver to active metabolites, which are further metabolized and
subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion
may be reduced by impaired renal function. WELLBUTRIN SR should be used with caution in
patients with renal impairment and a reduced frequency and/or dose should be considered [see
Use in Specific Populations (8.6)].
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of
bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease
and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half-life of
hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
for bupropion and the other metabolites in the 2 groups were minimal.
The second trial demonstrated no statistically significant differences in the
pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild–to-moderate
hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in
some of the pharmacokinetic parameters for bupropion (AUC, Cmax , and Tmax ) and its active
metabolites (t½) in subjects with mild–to-moderate hepatic cirrhosis. In subjects with severe
hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites
were seen (Table 5).
Table 5. Pharmacokinetics of Bupropion and Metabolites in Patients With Severe Hepatic
Cirrhosis: Ratio Relative to Healthy Matched Controls
Cmax
AUC
t½
Tmax
a
Bupropion
1.69
3.12
1.43
0.5 h
Hydroxybupropion
0.31
1.28
3.88
19 h
Threo/erythrohydrobupropion
amino alcohol
0.69
2.48
1.96
20 h
21
Reference ID: 3426387
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a = Difference.
Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14
depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-
ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites,
compared with healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have
not been fully characterized, but an exploration of steady-state bupropion concentrations from
several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day,
on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are
at increased risk for accumulation of bupropion and its metabolites [see Use in Specific
Populations (8.5)].
Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male
and 90 healthy female volunteers revealed no sex-related differences in the peak plasma
concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13%
higher in male volunteers compared with female volunteers. The clinical significance of this
finding is unknown.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion
were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and
17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
were no statistically significant differences in Cmax , half-life, Tmax , AUC, or clearance of
bupropion or its active metabolites between smokers and nonsmokers.
Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN SR: In vitro
studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6.
Therefore, the potential exists for drug interactions between WELLBUTRIN SR and drugs that
are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine,
sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.
Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male
volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures
(Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for
ticlopidine, respectively. The exposures (C max and AUC) of hydroxybupropion were decreased
50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This
effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.
Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects,
prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and
22
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
decreased C max and AUC values of hydroxybupropion, an active metabolite of bupropion, by
32% and 24%, respectively.
Cimetidine: The threohydrobupropion metabolite of bupropion does not appear
to be produced by cytochrome P450 enzymes. The effects of concomitant administration of
cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24
healthy young male volunteers. Following oral administration of bupropion 300 mg with and
without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were
unaffected. However, there were 16% and 32% increases in the AUC and Cmax , respectively of
the combined moieties of threohydrobupropion and erythrohydrobupropion.
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its
three metabolites.
Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial,
ritonavir 100 mg twice daily reduced the AUC and C max of bupropion by 22% and 21%,
respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the
threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and
the C max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion
metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the
erythrohydrobupropion decreased by 68%.
In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily
decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were
decreased by 50% and 31%, respectively.
Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for
2 weeks reduced the AUC and C max of bupropion by approximately 55% and 34%, respectively.
The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was
increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
these drugs may induce the metabolism of bupropion.
Potential for WELLBUTRIN SR to Affect Other Drugs: Animal data indicated that
bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following
chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14
days, there was no evidence of induction of its own metabolism. Nevertheless, there may be
potential for clinically important alterations of blood levels of co-administered drugs.
Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a
clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of
CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased
the C max , AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold,
respectively. The effect was present for at least 7 days after the last dose of bupropion.
23
Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally
studied.
Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in
one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.
Lamotrigine: Multiple oral doses of bupropion had no statistically significant
effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up
to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the
MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular
proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the
MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such
lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions
were not seen in the mouse study, and no increase in malignant tumors of the liver and other
organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of
5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in
chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
fertility.
14
CLINICAL STUDIES
The efficacy of the immediate-release formulation of bupropion in the treatment of major
depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients
with MDD (Trials 1 and 2 in Table 6) and in one 6-week, placebo-controlled trial in adult
outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range of bupropion was 300
mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of
300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate-release
formulation of bupropion by the Hamilton Depression Rating Scale (HDRS) total score, the
HDRS depressed mood item (item 1), and the Clinical Global Impressions severity score (CGI
S). The second trial included 2 doses of the immediate-release formulation of bupropion (300
and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the
immediate-release formulation of bupropion, but only at the 450-mg-per-day dose. The efficacy
results were significant for the HDRS total score and the CGI-S score, but not for HDRS item 1.
In the third trial, outpatients were treated with 300 mg per day of the immediate-release
formulation of bupropion. This trial demonstrated the efficacy of the immediate-release
formulation of bupropion as measured by the HDRS total score, the HDRS item 1, the
Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-
Improvement Scale (CGI-I) score.
24
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6. Efficacy of Immediate-Release Bupropion for the Treatment of Major Depressive
Disorder
Trial
Number
Treatment Group
Primary Efficacy Measure: HDRS
Mean Baseline
Score (SD)
LS Mean Score at
Endpoint Visit
(SE)
Placebo
substracted
Differencea (95%
CI)
Trial 1
Immediate-Release
Bupropion 300
600 mg/dayb
(n = 48)
28.5 (5.1)
14.9 (1.3)
-4.7 (-8.8, -0.6)
Placebo (n = 27)
29.3 (7.0)
19.6 (1.6)
-
Mean Baseline
Score (SD)
LS Mean Change
from Baseline (SE)
Placebo-subtracted
Differencea (95%
CI)
Trial 2
Immediate-Release
Bupropion 300
mg/day (n = 36)
32.4 (5.9)
-15.5 (1.7)
-4.1
Immediate-Release
Bupropion 450
mg/dayb (n = 34)
34.8 (4.6)
-17.4 (1.7)
-5.9 (-10.5, -1.4)
Placebo (n = 39)
32.9 (5.4)
-11.5 (1.6)
-
Trial 3
Immediate-Release
Bupropion 300
mg/dayb (n = 110)
26.5 (4.3)
-12.0 (NA)
-3.9 (-5.7, -1.0)
Placebo (n = 106)
27.0 (3.5)
-8.7 (NA)
-
n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI:
unadjusted confidence interval included for doses that were demonstrated to be effective; NA:
not available.
a Difference (drug minus placebo) in least-squares estimates with respect to the primary
efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2
and 3, it refers to the mean change from baseline to the endpoint visit.
b Doses that are demonstrated to be statistically significantly superior to placebo.
Although there are not as yet independent trials demonstrating the antidepressant
effectiveness of the sustained-release formulation of bupropion, trials have demonstrated the
bioequivalence of the immediate-release and sustained-release forms of bupropion under
steady-state conditions, i.e., bupropion sustained-release 150 mg twice daily was shown to be
25
Reference ID: 3426387
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bioequivalent to 100 mg 3 times daily of the immediate-release formulation of bupropion, with
regard to both rate and extent of absorption, for parent drug and metabolites.
In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder,
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
twice daily) were randomized to continuation of their same dose of WELLBUTRIN SR or
placebo for up to 44 weeks of observation for relapse. Response during the open phase was
defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of
the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s
judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving
continued treatment with WELLBUTRIN SR experienced significantly lower relapse rates over
the subsequent 44 weeks compared with those receiving placebo.
16
HOW SUPPLIED/STORAGE AND HANDLING
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are
blue, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
(NDC 0173-0947-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
purple, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 150” in bottles of
60 (NDC 0173-0135-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are
light pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles
of 60 (NDC 0173-0722-00) tablets.
Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between
15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from light
and moisture.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated
with treatment with WELLBUTRIN SR and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other
Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking
Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or
Actions,” and “What Other Important Information Should I Know About WELLBUTRIN SR?”
is available for WELLBUTRIN SR. Instruct patients, their families, and their caregivers to read
the Medication Guide and assist them in understanding its contents. Patients should be given the
opportunity to discuss the contents of the Medication Guide and to obtain answers to any
questions they may have. The complete text of the Medication Guide is reprinted at the end of
this document.
Advise patients regarding the following issues and to alert their prescriber if these occur
while taking WELLBUTRIN SR.
26
Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their
caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
early during antidepressant treatment and when the dose is adjusted up or down. Advise families
and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis,
since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or
healthcare professional, especially if they are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk
for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it contains the
same active ingredient as ZYBAN which is approved for this use. Advise patients, families and
caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal
symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness.
Some patients have experienced changes in mood (including depression and mania), psychosis,
hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as
suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while
taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking
or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they
should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and
to discontinue WELLBUTRIN SR if they have a severe allergic reaction.
Seizure: Instruct patients to discontinue and not restart WELLBUTRIN SR if they
experience a seizure while on treatment. Advise patients that the excessive use or abrupt
discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can
increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.
As the dose is increased during initial titration to doses above 150 mg per day, instruct
patients to take WELLBUTRIN SR in 2 divided doses, preferably with at least 8 hours between
successive doses, to minimize the risk of seizures.
Bupropion-Containing Products: Educate patients that WELLBUTRIN SR contains
the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid
to smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination
with ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN®, the
immediate-release formulation and WELLBUTRIN XL® or FORFIVO XL™, the extended-
release formulations, and APLENZIN®, the extended-release formulation of bupropion
hydrobromide). In addition, there are a number of generic bupropion HCl products for the
immediate-, sustained-, and extended-release formulations.
27
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Potential for Cognitive and Motor Impairment: Advise patients that any CNS-active
drug like WELLBUTRIN SR may impair their ability to perform tasks requiring judgment or
motor and cognitive skills. Advise patients that until they are reasonably certain that
WELLBUTRIN SR does not adversely affect their performance, they should refrain from driving
an automobile or operating complex, hazardous machinery. WELLBUTRIN SR may lead to
decreased alcohol tolerance.
Concomitant Medications: Counsel patients to notify their healthcare provider if they
are taking or plan to take any prescription or over-the-counter drugs because WELLBUTRIN SR
Sustained-Release Tablets and other drugs may affect each others’ metabolisms.
Pregnancy: Advise patients to notify their healthcare provider if they become pregnant
or intend to become pregnant during therapy.
Precautions for Nursing Mothers: Advise patients that WELLBUTRIN SR is present
in human milk in small amounts.
Storage Information: Instruct patients to store WELLBUTRIN SR at room temperature,
between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.
Administration Information: Instruct patients to swallow WELLBUTRIN SR Tablets
whole so that the release rate is not altered. Do not chew, divide, or crush tablets; they are
designed to slowly release drug in the body. When patients take more than 150 mg per day,
instruct them to take WELLBUTRIN SR in 2 doses at least 8 hours apart, to minimize the risk of
seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the
missed dose and to take the next tablet at the regular time because of the dose-related risk of
seizure. Instruct patients that WELLBUTRIN SR Tablets may have an odor. WELLBUTRIN SR
can be taken with or without food.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of the GlaxoSmithKline group of companies. The other brands listed are trademarks
of their respective owners and are not trademarks of the GlaxoSmithKline group of companies.
The makers of these brands are not affiliated with and do not endorse the GlaxoSmithKline
group of companies or its products.
Manufactured for:
company logo
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline group of companies. All rights reserved.
WLT:XPI
28
Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
WELLBUTRIN® SR (WELL byu-trin)
(bupropion hydrochloride) Sustained-Release Tablets
Read this Medication Guide carefully before you start taking WELLBUTRIN SR and
each time you get a refill. There may be new information. This information does not
take the place of talking with your healthcare provider about your medical condition
or your treatment. If you have any questions about WELLBUTRIN SR, ask your
healthcare provider or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide.
The first section is about the risk of suicidal thoughts and actions with
antidepressant medicines; the second section is about the risk of changes
in thinking and behavior, depression and suicidal thoughts or actions with
medicines used to quit smoking; and the third section is entitled “What
Other Important Information Should I Know About WELLBUTRIN SR?”
Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of suicidal thoughts and
actions with antidepressant medicines. Talk to your healthcare provider or your
family member’s healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about
antidepressant medicines, depression and other serious mental illnesses,
and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in
some children, teenagers, or young adults within the first few months of
treatment.
2. Depression or other serious mental illnesses are the most important
causes of suicidal thoughts and actions. Some people may have a
particularly high risk of having suicidal thoughts or actions. These include
people who have (or have a family history of) bipolar illness (also called manic-
depressive illness) or suicidal thoughts or actions.
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3. How can I watch for and try to prevent suicidal thoughts and actions in
myself or a family member?
• Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
• Call your healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call your healthcare provider right away if you or your family member has
any of the following symptoms, especially if they are new, worse, or worry
you:
• thoughts about suicide or dying
•
trouble sleeping (insomnia)
• attempts to commit suicide
•
new or worse irritability
• new or worse depression
•
acting aggressive, being angry, or violent
• new or worse anxiety
•
acting on dangerous impulses
• feeling very agitated or restless
•
an extreme increase in activity and talking (mania)
• panic attacks
•
other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a
healthcare provider. Stopping an antidepressant medicine suddenly can cause
other symptoms.
• Antidepressants are medicines used to treat depression and other
illnesses. It is important to discuss all the risks of treating depression and also
the risks of not treating it. Patients and their families or other caregivers should
discuss all treatment choices with the healthcare provider, not just the use of
antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare
provider about the side effects of the medicine prescribed for you or your family
member.
• Antidepressant medicines can interact with other medicines. Know all of
the medicines that you or your family member takes. Keep a list of all medicines
to show the healthcare provider. Do not start new medicines without first
checking with your healthcare provider.
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It is not known if WELLBUTRIN SR is safe and effective in children under the age of
18.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and
Behavior, Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking
and behavior, depression and suicidal thoughts or actions with drugs used to quit
smoking.
Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the
same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help
patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression, suicidal
thoughts or actions while taking bupropion to help them quit smoking. These
symptoms can develop during treatment with bupropion or after stopping treatment
with bupropion.
If you, your family member, or your caregiver notice agitation, hostility,
depression, or changes in thinking or behavior that are not typical for you, or you
have any of the following symptoms, stop taking bupropion and call your healthcare
provider right away:
• thoughts about suicide or dying
•
an extreme increase in activity and talking
• attempts to commit suicide
(mania)
• new or worse depression
•
abnormal thoughts or sensations
• new or worse anxiety
•
seeing or hearing things that are not there
• panic attacks
(hallucinations)
• feeling very agitated or restless
•
feeling people are against you (paranoia)
• acting aggressive, being angry, or
•
feeling confused
violent
•
other unusual changes in behavior or mood
• acting on dangerous impulses
When you try to quit smoking, with or without bupropion, you may have symptoms
that may be due to nicotine withdrawal, including urge to smoke, depressed mood,
trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty
concentrating, restlessness, decreased heart rate, and increased appetite or weight
gain. Some people have even experienced suicidal thoughts when trying to quit
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smoking without medication. Sometimes quitting smoking can lead to worsening of
mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had
depression or other mental illnesses. You should also tell your healthcare provider
about any symptoms you had during other times you tried to quit smoking, with or
without bupropion.
What Other Important Information Should I Know About WELLBUTRIN SR?
• Seizures: There is a chance of having a seizure (convulsion, fit) with
WELLBUTRIN SR, especially in people:
o with certain medical problems.
o who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN SR.
For more information, see the sections “Who should not take WELLBUTRIN SR?”
and “What should I tell my healthcare provider before taking WELLBUTRIN SR?”
Tell your healthcare provider about all of your medical conditions and all the
medicines you take. Do not take any other medicines while you are taking
WELLBUTRIN SR unless your healthcare provider has said it is okay to
take them.
If you have a seizure while taking WELLBUTRIN SR, stop taking the
tablets and call your healthcare provider right away. Do not take
WELLBUTRIN SR again if you have a seizure.
• High blood pressure (hypertension). Some people get high blood
pressure, that can be severe, while taking WELLBUTRIN SR. The chance
of high blood pressure may be higher if you also use nicotine replacement
therapy (such as a nicotine patch) to help you stop smoking.
• Manic episodes. Some people may have periods of mania while taking
WELLBUTRIN SR, including:
o
Greatly increased energy
o
Severe trouble sleeping
o
Racing thoughts
o
Reckless behavior
o
Unusually grand ideas
o
Excessive happiness or irritability
o
Talking more or faster than usual
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If you have any of the above symptoms of mania, call your healthcare provider.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or
behaviors while taking WELLBUTRIN, including delusions (believe you are
someone else), hallucinations (seeing or hearing things that are not there),
paranoia (feeling that people are against you), or feeling confused. If this
happens to you, call your healthcare provider.
• Severe allergic reactions. Some people can have severe allergic
reactions to WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your
healthcare provider right away if you get a rash, itching, hives, fever,
swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
the lips or tongue, chest pain, or have trouble breathing. These could be signs of
a serious allergic reaction.
What is WELLBUTRIN SR?
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type
of depression called major depressive disorder.
Who should not take WELLBUTRIN SR?
Do not take WELLBUTRIN SR if you
• have or had a seizure disorder or epilepsy.
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are taking any other medicines that contain bupropion, ZYBAN (used to
help people stop smoking) APLENZIN®, FORFIVO XL™, WELLBUTRIN®, or
WELLBUTRIN XL® .Bupropion is the same active ingredient that is in
WELLBUTRIN SR.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called
sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines,
and you stop using them all of a sudden.
• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
• do not take an MAOI within 2 weeks of stopping WELLBUTRIN SR unless
directed to do so by your healthcare provider.
• do not start WELLBUTRIN SR if you stopped taking an MAOI in the last 2
weeks unless directed to do so by your healthcare provider.
• are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of
the inactive ingredients. See the end of this Medication Guide for a complete list
of ingredients in WELLBUTRIN SR.
What should I tell my healthcare provider before taking WELLBUTRIN SR?
33
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider if you have ever had depression, suicidal thoughts or
actions, or other mental health problems. See “Antidepressant Medicines,
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”
Tell your healthcare provider about your other medical conditions including
if you:
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
• have, or have had, an eating disorder, such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
• drink alcohol.
• abuse prescription medicines or street drugs.
• are pregnant or plan to become pregnant.
• are breastfeeding. WELLBUTRIN passes into your milk in small amounts.
Tell your healthcare provider about all the medicines you take, including
prescription, over-the-counter medicines, vitamins, and herbal supplements. Many
medicines increase your chances of having seizures or other serious side effects if
you take them while you are taking WELLBUTRIN SR.
How should I take WELLBUTRIN SR?
• Take WELLBUTRIN SR exactly as prescribed by your healthcare provider.
• Swallow WELLBUTRIN SR Tablets whole. Do not chew, cut, or crush
WELLBUTRIN SR Tablets. If you do, the medicine will be released into your
body too quickly. If this happens you may be more likely to get side effects
including seizures. Tell your healthcare provider if you cannot swallow
tablets.
• Take WELLBUTRIN SR at the same time each day.
• Take your doses of WELLBUTRIN SR at least 8 hours apart.
• You may take WELLBUTRIN SR with or without food.
• If you miss a dose, do not take an extra dose to make up for the dose you
missed. Wait and take your next dose at the regular time. This is very
important. Too much WELLBUTRIN SR can increase your chance of having a
seizure.
• If you take too much WELLBUTRIN SR, or overdose, call your local emergency
room or poison control center right away.
34
Reference ID: 3426387
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• Do not take any other medicines while taking WELLBUTRIN SR unless
your healthcare provider has told you it is okay.
• If you are taking WELLBUTRIN SR for the treatment of major depressive
disorder, it may take several weeks for you to feel that WELLBUTRIN SR is
working. Once you feel better, it is important to keep taking WELLBUTRIN SR
exactly as directed by your healthcare provider. Call your healthcare provider if
you do not feel WELLBUTRIN SR is working for you.
• Do not change your dose or stop taking WELLBUTRIN SR without talking with
your healthcare provider first.
What should I avoid while taking WELLBUTRIN SR?
• Limit or avoid using alcohol during treatment with WELLBUTRIN SR. If you
usually drink a lot of alcohol, talk with your healthcare provider before suddenly
stopping. If you suddenly stop drinking alcohol, you may increase your chance
of having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR
affects you. WELLBUTRIN SR can affect your ability to do these things safely.
What are possible side effects of WELLBUTRIN SR?
See “What Other Important Information Should I Know About
WELLBUTRIN SR?”
WELLBUTRIN SR can cause serious side effects.
The most common side effects of WELLBUTRIN SR include:
• Headache
• Dry mouth
• Nausea
• Trouble sleeping
• Dizziness
• Sore throat
• Constipation
If you have nausea, take your medicine with food. If you have trouble sleeping, do
not take your medicine too close to bedtime.
Tell your healthcare provider right away about any side effects that bother you.
These are not all the possible side effects of WELLBUTRIN SR. For more
information, ask your healthcare provider or pharmacist.
35
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
You may also report side effects to GlaxoSmithKline at 1-888-825-5249.
How should I store WELLBUTRIN SR?
• Store WELLBUTRIN SR at room temperature between 59°F and 86°F (15°C to
30°C).
• Keep WELLBUTRIN SR dry and out of the light.
• WELLBUTRIN SR Tablets may have an odor.
Keep WELLBUTRIN SR and all medicines out of the reach of children.
General Information about WELLBUTRIN SR.
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use WELLBUTRIN SR for a condition for which it was not
prescribed. Do not give WELLBUTRIN SR to other people, even if they have the
same symptoms you have. It may harm them.
If you take a urine drug screening test, WELLBUTRIN SR may make the test result
positive for amphetamines. If you tell the person giving you the drug screening test
that you are taking WELLBUTRIN SR, they can do a more specific drug screening
test that should not have this problem.
This Medication Guide summarizes important information about WELLBUTRIN SR. If
you would like more information, talk with your healthcare provider. You can ask
your healthcare provider or pharmacist for information about WELLBUTRIN SR that
is written for healthcare professionals.
For more information about WELLBUTRIN SR, go to www.wellbutrin.com or call 1
888-825-5249.
What are the ingredients in WELLBUTRIN SR?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80,
and titanium dioxide. In addition, the 100-mg tablet contains FD&C Blue No. 1
Lake, the 150-mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake,
36
Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
and the 200-mg tablet contains FD&C Red No. 40 Lake. The tablets are printed with
edible black ink.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of the GlaxoSmithKline group of companies. The other brands listed
are trademarks of their respective owners and are not trademarks of the
GlaxoSmithKline group of companies. The makers of these brands are not affiliated
with and do not endorse the GlaxoSmithKline group of companies or its products.
company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline group of companies. All rights reserved.
Month Year
WLS: MG
37
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:31.344226
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020358s053s054lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 53}
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
WELLBUTRIN safely and effectively. See full prescribing information
for WELLBUTRIN.
WELLBUTRIN (bupropion hydrochloride) Tablets, for oral use
Initial U.S. Approval: 1985
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
See full prescribing information for complete boxed warning.
• Increased risk of suicidal thinking and behavior in children,
adolescents, and young adults taking antidepressants. (5.1)
• Monitor for worsening and emergence of suicidal thoughts and
behaviors. (5.1)
• Serious neuropsychiatric events have been reported in patients
taking bupropion for smoking cessation. (5.2)
---------------------------RECENT MAJOR CHANGES --------------------------
Warnings and Precautions, Angle-Closure Glaucoma (5.7)
07/2014
----------------------------INDICATIONS AND USAGE ---------------------------
WELLBUTRIN is an aminoketone antidepressant, indicated for the
treatment of major depressive disorder (MDD). (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
•
Starting dose: 200 mg per day given as 100 mg twice daily (2.1)
•
General: Increase dose gradually to reduce seizure risk. (2.1, 5.3)
• After 3 days, may increase the dose to 300 mg per day, given as 100 mg
3 times daily at an interval of at least 6 hours between doses. (2.1)
• Usual target dose: 300 mg per day as 100 mg 3 times daily. (2.1)
• Maximum dose: 450 mg per day given as 150 mg 3 times daily. (2.1)
• Periodically reassess the dose and need for maintenance treatment. (2.1)
• Moderate to severe hepatic impairment: 75 mg once daily. (2.2, 8.7)
• Mild hepatic impairment: Consider reducing the dose and/or frequency of
dosing. (2.2, 8.7)
•
Renal impairment: Consider reducing the dose and/or frequency. (2.3,
8.6)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets: 75 mg and 100 mg. (3)
-------------------------------CONTRAINDICATIONS ------------------------------
• Seizure disorder. (4, 5.3)
• Current or prior diagnosis of bulimia or anorexia nervosa. (4, 5.3)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates,
antiepileptic drugs. (4, 5.3)
• Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to
treat psychiatric disorders with WELLBUTRIN or within 14 days of
stopping treatment with WELLBUTRIN. Do not use WELLBUTRIN
within 14 days of stopping an MAOI intended to treat psychiatric
disorders. In addition, do not start WELLBUTRIN in a patient who is
being treated with linezolid or intravenous methylene blue. (4, 7.6)
•
Known hypersensitivity to bupropion or other ingredients of
WELLBUTRIN. (4, 5.8)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Seizure risk: The risk is dose-related. Can minimize risk by gradually
increasing the dose and limiting daily dose to 450 mg. Discontinue if
seizure occurs. (4, 5.3, 7.3)
•
Hypertension: WELLBUTRIN can increase blood pressure. Monitor
blood pressure before initiating treatment and periodically during
treatment. (5.4)
•
Activation of mania/hypomania: Screen patients for bipolar disorder and
monitor for these symptoms. (5.5)
•
Psychosis and other neuropsychiatric reactions: Instruct patients to
contact a healthcare professional if such reactions occur. (5.6)
•
Angle-closure glaucoma: Angle-closure glaucoma has occurred in
patients with untreated anatomically narrow angles treated with
antidepressants. (5.7)
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions (incidence ≥5% and ≥1% more than placebo
rate) are: agitation, dry mouth, constipation, headache/migraine,
nausea/vomiting, dizziness, excessive sweating, tremor, insomnia, blurred
vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and
auditory disturbance. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• CYP2B6 inducers: Dose increase may be necessary if coadministered
with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz,
carbamazepine, phenobarbital, and phenytoin) based on clinical response,
but should not exceed the maximum recommended dose. (7.1)
• Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can
increase concentrations of: antidepressants (e.g., venlafaxine,
nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline),
antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers
(e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone,
flecainide). Consider dose reduction when using with bupropion. (7.2)
• Drugs that lower seizure threshold: Dose WELLBUTRIN with caution.
(5.3, 7.3)
• Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur
when used concomitantly with WELLBUTRIN. (7.4)
•
MAOIs: Increased risk of hypertensive reactions can occur when used
concomitantly with WELLBUTRIN. (7.6)
•
Drug-laboratory test interactions: WELLBUTRIN can cause false-
positive urine test results for amphetamines. (7.7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
•
Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: Month/Year
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
2.2
Dose Adjustment in Patients with Hepatic Impairment
2.3
Dose Adjustment in Patients with Renal Impairment
2.4
Switching a Patient to or from a Monoamine Oxidase
Inhibitor (MAOI) Antidepressant
2.5
Use of WELLBUTRIN with Reversible MAOIs Such as
Linezolid or Methylene Blue
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children,
Adolescents, and Young Adults
5.2
Neuropsychiatric Symptoms and Suicide Risk in
Smoking Cessation Treatment
5.3
Seizure
5.4
Hypertension
5.5
Activation of Mania/Hypomania
5.6
Psychosis and Other Neuropsychiatric Reactions
5.7
Angle-Closure Glaucoma
5.8
Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN
7.2
Potential for WELLBUTRIN to Affect Other Drugs
7.3
Drugs that Lower Seizure Threshold
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
7.5
Use with Alcohol
7.6
MAO Inhibitors
7.7
Drug-Laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
1
Reference ID: 3674083
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8.4
Pediatric Use
11 DESCRIPTION
8.5
Geriatric Use
12 CLINICAL PHARMACOLOGY
8.6
Renal Impairment
12.1 Mechanism of Action
8.7
Hepatic Impairment
12.3 Pharmacokinetics
9
DRUG ABUSE AND DEPENDENCE
13 NONCLINICAL TOXICOLOGY
9.1
Controlled Substance
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
9.2
Abuse
14 CLINICAL STUDIES
10 OVERDOSAGE
16 HOW SUPPLIED/STORAGE AND HANDLING
10.1 Human Overdose Experience
17 PATIENT COUNSELING INFORMATION
10.2 Overdosage Management
*Sections or subsections omitted from the full prescribing information are not
listed.
1
FULL PRESCRIBING INFORMATION
2
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC
3
REACTIONS
4
5
SUICIDALITY AND ANTIDEPRESSANT DRUGS
6
Antidepressants increased the risk of suicidal thoughts and behavior in children,
7
adolescents, and young adults in short-term trials. These trials did not show an increase in
8
the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24;
9
there was a reduction in risk with antidepressant use in subjects aged 65 and older [see
10
Warnings and Precautions (5.1)].
11
In patients of all ages who are started on antidepressant therapy, monitor closely for
12
worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
13
caregivers of the need for close observation and communication with the prescriber [see
14
Warnings and Precautions (5.1)].
15
16
NEUROPSYCHIATRIC REACTIONS IN PATIENTS TAKING BUPROPION FOR
17
SMOKING CESSATION
18
Serious neuropsychiatric reactions have occurred in patients taking bupropion for
19
smoking cessation [see Warnings and Precautions (5.2)]. The majority of these reactions
20
occurred during bupropion treatment, but some occurred in the context of discontinuing
21
treatment. In many cases, a causal relationship to bupropion treatment is not certain,
22
because depressed mood may be a symptom of nicotine withdrawal. However, some of the
23
cases occurred in patients taking bupropion who continued to smoke. Although
24
WELLBUTRIN® is not approved for smoking cessation, observe all patients for
25
neuropsychiatric reactions. Instruct the patient to contact a healthcare provider if such
26
reactions occur [see Warnings and Precautions (5.2)].
27
1
INDICATIONS AND USAGE
28
WELLBUTRIN (bupropion hydrochloride) is indicated for the treatment of major
29
depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
30
The efficacy of WELLBUTRIN in the treatment of a major depressive episode was
31
established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of
32
adult subjects with MDD [see Clinical Studies (14)].
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
33
2
DOSAGE AND ADMINISTRATION
34
2.1
General Instructions for Use
35
To minimize the risk of seizure, increase the dose gradually [see Warnings and
36
Precautions (5.3)]. Increases in dose should not exceed 100 mg per day in a 3-day period.
37
WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or chewed.
38
WELLBUTRIN may be taken with or without food.
39
The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3
40
days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily,
41
with at least 6 hours between successive doses. Dosing above 300 mg per day may be
42
accomplished using the 75- or 100-mg tablets.
43
A maximum of 450 mg per day, given in divided doses of not more than 150 mg each,
44
may be considered for patients who show no clinical improvement after several weeks of
45
treatment at 300 mg per day. Administer the 100-mg tablet 4 times daily to not exceed the limit
46
of 150 mg in a single dose.
47
It is generally agreed that acute episodes of depression require several months or longer
48
of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether
49
the dose of WELLBUTRIN needed for maintenance treatment is identical to the dose that
50
provided an initial response. Periodically reassess the need for maintenance treatment and the
51
appropriate dose for such treatment.
52
2.2
Dose Adjustment in Patients with Hepatic Impairment
53
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
54
maximum dose of WELLBUTRIN is 75 mg per day. In patients with mild hepatic impairment
55
(Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in
56
Specific Populations (8.7), Clinical Pharmacology (12.3)].
57
2.3
Dose Adjustment in Patients with Renal Impairment
58
Consider reducing the dose and/or frequency of WELLBUTRIN in patients with renal
59
impairment (Glomerular Filtration Rate <90 mL/min) [see Use in Specific Populations (8.6),
60
Clinical Pharmacology (12.3)].
61
2.4
Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI)
62
Antidepressant
63
At least 14 days should elapse between discontinuation of an MAOI intended to treat
64
depression and initiation of therapy with WELLBUTRIN. Conversely, at least 14 days should be
65
allowed after stopping WELLBUTRIN before starting an MAOI antidepressant [see
66
Contraindications (4), Drug Interactions (7.6)].
67
2.5
Use of WELLBUTRIN with Reversible MAOIs Such as Linezolid or
68
Methylene Blue
69
Do not start WELLBUTRIN in a patient who is being treated with a reversible MAOI
70
such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of
71
hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric
3
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72
condition, non-pharmacological interventions, including hospitalization, should be considered
73
[see Contraindications (4), Drug Interactions (7.6)].
74
In some cases, a patient already receiving therapy with WELLBUTRIN may require
75
urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
76
linezolid or intravenous methylene blue treatment are not available and the potential benefits of
77
linezolid or intravenous methylene blue treatment are judged to outweigh the risks of
78
hypertensive reactions in a particular patient, WELLBUTRIN should be stopped promptly, and
79
linezolid or intravenous methylene blue can be administered. The patient should be monitored
80
for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue,
81
whichever comes first. Therapy with WELLBUTRIN may be resumed 24 hours after the last
82
dose of linezolid or intravenous methylene blue.
83
The risk of administering methylene blue by non-intravenous routes (such as oral tablets
84
or by local injection) or in intravenous doses much lower than 1 mg/kg with WELLBUTRIN is
85
unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with
86
such use [see Contraindications (4), Drug Interactions (7.6)].
87
3
DOSAGE FORMS AND STRENGTHS
88
• 75 mg – yellow-gold, round, biconvex tablets printed with “WELLBUTRIN 75”.
89
• 100 mg – red, round, biconvex tablets printed with “WELLBUTRIN 100”.
90
4
CONTRAINDICATIONS
91
• WELLBUTRIN is contraindicated in patients with a seizure disorder.
92
• WELLBUTRIN is contraindicated in patients with a current or prior diagnosis of bulimia or
93
anorexia nervosa as a higher incidence of seizures was observed in such patients treated with
94
WELLBUTRIN [see Warnings and Precautions (5.3)].
95
• WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol,
96
benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3),
97
Drug Interactions (7.3)].
98
• The use of MAOIs (intended to treat psychiatric disorders) concomitantly with
99
WELLBUTRIN or within 14 days of discontinuing treatment with WELLBUTRIN is
100
contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN is
101
used concomitantly with MAOIs. The use of WELLBUTRIN within 14 days of
102
discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN in a
103
patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is
104
contraindicated [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.4),
105
Drug Interactions (7.6)].
106
• WELLBUTRIN is contraindicated in patients with known hypersensitivity to bupropion or
107
other ingredients of WELLBUTRIN. Anaphylactoid/anaphylactic reactions and Stevens
108
Johnson syndrome have been reported [see Warnings and Precautions (5.8)].
4
Reference ID: 3674083
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109
5
WARNINGS AND PRECAUTIONS
110
5.1
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young
111
Adults
112
Patients with MDD, both adult and pediatric, may experience worsening of their
113
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
114
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
115
persist until significant remission occurs. Suicide is a known risk of depression and certain other
116
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
117
There has been a long-standing concern that antidepressants may have a role in inducing
118
worsening of depression and the emergence of suicidality in certain patients during the early
119
phases of treatment.
120
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective
121
serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of
122
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to
123
24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase
124
in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24;
125
there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
126
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
127
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
128
short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of
129
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
130
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
131
subjects. There was considerable variation in risk of suicidality among drugs, but a tendency
132
toward an increase in the younger subjects for almost all drugs studied. There were differences in
133
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
134
The risk differences (drug vs. placebo), however, were relatively stable within age strata and
135
across indications. These risk differences (drug-placebo difference in the number of cases of
136
suicidality per 1,000 subjects treated) are provided in Table 1.
137
138
Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled
139
Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1,000 Subjects Treated
Increases Compared With Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared With Placebo
25-64
1 fewer case
≥65
6 fewer cases
140
5
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141
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
142
but the number was not sufficient to reach any conclusion about drug effect on suicide.
143
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
144
months. However, there is substantial evidence from placebo-controlled maintenance trials in
145
adults with depression that the use of antidepressants can delay the recurrence of depression.
146
All patients being treated with antidepressants for any indication should be
147
monitored appropriately and observed closely for clinical worsening, suicidality, and
148
unusual changes in behavior, especially during the initial few months of a course of drug
149
therapy, or at times of dose changes, either increases or decreases [see Boxed Warning].
150
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
151
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
152
been reported in adult and pediatric patients being treated with antidepressants for major
153
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
154
Although a causal link between the emergence of such symptoms and either the worsening of
155
depression and/or the emergence of suicidal impulses has not been established, there is concern
156
that such symptoms may represent precursors to emerging suicidality.
157
Consideration should be given to changing the therapeutic regimen, including possibly
158
discontinuing the medication, in patients whose depression is persistently worse, or who are
159
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
160
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
161
patient’s presenting symptoms.
162
Families and caregivers of patients being treated with antidepressants for MDD or
163
other indications, both psychiatric and nonpsychiatric, should be alerted about the need to
164
monitor patients for the emergence of agitation, irritability, unusual changes in behavior,
165
and the other symptoms described above, as well as the emergence of suicidality, and to
166
report such symptoms immediately to healthcare providers. Such monitoring should
167
include daily observation by families and caregivers. Prescriptions for WELLBUTRIN
168
should be written for the smallest quantity of tablets consistent with good patient
169
management, in order to reduce the risk of overdose.
170
5.2
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
171
Treatment
172
WELLBUTRIN is not approved for smoking cessation treatment; however, bupropion
173
HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been
174
reported in patients taking bupropion for smoking cessation. These have included changes in
175
mood (including depression and mania), psychosis, hallucinations, paranoia, delusions,
176
homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal
177
ideation, suicide attempt, and completed suicide [see Boxed Warning, Adverse Reactions (6.2)].
178
Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a
179
healthcare professional if such reactions occur.
6
Reference ID: 3674083
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180
In many of these cases, a causal relationship to bupropion treatment is not certain,
181
because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases
182
occurred in patients taking bupropion who continued to smoke.
183
5.3
Seizure
184
WELLBUTRIN can cause seizure. The risk of seizure is dose-related. The dose should
185
not exceed 450 mg per day. Increase the dose gradually. Discontinue WELLBUTRIN and do not
186
restart treatment if the patient experiences a seizure.
187
The risk of seizures is also related to patient factors, clinical situations, and concomitant
188
medications that lower the seizure threshold. Consider these risks before initiating treatment with
189
WELLBUTRIN. WELLBUTRIN is contraindicated in patients with a seizure disorder, current or
190
prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol,
191
benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4), Drug
192
Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe head
193
injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant
194
use of other medications that lower the seizure threshold (e.g., other bupropion products,
195
antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic
196
disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of
197
illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants.
198
Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic
199
drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines,
200
sedative/hypnotics, or opiates.
201
Incidence of Seizure with Bupropion Use: Bupropion is associated with seizures in
202
approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg per day. The estimated
203
seizure incidence for WELLBUTRIN increases almost 10-fold between 450 and 600 mg per day.
204
The risk of seizure can be reduced if the dose of WELLBUTRIN does not exceed 450 mg
205
per day, given as 150 mg 3 times daily, and the titration rate is gradual.
206
5.4
Hypertension
207
Treatment with WELLBUTRIN can result in elevated blood pressure and hypertension.
208
Assess blood pressure before initiating treatment with WELLBUTRIN, and monitor periodically
209
during treatment. The risk of hypertension is increased if WELLBUTRIN is used concomitantly
210
with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see
211
Contraindications (4)].
212
Data from a comparative trial of the sustained-release formulation of bupropion HCl,
213
nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS,
214
and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent
215
hypertension in patients treated with the combination of sustained-release bupropion and NTS. In
216
this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS
217
had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with
218
sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had
219
evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of
7
Reference ID: 3674083
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220
sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study
221
medication discontinued due to hypertension compared with none of the subjects treated with
222
sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in
223
patients who receive the combination of bupropion and nicotine replacement.
224
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive
225
heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing
226
hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no
227
controlled trials assessing the safety of bupropion in patients with a recent history of myocardial
228
infarction or unstable cardiac disease.
229
5.5
Activation of Mania/Hypomania
230
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode.
231
The risk appears to be increased in patients with bipolar disorder or who have risk factors for
232
bipolar disorder. Prior to initiating WELLBUTRIN, screen patients for a history of bipolar
233
disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar
234
disorder, suicide, or depression). WELLBUTRIN is not approved for use in treating bipolar
235
depression.
236
5.6
Psychosis and Other Neuropsychiatric Reactions
237
Depressed patients treated with WELLBUTRIN have had a variety of neuropsychiatric
238
signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance,
239
paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some
240
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct
241
patients to contact a healthcare professional if such reactions occur.
242
5.7
Angle-Closure Glaucoma
243
The pupillary dilation that occurs following use of many antidepressant drugs including
244
WELLBUTRIN may trigger an angle-closure attack in a patient with anatomically narrow angles
245
who does not have a patent iridectomy.
246
5.8
Hypersensitivity Reactions
247
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion.
248
Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring
249
medical treatment. In addition, there have been rare, spontaneous postmarketing reports of
250
erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with
251
bupropion. Instruct patients to discontinue WELLBUTRIN and consult a healthcare provider if
252
they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives,
253
chest pain, edema, and shortness of breath) during treatment.
254
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like
255
symptoms suggestive of delayed hypersensitivity.
256
6
ADVERSE REACTIONS
257
The following adverse reactions are discussed in greater detail in other sections of the
258
labeling:
8
Reference ID: 3674083
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259
• Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning,
260
Warnings and Precautions (5.1)]
261
• Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed
262
Warning, Warnings and Precautions (5.2)]
263
• Seizure [see Warnings and Precautions (5.3)]
264
• Hypertension [see Warnings and Precautions (5.4)]
265
• Activation of mania or hypomania [see Warnings and Precautions (5.5)]
266
• Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6)]
267
• Angle-closure glaucoma [see Warnings and Precautions (5.7)]
268
• Hypersensitivity reactions [see Warnings and Precautions (5.8)]
269
6.1
Clinical Trials Experience
270
Because clinical trials are conducted under widely varying conditions, adverse reaction
271
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
272
clinical trials of another drug and may not reflect the rates observed in clinical practice.
273
Adverse Reactions Leading to Discontinuation of Treatment: Adverse reactions
274
were sufficiently troublesome to cause discontinuation of treatment with WELLBUTRIN in
275
approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical
276
trials during the product’s initial development. The more common events causing discontinuation
277
include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental
278
status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological
279
disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic
280
problems (1.4%), primarily rashes. It is important to note, however, that many of these events
281
occurred at doses that exceed the recommended daily dose.
282
Commonly Observed Adverse Reactions: Adverse reactions commonly encountered
283
in subjects treated with WELLBUTRIN are agitation, dry mouth, insomnia, headache/migraine,
284
nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia,
285
confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance.
286
Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an
287
incidence of at least 1% of subjects receiving WELLBUTRIN and more frequently in these
288
subjects than in the placebo group.
289
290
Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater
291
Frequency than Placebo in Controlled Clinical Trials
Adverse Reaction
WELLBUTRIN
(n = 323)
%
Placebo
(n = 185)
%
Cardiovascular
Cardiac arrhythmias
Dizziness
Hypertension
5.3
22.3
4.3
4.3
16.2
1.6
9
Reference ID: 3674083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypotension
2.5
2.2
Palpitations
3.7
2.2
Syncope
1.2
0.5
Tachycardia
10.8
8.6
Dermatologic
Pruritus
Rash
2.2
8.0
0.0
6.5
Gastrointestinal
Appetite increase
3.7
2.2
Constipation
26.0
17.3
Dyspepsia
3.1
2.2
Nausea/vomiting
22.9
18.9
Genitourinary
Impotence
3.4
3.1
Menstrual complaints
4.7
1.1
Urinary frequency
2.5
2.2
Musculoskeletal
Arthritis
3.1
2.7
Neurological
Akathisia
1.5
1.1
Cutaneous temperature
1.9
1.6
disturbance
Dry mouth
27.6
18.4
Excessive sweating
22.3
14.6
Headache/migraine
25.7
22.2
Impaired sleep quality
4.0
1.6
Insomnia
18.6
15.7
Sedation
19.8
19.5
Sensory disturbance
4.0
3.2
Tremor
21.1
7.6
Neuropsychiatric
Agitation
31.9
22.2
Anxiety
3.1
1.1
Confusion
8.4
4.9
Decreased libido
3.1
1.6
Delusions
1.2
1.1
Euphoria
1.2
0.5
10
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Hostility
5.6
3.8
Nonspecific
Fever/chills
1.2
0.5
Special Senses
Auditory disturbance
Blurred vision
Gustatory disturbance
5.3
14.6
3.1
3.2
10.3
1.1
292
293
Other Adverse Reactions Observed During the Clinical Development of
294
WELLBUTRIN: The conditions and duration of exposure to WELLBUTRIN varied greatly, and
295
a substantial proportion of the experience was gained in open and uncontrolled clinical settings.
296
During this experience, numerous adverse events were reported; however, without appropriate
297
controls, it is impossible to determine with certainty which events were or were not caused by
298
WELLBUTRIN. The following enumeration is organized by organ system and describes events
299
in terms of their relative frequency of reporting in the database.
300
The following definitions of frequency are used: Frequent adverse reactions are defined
301
as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in
302
1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.
303
Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram
304
(ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of
305
breath/dyspnea; rare were flushing, and myocardial infarction.
306
Dermatologic: Infrequent was alopecia.
307
Endocrine: Infrequent was gynecomastia; rare was glycosuria.
308
Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver
309
damage/jaundice; rare was intestinal perforation.
310
Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular
311
swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were enuresis,
312
and urinary incontinence.
313
Neurological: Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia,
314
and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram
315
(EEG) abnormality, and impaired attention.
316
Neuropsychiatric: Frequent were mania/hypomania, increased libido, hallucinations,
317
decrease in sexual function, and depression; infrequent were memory impairment,
318
depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought disorder, and
319
frigidity; rare was suicidal ideation.
320
Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum
321
irritation, and oral edema.
322
Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare was
323
pulmonary embolism.
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324
Special Senses: Infrequent was visual disturbance; rare was diplopia.
325
Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare
326
was overdose.
327
Altered Appetite and Weight: A weight loss of greater than 5 lbs occurred in 28% of
328
subjects receiving WELLBUTRIN. This incidence is approximately double that seen in
329
comparable subjects treated with tricyclics or placebo. Furthermore, while 35% of subjects
330
receiving tricyclic antidepressants gained weight, only 9.4% of subjects treated with
331
WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a patient’s
332
depressive illness, the anorectic and/or weight reducing potential of WELLBUTRIN should be
333
considered.
334
6.2
Postmarketing Experience
335
The following adverse reactions have been identified during post-approval use of
336
WELLBUTRIN and are not described elsewhere in the label. Because these reactions are
337
reported voluntarily from a population of uncertain size, it is not always possible to reliably
338
estimate their frequency or establish a causal relationship to drug exposure.
339
Body (General): Arthralgia, myalgia, and fever with rash and other symptoms
340
suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see
341
Warnings and Precautions (5.8)].
342
Cardiovascular: Hypertension (in some cases severe), orthostatic hypotension, third
343
degree heart block.
344
Endocrine: Syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia,
345
hypoglycemia.
346
Gastrointestinal: Esophagitis, hepatitis.
347
Hemic and Lymphatic: Ecchymosis, leukocytosis, leukopenia, thrombocytopenia.
348
Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications,
349
were observed when bupropion was coadministered with warfarin.
350
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis, muscle weakness.
351
Nervous System: Aggression, coma, completed suicide, delirium, dream abnormalities,
352
paranoid ideation, paresthesia, restlessness, suicide attempt, unmasking of tardive dyskinesia.
353
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis,
354
urticaria.
355
Special Senses: Tinnitus, increased intraocular pressure.
356
7
DRUG INTERACTIONS
357
7.1
Potential for Other Drugs to Affect WELLBUTRIN
358
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the
359
potential exists for drug interactions between WELLBUTRIN and drugs that are inhibitors or
360
inducers of CYP2B6.
361
Inhibitors of CYP2B6: Ticlopidine and Clopidogrel: Concomitant treatment with these
362
drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on
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363
clinical response, dosage adjustment of WELLBUTRIN may be necessary when coadministered
364
with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].
365
Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment
366
with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of
367
WELLBUTRIN may be necessary when coadministered with ritonavir, lopinavir, or efavirenz
368
[see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended dose.
369
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
370
these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see
371
Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may
372
be necessary to increase the dose of bupropion, but the maximum recommended dose should not
373
be exceeded.
374
7.2
Potential for WELLBUTRIN to Affect Other Drugs
375
Drugs Metabolized by CYP2D6: Bupropion and its metabolites
376
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors.
377
Therefore, coadministration of WELLBUTRIN with drugs that are metabolized by CYP2D6 can
378
increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain
379
antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine,
380
and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g.,
381
metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used
382
concomitantly with WELLBUTRIN, it may be necessary to decrease the dose of these CYP2D6
383
substrates, particularly for drugs with a narrow therapeutic index.
384
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen)
385
theoretically could have reduced efficacy when administered concomitantly with inhibitors of
386
CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN and such drugs
387
may require increased doses of the drug [see Clinical Pharmacology (12.3)].
388
7.3
Drugs that Lower Seizure Threshold
389
Use extreme caution when coadministering WELLBUTRIN with other drugs that lower
390
seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline,
391
or systemic corticosteroids). Use low initial doses and increase the dose gradually [see
392
Contraindications (4), Warnings and Precautions (5.3)].
393
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
394
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has
395
been reported when bupropion was coadministered with levodopa or amantadine. Adverse
396
reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and
397
dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use
398
caution when administering WELLBUTRIN concomitantly with these drugs.
399
7.5
Use with Alcohol
400
In postmarketing experience, there have been rare reports of adverse neuropsychiatric
401
events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with
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402
WELLBUTRIN. The consumption of alcohol during treatment with WELLBUTRIN should be
403
minimized or avoided.
404
7.6
MAO Inhibitors
405
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of
406
MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive
407
reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that
408
the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days
409
should elapse between discontinuation of an MAOI intended to treat depression and initiation of
410
treatment with WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping
411
WELLBUTRIN before starting an MAOI antidepressant [see Dosage and Administration (2.4,
412
2.5), Contraindications (4)].
413
7.7
Drug-Laboratory Test Interactions
414
False-positive urine immunoassay screening tests for amphetamines have been reported
415
in patients taking bupropion. This is due to lack of specificity of some screening tests. False
416
positive test results may result even following discontinuation of bupropion therapy.
417
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion
418
from amphetamines.
419
8
USE IN SPECIFIC POPULATIONS
420
8.1
Pregnancy
421
Pregnancy Category C
422
Risk Summary: Data from epidemiological studies of pregnant women exposed to
423
bupropion in the first trimester indicate no increased risk of congenital malformations overall.
424
All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major
425
malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity
426
was found in reproductive developmental studies conducted in rats and rabbits; however, in
427
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
428
observed at doses approximately equal to the maximum recommended human dose (MRHD) and
429
greater and decreased fetal weights were seen at doses twice the MRHD and greater.
430
WELLBUTRIN should be used during pregnancy only if the potential benefit justifies the
431
potential risk to the fetus.
432
Clinical Considerations: Consider the risks of untreated depression when discontinuing
433
or changing treatment with antidepressant medications during pregnancy and postpartum.
434
Human Data: Data from the international bupropion Pregnancy Registry (675 first
435
trimester exposures) and a retrospective cohort study using the United Healthcare database
436
(1,213 first trimester exposures) did not show an increased risk for malformations overall.
437
No increased risk for cardiovascular malformations overall has been observed after
438
bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular
439
malformations in pregnancies with exposure to bupropion in the first trimester from the
440
international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
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Reference ID: 3674083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
441
maternal bupropion exposures), which is similar to the background rate of cardiovascular
442
malformations (approximately 1%). Data from the United Healthcare database and a case-control
443
study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular
444
malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an
445
increased risk for cardiovascular malformations overall after bupropion exposure during the first
446
trimester.
447
Study findings on bupropion exposure during the first trimester and risk for left
448
ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions
449
regarding a possible association. The United Healthcare database lacked sufficient power to
450
evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
451
2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk
452
for LVOTO.
453
Study findings on bupropion exposure during the first trimester and risk for ventricular
454
septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible
455
association. The Slone Epidemiology Study found an increased risk for VSD following first
456
trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not
457
find increased risk for any other cardiovascular malformations studied (including LVOTO as
458
above). The NBDPS and United Healthcare database study did not find an association between
459
first trimester maternal bupropion exposure and VSD.
460
For the findings of LVOTO and VSD, the studies were limited by the small number of
461
exposed cases, inconsistent findings among studies, and the potential for chance findings from
462
multiple comparisons in case control studies.
463
Animal Data: In studies conducted in rats and rabbits, bupropion was administered
464
orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively
465
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis). No clear evidence of
466
teratogenic activity was found in either species; however, in rabbits, slightly increased incidences
467
of fetal malformations and skeletal variations were observed at the lowest dose tested (25
468
mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal
469
weights were observed at 50 mg/kg and greater.
470
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
471
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
472
and lactation, there were no apparent adverse effects on offspring development.
473
8.3
Nursing Mothers
474
Bupropion and its metabolites are present in human milk. In a lactation study of 10
475
women, levels of orally dosed bupropion and its active metabolites were measured in expressed
476
milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion
477
and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when
478
WELLBUTRIN is administered to a nursing woman.
479
8.4
Pediatric Use
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Reference ID: 3674083
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480
Safety and effectiveness in the pediatric population have not been established [see Boxed
481
Warning, Warnings and Precautions (5.1)].
482
8.5
Geriatric Use
483
Of the approximately 6,000 subjects who participated in clinical trials with bupropion
484
sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and
485
47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in
486
clinical trials using the immediate-release formulation of bupropion (depression trials). No
487
overall differences in safety or effectiveness were observed between these subjects and younger
488
subjects. Reported clinical experience has not identified differences in responses between the
489
elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
490
out.
491
Bupropion is extensively metabolized in the liver to active metabolites, which are further
492
metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients
493
with impaired renal function. Because elderly patients are more likely to have decreased renal
494
function, it may be necessary to consider this factor in dose selection; it may be useful to monitor
495
renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), Clinical
496
Pharmacology (12.3)].
497
8.6
Renal Impairment
498
Consider a reduced dose and/or dosing frequency of WELLBUTRIN in patients with
499
renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are
500
cleared renally and may accumulate in such patients to a greater extent than usual. Monitor
501
closely for adverse reactions that could indicate high bupropion or metabolite exposures [see
502
Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
503
8.7
Hepatic Impairment
504
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
505
maximum dose of WELLBUTRIN is 75 mg daily. In patients with mild hepatic impairment
506
(Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Dosage
507
and Administration (2.2), Clinical Pharmacology (12.3)].
508
9
DRUG ABUSE AND DEPENDENCE
509
9.1
Controlled Substance
510
Bupropion is not a controlled substance.
511
9.2
Abuse
512
Humans: Controlled clinical trials conducted in normal volunteers, in subjects with a
513
history of multiple drug abuse, and in depressed subjects showed some increase in motor activity
514
and agitation/excitement, often typical of central stimulant activity.
515
In a population of individuals experienced with drugs of abuse, a single oral dose of
516
400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the
517
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
518
score greater than placebo but less than 15 mg of the Schedule II stimulant dextroamphetamine
16
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
519
on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug
520
liking which are often associated with abuse potential.
521
Findings in clinical trials, however, are not known to reliably predict the abuse potential
522
of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily
523
dosage of bupropion when administered orally in divided doses is not likely to be significantly
524
reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be
525
tested because of the risk of seizure) might be modestly attractive to those who abuse CNS
526
stimulant drugs.
527
WELLBUTRIN is intended for oral use only. The inhalation of crushed tablets or
528
injection of dissolved bupropion has been reported. aSeizures and/or cases of death have been
529
reported when bupropion has been administered intranasally or by parenteral injection.
530
Animals: Studies in rodents and primates demonstrated that bupropion exhibits some
531
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
532
locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding
533
in several schedule-controlled behavior paradigms. In primate models assessing the positive
534
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
535
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
536
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
537
10
OVERDOSAGE
538
10.1 Human Overdose Experience
539
Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was
540
reported in approximately one-third of all cases. Other serious reactions reported with overdoses
541
of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG
542
changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever,
543
muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been
544
reported mainly when bupropion was part of multiple drug overdoses.
545
Although most patients recovered without sequelae, deaths associated with overdoses of
546
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
547
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
548
in these patients.
549
10.2 Overdosage Management
550
Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone
551
numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR).
552
Call 1-800-222-1222 or refer to www.poison.org.
553
There are no known antidotes for bupropion. In case of an overdose, provide supportive
554
care, including close medical supervision and monitoring. Consider the possibility of multiple
555
drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm
556
and vital signs. Induction of emesis is not recommended.
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Reference ID: 3674083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
557
11
DESCRIPTION
558
WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class,
559
is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
560
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
561
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
562
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
563
C13 H18 ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
564
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
565
structural formula is: structural formula
566
567
568
WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold) and 100-mg
569
(red) film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride
570
and the inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6
571
Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol,
572
talc, and titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
573
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
574
titanium dioxide.
575
12
CLINICAL PHARMACOLOGY
576
12.1 Mechanism of Action
577
The exact mechanism of the antidepressant action of bupropion is not known, but is
578
presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a
579
relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not
580
inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.
581
12.3 Pharmacokinetics
582
Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of
583
the individual enantiomers have not been studied. The mean elimination half-life (±SD) of
584
bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of
585
bupropion are reached within 8 days.
586
Absorption: The absolute bioavailability of WELLBUTRIN in humans has not been
587
determined because an intravenous formulation for human use is not available. However, it
588
appears likely that only a small proportion of any orally administered dose reaches the systemic
589
circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to
590
20%.
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Reference ID: 3674083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
591
In humans, following oral administration of WELLBUTRIN, peak plasma bupropion
592
concentrations are usually achieved within 2 hours. Plasma bupropion concentrations are
593
dose-proportional following single doses of 100 to 250 mg; however, it is not known if the
594
proportionality between dose and plasma level is maintained in chronic use.
595
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins
596
at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
597
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
598
threohydrobupropion metabolite is about half that seen with bupropion.
599
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are
600
active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of
601
bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
602
which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is
603
the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450
604
enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion
605
side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is
606
then excreted as the major urinary metabolite. The potency and toxicity of the metabolites
607
relative to bupropion have not been fully characterized. However, it has been demonstrated in an
608
antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion,
609
while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion.
610
This may be of clinical importance because the plasma concentrations of the metabolites are as
611
high as or higher than those of bupropion.
612
Following a single dose in humans, peak plasma concentrations of hydroxybupropion
613
occur approximately 3 hours after administration of WELLBUTRIN and are approximately
614
10 times the peak level of the parent drug at steady state. The elimination half-life of
615
hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 17 times
616
that of bupropion. The times to peak concentrations for the erythrohydrobupropion and
617
threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite.
618
However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and
619
steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.
620
Bupropion and its metabolites exhibit linear kinetics following chronic administration of
621
300 to 450 mg per day.
622
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87%
623
and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5%
624
of the oral dose was excreted as unchanged bupropion.
625
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
626
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
627
be expected to influence the degree and extent of accumulation of the active metabolites of
628
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
629
renal or hepatic function because they are moderately polar compounds and are likely to undergo
630
further metabolism or conjugation in the liver prior to urinary excretion.
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Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
631
Renal Impairment: There is limited information on the pharmacokinetics of
632
bupropion in patients with renal impairment. An inter-trial comparison between normal subjects
633
and subjects with end-stage renal failure demonstrated that the parent drug C max and AUC values
634
were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
635
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage
636
renal failure. A second trial, comparing normal subjects and subjects with moderate-to-severe
637
renal impairment (GFR 30.9 ± 10.8 mL/min) showed that after a single 150-mg dose of
638
sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects
639
with impaired renal function, while levels of the hydroxybupropion and
640
threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is
641
extensively metabolized in the liver to active metabolites, which are further metabolized and
642
subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion
643
may be reduced by impaired renal function. WELLBUTRIN should be used with caution in
644
patients with renal impairment and a reduced frequency and/or dose should be considered [see
645
Use in Specific Populations (8.6)].
646
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of
647
bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease
648
and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half-life of
649
hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in
650
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
651
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
652
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
653
for bupropion and the other metabolites in the 2 groups were minimal.
654
The second trial demonstrated no statistically significant differences in the
655
pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate
656
hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in
657
some of the pharmacokinetic parameters for bupropion (AUC, Cmax , and Tmax ) and its active
658
metabolites (t½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe
659
hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites
660
were seen (Table 3).
661
662
Table 3. Pharmacokinetics of Bupropion and Metabolites in Patients with Severe Hepatic
663
Cirrhosis: Ratio Relative to Healthy Matched Controls
Cmax
AUC
t½
Tmax
a
Bupropion
1.69
3.12
1.43
0.5 h
Hydroxybupropion
0.31
1.28
3.88
19 h
Threo/erythrohydrobupropion
amino alcohol
0.69
2.48
1.96
20 h
664
a = Difference.
665
20
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
666
Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14
667
depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x
668
ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites,
669
compared with healthy volunteers.
670
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have
671
not been fully characterized, but an exploration of steady-state bupropion concentrations from
672
several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day,
673
on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
674
concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the
675
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
676
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
677
however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are
678
at increased risk for accumulation of bupropion and its metabolites [see Use in Specific
679
Populations (8.5)].
680
Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male
681
and 90 healthy female volunteers revealed no sex-related differences in the peak plasma
682
concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13%
683
higher in male volunteers compared with female volunteers. The clinical significance of this
684
finding is unknown.
685
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion
686
were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and
687
17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
688
were no statistically significant differences in C max , half-life, Tmax , AUC, or clearance of
689
bupropion or its active metabolites between smokers and nonsmokers.
690
Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN: In vitro
691
studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6.
692
Therefore, the potential exists for drug interactions between WELLBUTRIN and drugs that are
693
inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline,
694
norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.
695
Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male
696
volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures
697
(Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for
698
ticlopidine, respectively. The exposures (C max and AUC) of hydroxybupropion were decreased
699
50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This
700
effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.
701
Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects,
702
prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and
703
decreased C max and AUC values of hydroxybupropion, an active metabolite of bupropion, by
704
32% and 24%, respectively.
21
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
705
Cimetidine: The threohydrobupropion metabolite of bupropion does not appear
706
to be produced by cytochrome P450 enzymes. The effects of concomitant administration of
707
cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24
708
healthy young male volunteers. Following oral administration of bupropion 300 mg with and
709
without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were
710
unaffected. However, there were 16% and 32% increases in the AUC and Cmax , respectively of
711
the combined moieties of threohydrobupropion and erythrohydrobupropion.
712
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its
713
three metabolites.
714
Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial,
715
ritonavir 100 mg twice daily reduced the AUC and C max of bupropion by 22% and 21%,
716
respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the
717
threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
718
In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and
719
the C max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion
720
metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the
721
erythrohydrobupropion decreased by 68%.
722
In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily
723
decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were
724
decreased by 50% and 31%, respectively.
725
Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for
726
2 weeks reduced the AUC and C max of bupropion by approximately 55% and 34%, respectively.
727
The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was
728
increased by 50%.
729
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
730
these drugs may induce the metabolism of bupropion.
731
Potential for WELLBUTRIN to Affect Other Drugs: Animal data indicated that
732
bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following
733
chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14
734
days, there was no evidence of induction of its own metabolism. Nevertheless, there may be
735
potential for clinically important alterations of blood levels of co-administered drugs.
736
Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites
737
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a
738
clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of
739
CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased
740
the C max , AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold,
741
respectively. The effect was present for at least 7 days after the last dose of bupropion.
742
Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally
743
studied.
22
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
744
Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in
745
one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.
746
Lamotrigine: Multiple oral doses of bupropion had no statistically significant
747
effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
748
13
NONCLINICAL TOXICOLOGY
749
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
750
Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up
751
to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the
752
MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular
753
proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the
754
MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such
755
lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions
756
were not seen in the mouse study, and no increase in malignant tumors of the liver and other
757
organs was seen in either study.
758
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5
759
strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in
760
chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
761
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
762
fertility.
763
14
CLINICAL STUDIES
764
The efficacy of WELLBUTRIN in the treatment of major depressive disorder was
765
established in two 4-week, placebo-controlled trials in adult inpatients with MDD (Trials 1 and 2
766
in Table 4) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in
767
Table 4). In the first trial, the dose range of WELLBUTRIN was 300 mg to 600 mg per day
768
administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg
769
per day. The trial demonstrated the efficacy of WELLBUTRIN as measured by the Hamilton
770
Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (item 1), and the
771
Clinical Global Impressions-severity score (CGI-S). The second trial included 2 doses of
772
WELLBUTRIN (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness
773
of WELLBUTRIN for only the 450-mg-per-day dose. The efficacy results were statistically
774
significant for the HDRS total score and the CGI-S score, but not for HDRS item 1. In the third
775
trial, outpatients were treated with 300 mg per day of WELLBUTRIN. This trial demonstrated
776
the efficacy of WELLBUTRIN as measured by the HDRS total score, the HDRS item 1, the
777
Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI
778
Improvement Scale (CGI-I) score. Effectiveness of WELLBUTRIN in long-term use, that is, for
779
more than 6 weeks, has not been systematically evaluated in controlled trials.
780
23
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
781
Table 4. Efficacy of WELLBUTRIN for the Treatment of Major Depressive Disorder
Trial
Number
Treatment Group
Primary Efficacy Measure: HDRS
Mean Baseline
Score (SD)
LS Mean Score at
Endpoint Visit
(SE)
Placebo-subtracted
Differencea (95%
CI)
Trial 1
WELLBUTRIN
300-600 mg/dayb
(n = 48)
28.5 (5.1)
14.9 (1.3)
-4.7 (-8.8, -0.6)
Placebo (n = 27)
29.3 (7.0)
19.6 (1.6)
-
Mean Baseline
Score (SD)
LS Mean Change
from Baseline (SE)
Placebo-subtracted
Differencea (95%
CI)
Trial 2
WELLBUTRIN
300 mg/day
(n = 36)
32.4 (5.9)
-15.5 (1.7)
-4.1
WELLBUTRIN
450 mg/dayb
(n = 34)
34.8 (4.6)
-17.4 (1.7)
-5.9 (-10.5, -1.4)
Placebo (n=39)
32.9 (5.4)
-11.5 (1.6)
-
Trial 3
WELLBUTRIN
300 mg/dayb
(n = 110)
26.5 (4.3)
-12.0 (NA)
-3.9 (-5.7, -1.0)
Placebo (n = 106)
27.0 (3.5)
-8.7 (NA)
-
782
n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI:
783
unadjusted confidence interval included for doses that were demonstrated to be effective; NA:
784
not available.
785
a Difference (drug minus placebo) in least-squares estimates with respect to the primary
786
efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2
787
and 3, it refers to the mean change from baseline to the endpoint visit.
788
b Doses that are demonstrated to be statistically significantly superior to placebo.
789
16
HOW SUPPLIED/STORAGE AND HANDLING
790
WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow-gold, round,
791
biconvex tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).
792
WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex
793
tablets printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).
794
Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between
795
15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Protect from light
796
and moisture.
24
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
797
17
PATIENT COUNSELING INFORMATION
798
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
799
Inform patients, their families, and their caregivers about the benefits and risks associated
800
with treatment with WELLBUTRIN and counsel them in its appropriate use.
801
A patient Medication Guide about “Antidepressant Medicines, Depression and Other
802
Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking
803
Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or
804
Actions,” and “What Other Important Information Should I Know About WELLBUTRIN?” is
805
available for WELLBUTRIN. Instruct patients, their families, and their caregivers to read the
806
Medication Guide and assist them in understanding its contents. Patients should be given the
807
opportunity to discuss the contents of the Medication Guide and to obtain answers to any
808
questions they may have. The complete text of the Medication Guide is reprinted at the end of
809
this document.
810
Advise patients regarding the following issues and to alert their prescriber if these occur
811
while taking WELLBUTRIN.
812
Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their
813
caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
814
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
815
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
816
early during antidepressant treatment and when the dose is adjusted up or down. Advise families
817
and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis,
818
since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or
819
healthcare professional, especially if they are severe, abrupt in onset, or were not part of the
820
patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk
821
for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
822
changes in the medication.
823
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
824
Although WELLBUTRIN is not indicated for smoking cessation treatment, it contains the same
825
active ingredient as ZYBAN® which is approved for this use. Advise patients, families and
826
caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal
827
symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness.
828
Some patients have experienced changes in mood (including depression and mania), psychosis,
829
hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as
830
suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while
831
taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking
832
or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they
833
should be urged to report these symptoms to their healthcare provider immediately.
834
Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and
835
to discontinue WELLBUTRIN if they have a severe allergic reaction.
25
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
836
Seizure: Instruct patients to discontinue and not restart WELLBUTRIN if they
837
experience a seizure while on treatment. Advise patients that the excessive use or abrupt
838
discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can
839
increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.
840
Angle-Closure Glaucoma: Patients should be advised that taking WELLBUTRIN can
841
cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle
842
closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle
843
closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle
844
glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to
845
determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g.,
846
iridectomy), if they are susceptible [see Warnings and Precautions (5.7)].
847
Bupropion-Containing Products: Educate patients that WELLBUTRIN contains the
848
same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid to
849
smoking cessation treatment, and that WELLBUTRIN should not be used in combination with
850
ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN SR®, the
851
sustained-release formulation and WELLBUTRIN XL® or FORFIVO XL™, the extended
852
release formulations, and APLENZIN®, the extended-release formulation of bupropion
853
hydrobromide). In addition, there are a number of generic bupropion HCl products for the
854
immediate-, sustained-, and extended-release formulations.
855
Potential for Cognitive and Motor Impairment: Advise patients that any CNS-active
856
drug like WELLBUTRIN may impair their ability to perform tasks requiring judgment or motor
857
and cognitive skills. Advise patients that until they are reasonably certain that WELLBUTRIN
858
does not adversely affect their performance, they should refrain from driving an automobile or
859
operating complex, hazardous machinery. WELLBUTRIN may lead to decreased alcohol
860
tolerance.
861
Concomitant Medications: Counsel patients to notify their healthcare provider if they
862
are taking or plan to take any prescription or over-the-counter drugs because WELLBUTRIN
863
and other drugs may affect each others’ metabolisms.
864
Pregnancy: Advise patients to notify their healthcare provider if they become pregnant
865
or intend to become pregnant during therapy.
866
Precautions for Nursing Mothers: Advise patients that WELLBUTRIN is present in
867
human milk in small amounts.
868
Storage Information: Instruct patients to store WELLBUTRIN at room temperature,
869
between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.
870
Administration Information: Instruct patients to take WELLBUTRIN in equally divided
871
doses 3 or 4 times a day, with doses separated by least 6 hours to minimize the risk of seizure.
872
Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose
873
and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct
874
patients that WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or
875
chewed. WELLBUTRIN can be taken with or without food.
26
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
876
877
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
878
trademarks of the GSK group of companies. The other brands listed are trademarks of their
879
respective owners and are not trademarks of the GSK group of companies. The makers of these
880
brands are not affiliated with and do not endorse the GSK group of companies or its products.
881
882
Manufactured for:
883 company logo
884
GlaxoSmithKline
885
Research Triangle Park, NC 27709
886
887
©201X, the GSK group of companies. All rights reserved.
888
889
WLT:XXPI
27
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
890
891
MEDICATION GUIDE
892
WELLBUTRIN® (WELL byu-trin)
893
(bupropion hydrochloride) Tablets
894
895
Read this Medication Guide carefully before you start taking WELLBUTRIN and each
896
time you get a refill. There may be new information. This information does not take
897
the place of talking with your healthcare provider about your medical condition or
898
your treatment. If you have any questions about WELLBUTRIN, ask your
899
healthcare provider or pharmacist.
900
901
IMPORTANT: Be sure to read the three sections of this Medication Guide.
902
The first section is about the risk of suicidal thoughts and actions with
903
antidepressant medicines; the second section is about the risk of changes
904
in thinking and behavior, depression and suicidal thoughts or actions with
905
medicines used to quit smoking; and the third section is entitled “What
906
Other Important Information Should I Know About WELLBUTRIN?”
907
908
Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
909
and Suicidal Thoughts or Actions
910
911
This section of the Medication Guide is only about the risk of suicidal
912
thoughts and actions with antidepressant medicines. Talk to your healthcare
913
provider or your family member’s healthcare provider about:
914
• all risks and benefits of treatment with antidepressant medicines
915
• all treatment choices for depression or other serious mental illness
916
917
What is the most important information I should know about
918
antidepressant medicines, depression and other serious mental illnesses,
919
and suicidal thoughts or actions?
920
1. Antidepressant medicines may increase suicidal thoughts or actions in
921
some children, teenagers, or young adults within the first few months of
922
treatment.
923
2. Depression or other serious mental illnesses are the most important
924
causes of suicidal thoughts and actions. Some people may have a
925
particularly high risk of having suicidal thoughts or actions. These include
926
people who have (or have a family history of) bipolar illness (also called manic
927
depressive illness) or suicidal thoughts or actions.
28
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
928
3. How can I watch for and try to prevent suicidal thoughts and actions in
929
myself or a family member?
930
•
Pay close attention to any changes, especially sudden changes, in mood,
931
behaviors, thoughts, or feelings. This is very important when an antidepressant
932
medicine is started or when the dose is changed.
933
•
Call your healthcare provider right away to report new or sudden changes in
934
mood, behavior, thoughts, or feelings.
935
•
Keep all follow-up visits with your healthcare provider as scheduled. Call the
936
healthcare provider between visits as needed, especially if you have concerns
937
about symptoms.
938
939
Call your healthcare provider right away if you or your family member has
940
any of the following symptoms, especially if they are new, worse, or worry
941
you:
942
• thoughts about suicide or
dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or
restless
• panic attacks
943
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or
violent
• acting on dangerous impulses
• an extreme increase in activity and
talking (mania)
• other unusual changes in behavior
or mood
944
What else do I need to know about antidepressant medicines?
945
•
Never stop an antidepressant medicine without first talking to a
946
healthcare provider. Stopping an antidepressant medicine suddenly can cause
947
other symptoms.
948
•
Antidepressants are medicines used to treat depression and other
949
illnesses. It is important to discuss all the risks of treating depression and also
950
the risks of not treating it. Patients and their families or other caregivers should
951
discuss all treatment choices with the healthcare provider, not just the use of
952
antidepressants.
953
•
Antidepressant medicines have other side effects. Talk to the healthcare
954
provider about the side effects of the medicine prescribed for you or your family
955
member.
956
•
Antidepressant medicines can interact with other medicines. Know all of
957
the medicines that you or your family member takes. Keep a list of all medicines
29
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
958
to show the healthcare provider. Do not start new medicines without first
959
checking with your healthcare provider.
960
961
It is not known if WELLBUTRIN is safe and effective in children under the age of
962
18.
963
964
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and
965
Behavior, Depression, and Suicidal Thoughts or Actions
966
967
This section of the Medication Guide is only about the risk of changes in thinking
968
and behavior, depression and suicidal thoughts or actions with drugs used to quit
969
smoking.
970
971
Although WELLBUTRIN is not a treatment for quitting smoking, it contains the
972
same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help
973
patients quit smoking.
974
975
Some people have had changes in behavior, hostility, agitation, depression,
976
suicidal thoughts or actions while taking bupropion to help them quit smoking.
977
These symptoms can develop during treatment with bupropion or after stopping
978
treatment with bupropion.
979
980
If you, your family member, or your caregiver notice agitation, hostility,
981
depression, or changes in thinking or behavior that are not typical for you, or you
982
have any of the following symptoms, stop taking bupropion and call your
983
healthcare provider right away:
984
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• panic attacks
• feeling very agitated or restless
• acting aggressive, being angry, or
violent
• acting on dangerous impulses
• an extreme increase in activity and
talking (mania)
• abnormal thoughts or sensations
• seeing or hearing things that are
not there (hallucinations)
• feeling people are against you
(paranoia)
• feeling confused
• other unusual changes in behavior
or mood
985
Reference ID: 3674083
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
986
When you try to quit smoking, with or without bupropion, you may have symptoms
987
that may be due to nicotine withdrawal, including urge to smoke, depressed mood,
988
trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty
989
concentrating, restlessness, decreased heart rate, and increased appetite or weight
990
gain. Some people have even experienced suicidal thoughts when trying to quit
991
smoking without medication. Sometimes quitting smoking can lead to worsening of
992
mental health problems that you already have, such as depression.
993
994
Before taking bupropion, tell your healthcare provider if you have ever had
995
depression or other mental illnesses. You should also tell your healthcare provider
996
about any symptoms you had during other times you tried to quit smoking, with or
997
without bupropion.
998
999
What Other Important Information Should I Know About WELLBUTRIN?
1000
•
Seizures: There is a chance of having a seizure (convulsion, fit) with
1001
WELLBUTRIN, especially in people:
1002
•
with certain medical problems.
1003
•
who take certain medicines.
1004
1005
The chance of having seizures increases with higher doses of WELLBUTRIN. For
1006
more information, see the sections “Who should not take WELLBUTRIN?” and
1007
“What should I tell my healthcare provider before taking WELLBUTRIN?” Tell your
1008
healthcare provider about all of your medical conditions and all the medicines you
1009
take. Do not take any other medicines while you are taking WELLBUTRIN
1010
unless your healthcare provider has said it is okay to take them.
1011
1012
If you have a seizure while taking WELLBUTRIN, stop taking the tablets
1013
and call your healthcare provider right away. Do not take WELLBUTRIN again
1014
if you have a seizure.
1015
1016
•
High blood pressure (hypertension). Some people get high blood
1017
pressure that can be severe, while taking WELLBUTRIN. The chance of
1018
high blood pressure may be higher if you also use nicotine replacement therapy
1019
(such as a nicotine patch) to help you stop smoking.
1020
•
Manic episodes. Some people may have periods of mania while taking
1021
WELLBUTRIN, including:
1022
•
Greatly increased energy
1023
•
Severe trouble sleeping
1024
•
Racing thoughts
1025
•
Reckless behavior
31
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1026
•
Unusually grand ideas
1027
•
Excessive happiness or irritability
1028
•
Talking more or faster than usual
1029
If you have any of the above symptoms of mania, call your healthcare provider.
1030
•
Unusual thoughts or behaviors. Some patients have unusual thoughts or
1031
behaviors while taking WELLBUTRIN, including delusions (believe you are
1032
someone else), hallucinations (seeing or hearing things that are not there),
1033
paranoia (feeling that people are against you), or feeling confused. If this
1034
happens to you, call your healthcare provider.
1035
•
Visual problems.
1036
•
eye pain
1037
•
changes in vision
1038
•
swelling or redness in or around the eye
1039
Only some people are at risk for these problems. You may want to undergo an
1040
eye examination to see if you are at risk and receive preventative treatment if
1041
you are.
1042
•
Severe allergic reactions. Some people can have severe allergic
1043
reactions to WELLBUTRIN. Stop taking WELLBUTRIN and call your
1044
healthcare provider right away if you get a rash, itching, hives, fever,
1045
swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
1046
the lips or tongue, chest pain, or have trouble breathing. These could be signs of
1047
a serious allergic reaction.
1048
1049
What is WELLBUTRIN?
1050
WELLBUTRIN is a prescription medicine used to treat adults with a certain type of
1051
depression called major depressive disorder.
1052
1053
Who should not take WELLBUTRIN?
1054
Do not take WELLBUTRIN if you
1055
•
have or had a seizure disorder or epilepsy.
1056
•
have or had an eating disorder such as anorexia nervosa or bulimia.
1057
•
are taking any other medicines that contain bupropion, including ZYBAN
1058
(used to help people stop smoking) APLENZIN®, FORFIVO XL™ ,
1059
WELLBUTRIN SR®, or WELLBUTRIN XL®. Bupropion is the same active
1060
ingredient that is in WELLBUTRIN.
1061
•
drink a lot of alcohol and abruptly stop drinking, or use medicines called
1062
sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines,
1063
and you stop using them all of a sudden.
32
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1064
•
take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
1065
pharmacist if you are not sure if you take an MAOI, including the antibiotic
1066
linezolid.
1067
•
do not take an MAOI within 2 weeks of stopping WELLBUTRIN unless directed
1068
to do so by your healthcare provider.
1069
•
do not start WELLBUTRIN if you stopped taking an MAOI in the last 2 weeks
1070
unless directed to do so by your healthcare provider.
1071
•
are allergic to the active ingredient in WELLBUTRIN, bupropion, or to any of the
1072
inactive ingredients. See the end of this Medication Guide for a complete list of
1073
ingredients in WELLBUTRIN.
1074
1075
What should I tell my healthcare provider before taking WELLBUTRIN?
1076
Tell your healthcare provider if you have ever had depression, suicidal thoughts or
1077
actions, or other mental health problems. See “Antidepressant Medicines,
1078
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”
1079
1080
Tell your healthcare provider about your other medical conditions including
1081
if you:
1082
•
have liver problems, especially cirrhosis of the liver.
1083
•
have kidney problems.
1084
•
have, or have had, an eating disorder, such as anorexia nervosa or bulimia.
1085
•
have had a head injury.
1086
•
have had a seizure (convulsion, fit).
1087
•
have a tumor in your nervous system (brain or spine).
1088
•
have had a heart attack, heart problems, or high blood pressure.
1089
•
are a diabetic taking insulin or other medicines to control your blood sugar.
1090
•
drink alcohol.
1091
•
abuse prescription medicines or street drugs.
1092
•
are pregnant or plan to become pregnant.
1093
•
are breastfeeding. WELLBUTRIN passes into your milk in small amounts.
1094
1095
Tell your healthcare provider about all the medicines you take, including
1096
prescription, over-the-counter medicines, vitamins, and herbal supplements. Many
1097
medicines increase your chances of having seizures or other serious side effects if
1098
you take them while you are taking WELLBUTRIN.
1099
1100
How should I take WELLBUTRIN?
1101
•
Take WELLBUTRIN exactly as prescribed by your healthcare provider.
1102
•
Take WELLBUTRIN at the same time each day.
1103
•
Take your doses of WELLBUTRIN at least 6 hours apart.
33
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1104
•
Do not chew, cut, or crush WELLBUTRIN tablets.
1105
•
You may take WELLBUTRIN with or without food.
1106
•
If you miss a dose, do not take an extra dose to make up for the dose you
1107
missed. Wait and take your next dose at the regular time. This is very
1108
important. Too much WELLBUTRIN can increase your chance of having a
1109
seizure.
1110
•
If you take too much WELLBUTRIN, or overdose, call your local emergency room
1111
or poison control center right away.
1112
•
Do not take any other medicines while taking WELLBUTRIN unless your
1113
healthcare provider has told you it is okay.
1114
•
If you are taking WELLBUTRIN for the treatment of major depressive disorder, it
1115
may take several weeks for you to feel that WELLBUTRIN is working. Once you
1116
feel better, it is important to keep taking WELLBUTRIN exactly as directed by
1117
your healthcare provider. Call your healthcare provider if you do not feel
1118
WELLBUTRIN is working for you.
1119
•
Do not change your dose or stop taking WELLBUTRIN without talking with your
1120
healthcare provider first.
1121
1122
What should I avoid while taking WELLBUTRIN?
1123
•
Limit or avoid using alcohol during treatment with WELLBUTRIN. If you usually
1124
drink a lot of alcohol, talk with your healthcare provider before suddenly
1125
stopping. If you suddenly stop drinking alcohol, you may increase your risk of
1126
having seizures.
1127
•
Do not drive a car or use heavy machinery until you know how WELLBUTRIN
1128
affects you. WELLBUTRIN can affect your ability to do these things safely.
1129
1130
What are possible side effects of WELLBUTRIN?
1131
See “What Other Important Information Should I Know About
1132
WELLBUTRIN?”
1133
WELLBUTRIN can cause serious side effects.
1134
The most common side effects of WELLBUTRIN include:
1135
•
Nervousness
1136
•
Dry mouth
1137
•
Constipation
1138
•
Headache
1139
•
Nausea or vomiting
1140
•
Dizziness
1141
•
Heavy sweating
1142
•
Shakiness (tremor)
1143
•
Trouble sleeping
34
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1144
•
Blurred vision
1145
•
Fast heartbeat
1146
1147
If you have nausea, take your medicine with food. If you have trouble sleeping, do
1148
not take your medicine too close to bedtime.
1149
Tell your healthcare provider right away about any side effects that bother you.
1150
1151
These are not all the possible side effects of WELLBUTRIN. For more information,
1152
ask your healthcare provider or pharmacist.
1153
1154
Call your healthcare provider for medical advice about side effects. You may report
1155
side effects to FDA at 1-800-FDA-1088.
1156
1157
You may also report side effects to GlaxoSmithKline at 1-888-825-5249.
1158
1159
How should I store WELLBUTRIN?
1160
•
Store WELLBUTRIN at room temperature between 59°F and 86°F (15°C to
1161
30°C).
1162
•
Keep WELLBUTRIN Tablets dry and out of the light.
1163
1164
Keep WELLBUTRIN and all medicines out of the reach of children.
1165
1166
General Information about WELLBUTRIN.
1167
Medicines are sometimes prescribed for purposes other than those listed in a
1168
Medication Guide. Do not use WELLBUTRIN for a condition for which it was not
1169
prescribed. Do not give WELLBUTRIN to other people, even if they have the same
1170
symptoms you have. It may harm them.
1171
1172
If you take a urine drug screening test, WELLBUTRIN may make the test result
1173
positive for amphetamines. If you tell the person giving you the drug screening
1174
test that you are taking WELLBUTRIN, they can do a more specific drug screening
1175
test that should not have this problem.
1176
1177
This Medication Guide summarizes important information about WELLBUTRIN. If
1178
you would like more information, talk with your healthcare provider. You can ask
1179
your healthcare provider or pharmacist for information about WELLBUTRIN that is
1180
written for healthcare professionals.
1181
1182
For more information about WELLBUTRIN, go to www.wellbutrin.com or call 1-888
1183
825-5249.
35
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1184
1185
What are the ingredients in WELLBUTRIN?
1186
Active ingredient: bupropion hydrochloride.
1187
Inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6
1188
Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose,
1189
polyethylene glycol, talc, and titanium dioxide; 100-mg tablet – FD&C Red No. 40
1190
Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose,
1191
microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
1192
1193
This Medication Guide has been approved by the U.S. Food and Drug
1194
Administration.
1195
1196
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
1197
trademarks of the GSK group of companies. The other brands listed are
1198
trademarks of their respective owners and are not trademarks of the GSK group of
1199
companies. The makers of these brands are not affiliated with and do not endorse
1200
the GSK group of companies or its products.
1201
1202
1203
Manufactured for:
1204 company logo
1205
GlaxoSmithKline
1206
Research Triangle Park, NC 27709
1207
1208
©2014, the GSK group of companies. All rights reserved.
1209
1210
December2014
1211
WLT:10MG
1212
36
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
WELLBUTRIN SR safely and effectively. See full prescribing
information for WELLBUTRIN SR.
WELLBUTRIN SR (bupropion hydrochloride) Sustained-Release
Tablets, for oral use
Initial U.S. Approval: 1985
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
See full prescribing information for complete boxed warning.
• Increased risk of suicidal thinking and behavior in children,
adolescents and young adults taking antidepressants. (5.1)
• Monitor for worsening and emergence of suicidal thoughts and
behaviors. (5.1)
• Serious neuropsychiatric events have been reported in patients
taking bupropion for smoking cessation. (5.2)
---------------------------RECENT MAJOR CHANGES --------------------------
Warnings and Precautions, Angle-Closure Glaucoma (5.7)
07/2014
----------------------------INDICATIONS AND USAGE ---------------------------
• WELLBUTRIN SR is an aminoketone antidepressant, indicated for the
treatment of major depressive disorder (MDD). (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
•
Starting dose: 150 mg per day (2.1)
•
General: Increase dose gradually to reduce seizure risk. (2.1, 5.3)
•
After 3 days, may increase the dose to 300 mg per day, given as 150 mg
twice daily at an interval of at least 8 hours. (2.1)
•
Usual target dose: 300 mg per day as 150 mg twice daily. (2.1)
•
Maximum dose: 400 mg per day, given as 200 mg twice daily, for
patients not responding to 300 mg per day. (2.1)
•
Periodically reassess the dose and need for maintenance treatment. (2.1)
• Moderate to severe hepatic impairment: 100 mg daily or 150 mg every
other day. (2.2, 8.7)
• Mild hepatic impairment: Consider reducing the dose and/or frequency of
dosing. (2.2, 8.7)
•
Renal impairment: Consider reducing the dose and/or frequency. (2.3,
8.6)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets: 100 mg, 150 mg, 200 mg. (3)
-------------------------------CONTRAINDICATIONS ------------------------------
•
Seizure disorder. (4, 5.3)
•
Current or prior diagnosis of bulimia or anorexia nervosa. (4, 5.3)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates,
antiepileptic drugs. (4, 5.3)
•
Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to
treat psychiatric disorders with WELLBUTRIN SR or within 14 days of
stopping treatment with WELLBUTRIN SR. Do not use WELLBUTRIN
SR within 14 days of stopping an MAOI intended to treat psychiatric
disorders. In addition, do not start WELLBUTRIN SR in a patient who is
being treated with linezolid or intravenous methylene blue. (4, 7.6)
• Known hypersensitivity to bupropion or other ingredients of
WELLBUTRIN SR. (4, 5.8)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Seizure risk: The risk is dose-related. Can minimize risk by gradually
increasing the dose and limiting daily dose to 400 mg. Discontinue if
seizure occurs. (4, 5.3, 7.3)
• Hypertension: WELLBUTRIN SR can increase blood pressure. Monitor
blood pressure before initiating treatment and periodically during
treatment. (5.4)
•
Activation of mania/hypomania: Screen patients for bipolar disorder and
monitor for these symptoms. (5.5)
•
Psychosis and other neuropsychiatric reactions: Instruct patients to
contact a healthcare professional if such reactions occur. (5.6)
•
Angle-closure glaucoma: Angle-closure glaucoma has occurred in
patients with untreated anatomically narrow angles treated with
antidepressants. (5.7)
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions (incidence ≥5% and ≥2% more than placebo
rate) are: headache, dry mouth, nausea, insomnia, dizziness, pharyngitis,
constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitation,
myalgia, sweating, rash, and anorexia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• CYP2B6 inducers: Dose increase may be necessary if coadministered
with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz,
carbamazepine, phenobarbital, and phenytoin) based on clinical response,
but should not exceed the maximum recommended dose. (7.1)
• Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can
increase concentrations of: antidepressants (e.g., venlafaxine,
nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline),
antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers
(e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone,
flecainide). Consider dose reduction when using with bupropion. (7.2)
• Drugs that lower seizure threshold: Dose WELLBUTRIN SR with
caution. (5.3, 7.3)
• Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur
when used concomitantly with WELLBUTRIN SR. (7.4)
•
MAOIs: Increased risk of hypertensive reactions can occur when used
concomitantly with WELLBUTRIN SR. (7.6)
•
Drug-laboratory test interactions: WELLBUTRIN SR can cause false-
positive urine test results for amphetamines. (7.7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
•
Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: Month/Year
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
2.2
Dose Adjustment in Patients with Hepatic Impairment
2.3 Dose Adjustment in Patients with Renal Impairment
2.4
Switching a Patient to or from a Monoamine Oxidase
Inhibitor (MAOI) Antidepressant
2.5
Use of WELLBUTRIN SR with Reversible MAOIs Such
as Linezolid or Methylene Blue
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children,
Adolescents, and Young Adults
5.2
Neuropsychiatric Symptoms and Suicide Risk in
Smoking Cessation Treatment
5.3
Seizure
5.4
Hypertension
5.5
Activation of Mania/Hypomania
5.6
Psychosis and Other Neuropsychiatric Reactions
5.7
Angle-Closure Glaucoma
5.8
Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN SR
7.2
Potential for WELLBUTRIN SR to Affect Other Drugs
7.3
Drugs that Lower Seizure Threshold
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
7.5
Use with Alcohol
7.6
MAO Inhibitors
1
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.7
Drug-Laboratory Test Interactions
10.2 Overdosage Management
8
USE IN SPECIFIC POPULATIONS
11 DESCRIPTION
8.1
Pregnancy
12 CLINICAL PHARMACOLOGY
8.3
Nursing Mothers
12.1 Mechanism of Action
8.4
Pediatric Use
12.3 Pharmacokinetics
8.5
Geriatric Use
13 NONCLINICAL TOXICOLOGY
8.6
Renal Impairment
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
8.7
Hepatic Impairment
14 CLINICAL STUDIES
9
DRUG ABUSE AND DEPENDENCE
16 HOW SUPPLIED/STORAGE AND HANDLING
9.1
Controlled Substance
17 PATIENT COUNSELING INFORMATION
9.2
Abuse
*Sections or subsections omitted from the full prescribing information are not
10 OVERDOSAGE
listed.
10.1 Human Overdose Experience
1
FULL PRESCRIBING INFORMATION
2
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC
3
REACTIONS
4
5
SUICIDALITY AND ANTIDEPRESSANT DRUGS
6
Antidepressants increased the risk of suicidal thoughts and behavior in children,
7
adolescents, and young adults in short-term trials. These trials did not show an increase in
8
the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24;
9
there was a reduction in risk with antidepressant use in subjects aged 65 and older [see
10
Warnings and Precautions (5.1)].
11
In patients of all ages who are started on antidepressant therapy, monitor closely for
12
worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
13
caregivers of the need for close observation and communication with the prescriber [see
14
Warnings and Precautions (5.1)].
15
NEUROPSYCHIATRIC REACTIONS IN PATIENTS TAKING BUPROPION FOR
16
SMOKING CESSATION
17
Serious neuropsychiatric reactions have occurred in patients taking bupropion for
18
smoking cessation [see Warnings and Precautions (5.2)]. The majority of these reactions
19
occurred during bupropion treatment, but some occurred in the context of discontinuing
20
treatment. In many cases, a causal relationship to bupropion treatment is not certain,
21
because depressed mood may be a symptom of nicotine withdrawal. However, some of the
22
cases occurred in patients taking bupropion who continued to smoke. Although
23
WELLBUTRIN® SR is not approved for smoking cessation, observe all patients for
24
neuropsychiatric reactions. Instruct the patient to contact a healthcare provider if such
25
reactions occur [see Warnings and Precautions (5.2)].
26
1
INDICATIONS AND USAGE
27
WELLBUTRIN SR (bupropion hydrochloride) is indicated for the treatment of major
28
depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
29
The efficacy of bupropion in the treatment of a major depressive episode was established
30
in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult
31
subjects with MDD [see Clinical Studies (14)].
2
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
33
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
34
[see Clinical Studies (14)].
35
2
DOSAGE AND ADMINISTRATION
36
2.1
General Instructions for Use
37
To minimize the risk of seizure, increase the dose gradually [see Warnings and
38
Precautions (5.3)]. WELLBUTRIN SR Tablets should be swallowed whole and not crushed,
39
divided, or chewed. WELLBUTRIN SR may be taken with or without food.
40
The usual adult target dose for WELLBUTRIN SR is 300 mg per day, given as 150 mg
41
twice daily. Initiate dosing with 150 mg per day given as a single daily dose in the morning.
42
After 3 days of dosing, the dose may be increased to the 300-mg-per-day target dose, given as
43
150 mg twice daily. There should be an interval of at least 8 hours between successive doses. A
44
maximum of 400 mg per day, given as 200 mg twice daily, may be considered for patients in
45
whom no clinical improvement is noted after several weeks of treatment at 300 mg per day. To
46
avoid high peak concentrations of bupropion and/or its metabolites, do not exceed 200 mg in any
47
single dose.
48
It is generally agreed that acute episodes of depression require several months or longer
49
of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether
50
the dose of WELLBUTRIN SR needed for maintenance treatment is identical to the dose that
51
provided an initial response. Periodically reassess the need for maintenance treatment and the
52
appropriate dose for such treatment.
53
2.2
Dose Adjustment in Patients with Hepatic Impairment
54
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
55
maximum dose of WELLBUTRIN SR is 100 mg per day or 150 mg every other day. In patients
56
with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or
57
frequency of dosing [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
58
2.3 Dose Adjustment in Patients with Renal Impairment
59
Consider reducing the dose and/or frequency of WELLBUTRIN SR in patients with renal
60
impairment (Glomerular Filtration Rate <90 mL/min) [see Use in Specific Populations (8.6),
61
Clinical Pharmacology (12.3)].
62
2.4
Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI)
63
Antidepressant
64
At least 14 days should elapse between discontinuation of an MAOI intended to treat
65
depression and initiation of therapy with WELLBUTRIN SR. Conversely, at least 14 days
66
should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant
67
[see Contraindications (4), Drug Interactions (7.6)].
68
2.5
Use of WELLBUTRIN SR with Reversible MAOIs Such as Linezolid or
69
Methylene Blue
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70
Do not start WELLBUTRIN SR in a patient who is being treated with a reversible MAOI
71
such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of
72
hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric
73
condition, non-pharmacological interventions, including hospitalization, should be considered
74
[see Contraindications (4), Drug Interactions (7.6)].
75
In some cases, a patient already receiving therapy with WELLBUTRIN SR may require
76
urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
77
linezolid or intravenous methylene blue treatment are not available and the potential benefits of
78
linezolid or intravenous methylene blue treatment are judged to outweigh the risks of
79
hypertensive reactions in a particular patient, WELLBUTRIN SR should be stopped promptly,
80
and linezolid or intravenous methylene blue can be administered. The patient should be
81
monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene
82
blue, whichever comes first. Therapy with WELLBUTRIN SR may be resumed 24 hours after
83
the last dose of linezolid or intravenous methylene blue.
84
The risk of administering methylene blue by non-intravenous routes (such as oral tablets
85
or by local injection) or in intravenous doses much lower than 1 mg/kg with WELLBUTRIN SR
86
is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction
87
with such use [see Contraindications (4), Drug Interactions (7.6)].
88
3
DOSAGE FORMS AND STRENGTHS
89
• 100 mg – blue, round, biconvex, film-coated, sustained-release tablets printed with
90
“WELLBUTRIN SR 100”.
91
• 150 mg – purple, round, biconvex, film-coated, sustained-release tablets printed with
92
“WELLBUTRIN SR 150”.
93
• 200 mg – light pink, round, biconvex, film-coated, sustained-release tablets printed with
94
“WELLBUTRIN SR 200”.
95
4
CONTRAINDICATIONS
96
• WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
97
• WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia
98
or anorexia nervosa as a higher incidence of seizures was observed in such patients treated
99
with the immediate-release formulation of bupropion [see Warnings and Precautions (5.3)].
100
• WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
101
alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and
102
Precautions (5.3), Drug Interactions (7.3)].
103
• The use of MAOIs (intended to treat psychiatric disorders) concomitantly with
104
WELLBUTRIN SR or within 14 days of discontinuing treatment with WELLBUTRIN SR is
105
contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN
106
SR is used concomitantly with MAOIs. The use of WELLBUTRIN SR within 14 days of
107
discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN SR
108
in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is
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109
contraindicated [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.4),
110
Drug Interactions (7.6)].
111
• WELLBUTRIN SR is contraindicated in patients with known hypersensitivity to bupropion
112
or other ingredients of WELLBUTRIN SR. Anaphylactoid/anaphylactic reactions and
113
Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.8)].
114
5
WARNINGS AND PRECAUTIONS
115
5.1
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young
116
Adults
117
Patients with MDD, both adult and pediatric, may experience worsening of their
118
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
119
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
120
persist until significant remission occurs. Suicide is a known risk of depression and certain other
121
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
122
There has been a long-standing concern that antidepressants may have a role in inducing
123
worsening of depression and the emergence of suicidality in certain patients during the early
124
phases of treatment.
125
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective
126
serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of
127
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to
128
24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase
129
in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24;
130
there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
131
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
132
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
133
short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of
134
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
135
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
136
subjects. There was considerable variation in risk of suicidality among drugs, but a tendency
137
toward an increase in the younger subjects for almost all drugs studied. There were differences in
138
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
139
The risk differences (drug vs. placebo), however, were relatively stable within age strata and
140
across indications. These risk differences (drug-placebo difference in the number of cases of
141
suicidality per 1,000 subjects treated) are provided in Table 1.
142
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143
Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled
144
Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1,000 Subjects Treated
Increases Compared With Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared With Placebo
25-64
1 fewer case
≥65
6 fewer cases
145
146
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
147
but the number was not sufficient to reach any conclusion about drug effect on suicide.
148
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
149
months. However, there is substantial evidence from placebo-controlled maintenance trials in
150
adults with depression that the use of antidepressants can delay the recurrence of depression.
151
All patients being treated with antidepressants for any indication should be
152
monitored appropriately and observed closely for clinical worsening, suicidality, and
153
unusual changes in behavior, especially during the initial few months of a course of drug
154
therapy, or at times of dose changes, either increases or decreases [see Boxed Warning].
155
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
156
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
157
been reported in adult and pediatric patients being treated with antidepressants for major
158
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
159
Although a causal link between the emergence of such symptoms and either the worsening of
160
depression and/or the emergence of suicidal impulses has not been established, there is concern
161
that such symptoms may represent precursors to emerging suicidality.
162
Consideration should be given to changing the therapeutic regimen, including possibly
163
discontinuing the medication, in patients whose depression is persistently worse, or who are
164
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
165
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
166
patient’s presenting symptoms.
167
Families and caregivers of patients being treated with antidepressants for MDD or
168
other indications, both psychiatric and nonpsychiatric, should be alerted about the need to
169
monitor patients for the emergence of agitation, irritability, unusual changes in behavior,
170
and the other symptoms described above, as well as the emergence of suicidality, and to
171
report such symptoms immediately to healthcare providers. Such monitoring should
172
include daily observation by families and caregivers. Prescriptions for WELLBUTRIN SR
173
should be written for the smallest quantity of tablets consistent with good patient
174
management, in order to reduce the risk of overdose.
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175
5.2
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
176
Treatment
177
WELLBUTRIN SR is not approved for smoking cessation treatment; however, ZYBAN®
178
is approved for this use. Serious neuropsychiatric symptoms have been reported in patients
179
taking bupropion for smoking cessation. These have included changes in mood (including
180
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
181
hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt,
182
and completed suicide [see Boxed Warning, Adverse Reactions (6.2)]. Observe patients for the
183
occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if
184
such reactions occur.
185
In many of these cases, a causal relationship to bupropion treatment is not certain,
186
because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases
187
occurred in patients taking bupropion who continued to smoke.
188
5.3
Seizure
189
WELLBUTRIN SR can cause seizure. The risk of seizure is dose-related. The dose
190
should not exceed 400 mg per day. Increase the dose gradually. Discontinue WELLBUTRIN SR
191
and do not restart treatment if the patient experiences a seizure.
192
The risk of seizures is also related to patient factors, clinical situations, and concomitant
193
medications that lower the seizure threshold. Consider these risks before initiating treatment with
194
WELLBUTRIN SR. WELLBUTRIN SR is contraindicated in patients with a seizure disorder,
195
current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation
196
of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4),
197
Drug Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe
198
head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke;
199
concomitant use of other medications that lower the seizure threshold (e.g., other bupropion
200
products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids);
201
metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and
202
hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as
203
CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral
204
hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol,
205
benzodiazepines, sedative/hypnotics, or opiates.
206
Incidence of Seizure with Bupropion Use: When WELLBUTRIN SR is dosed up to
207
300 mg per day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to
208
approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.
209
The risk of seizure can be reduced if the dose of WELLBUTRIN SR does not exceed
210
400 mg per day, given as 200 mg twice daily, and the titration rate is gradual.
211
5.4
Hypertension
212
Treatment with WELLBUTRIN SR can result in elevated blood pressure and
213
hypertension. Assess blood pressure before initiating treatment with WELLBUTRIN SR, and
214
monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN
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215
SR is used concomitantly with MAOIs or other drugs that increase dopaminergic or
216
noradrenergic activity [see Contraindications (4)].
217
Data from a comparative trial of the sustained-release formulation of bupropion HCl,
218
nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS,
219
and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent
220
hypertension in patients treated with the combination of sustained-release bupropion and NTS. In
221
this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS
222
had treatment-emergent hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated
223
with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects
224
had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of
225
sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study
226
medication discontinued due to hypertension compared with none of the subjects treated with
227
sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in
228
patients who receive the combination of bupropion and nicotine replacement.
229
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive
230
heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing
231
hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no
232
controlled trials assessing the safety of bupropion in patients with a recent history of myocardial
233
infarction or unstable cardiac disease.
234
5.5
Activation of Mania/Hypomania
235
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode.
236
The risk appears to be increased in patients with bipolar disorder or who have risk factors for
237
bipolar disorder. Prior to initiating WELLBUTRIN SR, screen patients for a history of bipolar
238
disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar
239
disorder, suicide, or depression). WELLBUTRIN SR is not approved for use in treating bipolar
240
depression.
241
5.6
Psychosis and Other Neuropsychiatric Reactions
242
Depressed patients treated with WELLBUTRIN SR have had a variety of
243
neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis,
244
concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of
245
bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal
246
of treatment. Instruct patients to contact a healthcare professional if such reactions occur.
247
5.7
Angle-Closure Glaucoma
248
The pupillary dilation that occurs following use of many antidepressant drugs including
249
WELLBUTRIN SR may trigger an angle-closure attack in a patient with anatomically narrow
250
angles who does not have a patent iridectomy.
251
5.8
Hypersensitivity Reactions
252
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion.
253
Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring
254
medical treatment. In addition, there have been rare, spontaneous postmarketing reports of
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255
erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with
256
bupropion. Instruct patients to discontinue WELLBUTRIN SR and consult a healthcare provider
257
if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives,
258
chest pain, edema, and shortness of breath) during treatment.
259
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like
260
symptoms suggestive of delayed hypersensitivity.
261
6
ADVERSE REACTIONS
262
The following adverse reactions are discussed in greater detail in other sections of the
263
labeling:
264
• Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning,
265
Warnings and Precautions (5.1)]
266
• Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed
267
Warning, Warnings and Precautions (5.2)]
268
• Seizure [see Warnings and Precautions (5.3)]
269
• Hypertension [see Warnings and Precautions (5.4)]
270
• Activation of mania or hypomania [see Warnings and Precautions (5.5)]
271
• Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6)]
272
• Angle-closure glaucoma [see Warnings and Precautions (5.7)]
273
• Hypersensitivity reactions [see Warnings and Precautions (5.8)]
274
6.1
Clinical Trials Experience
275
Because clinical trials are conducted under widely varying conditions, adverse reaction
276
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
277
clinical trials of another drug and may not reflect the rates observed in clinical practice.
278
Adverse Reactions Leading to Discontinuation of Treatment: In placebo-controlled
279
clinical trials, 4%, 9%, and 11% of the placebo, 300-mg-per-day, and 400-mg-per-day groups,
280
respectively, discontinued treatment due to adverse reactions. The specific adverse reactions
281
leading to discontinuation in at least 1% of the 300-mg-per-day or 400-mg-per-day groups and at
282
a rate at least twice the placebo rate are listed in Table 2.
283
284
Table 2. Treatment Discontinuations Due to Adverse Reactions in Placebo-Controlled
285
Trials
WELLBUTRIN SR
WELLBUTRIN SR
Placebo
300 mg/day
400 mg/day
Adverse Reaction
(n = 385)
(n = 376)
(n = 114)
Rash
0.0%
2.4%
0.9%
Nausea
0.3%
0.8%
1.8%
Agitation
0.3%
0.3%
1.8%
Migraine
0.3%
0.0%
1.8%
286
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287
Commonly Observed Adverse Reactions: Adverse reactions from Table 3 occurring
288
in at least 5% of subjects treated with WELLBUTRIN SR and at a rate at least twice the placebo
289
rate are listed below for the 300- and 400-mg-per-day dose groups.
290
WELLBUTRIN SR 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus,
291
and tremor.
292
WELLBUTRIN SR 400 mg per day: Abdominal pain, agitation, anxiety, dizziness,
293
dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
294
frequency.
295
Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported
296
adverse reactions were classified using a COSTART-based Dictionary.
297
298
Table 3. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater
299
Frequency than Placebo in Controlled Clinical Trials
Body System/
Adverse Reaction
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
Arthralgia
2%
1%
6%
4%
3%
1%
10
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Arthritis
Twitch
0%
1%
2%
2%
0%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous system
2%
1%
1%
stimulation
Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Blurred vision or
diplopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal hemorrhagea
0%
2%
—
Urinary tract infection
1%
0%
—
300
a Incidence based on the number of female subjects.
301
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects.
302
303
Other Adverse Reactions Observed During the Clinical Development of
304
Bupropion: In addition to the adverse reactions noted above, the following adverse reactions
305
have been reported in clinical trials with the sustained-release formulation of bupropion in
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306
depressed subjects and in nondepressed smokers, as well as in clinical trials with the
307
immediate-release formulation of bupropion.
308
Adverse reaction frequencies represent the proportion of subjects who experienced a
309
treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for
310
depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse
311
reaction requiring discontinuation of treatment in an open-label surveillance trial with
312
WELLBUTRIN SR (n = 3,100). All treatment-emergent adverse reactions are included except
313
those listed in Table 3, those listed in other safety-related sections of the prescribing information,
314
those subsumed under COSTART terms that are either overly general or excessively specific so
315
as to be uninformative, those not reasonably associated with the use of the drug, and those that
316
were not serious and occurred in fewer than 2 subjects.
317
Adverse reactions are further categorized by body system and listed in order of
318
decreasing frequency according to the following definitions of frequency: Frequent adverse
319
reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions
320
are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than
321
1/1,000 subjects.
322
Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was
323
malaise.
324
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
325
vasodilation. Rare were syncope and myocardial infarction.
326
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
327
increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.
328
Hemic and Lymphatic: Infrequent was ecchymosis.
329
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
330
Musculoskeletal: Infrequent were leg cramps.
331
Nervous System: Infrequent were abnormal coordination, decreased libido,
332
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
333
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.
334
Respiratory: Rare was bronchospasm.
335
Special Senses: Infrequent were accommodation abnormality and dry eye.
336
Urogenital: Infrequent were impotence, polyuria, and prostate disorder.
337
Changes in Body Weight: In placebo-controlled trials, subjects experienced weight
338
gain or weight loss as shown in Table 4.
339
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340
Table 4. Incidence of Weight Gain and Weight Loss (≥5 lbs) in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
Lost >5 lbs
3%
14%
2%
19%
4%
6%
341
342
In clinical trials conducted with the immediate-release formulation of bupropion, 35% of
343
subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated
344
with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of
345
a patient’s depressive illness, the anorectic and/or weight-reducing potential of
346
WELLBUTRIN SR should be considered.
347
6.2
Postmarketing Experience
348
The following adverse reactions have been identified during post-approval use of
349
WELLBUTRIN SR and are not described elsewhere in the label. Because these reactions are
350
reported voluntarily from a population of uncertain size, it is not always possible to reliably
351
estimate their frequency or establish a causal relationship to drug exposure.
352
Body (General): Arthralgia, myalgia, and fever with rash and other symptoms
353
suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see
354
Warnings and Precautions (5.8)].
355
Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension,
356
hypertension (in some cases severe), phlebitis, and pulmonary embolism.
357
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis,
358
intestinal perforation, pancreatitis, and stomach ulcer.
359
Endocrine: Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic
360
hormone.
361
Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy,
362
pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with
363
hemorrhagic or thrombotic complications, were observed when bupropion was coadministered
364
with warfarin.
365
Metabolic and Nutritional: Glycosuria.
366
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness.
367
Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia,
368
aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria,
369
extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction,
370
neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive
371
dyskinesia.
372
Respiratory: Pneumonia.
373
Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson
374
syndrome.
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Reference ID: 3674083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
375
Special Senses: Deafness, increased intraocular pressure, and mydriasis.
376
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia,
377
menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
378
7
DRUG INTERACTIONS
379
7.1
Potential for Other Drugs to Affect WELLBUTRIN SR
380
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the
381
potential exists for drug interactions between WELLBUTRIN SR and drugs that are inhibitors or
382
inducers of CYP2B6.
383
Inhibitors of CYP2B6: Ticlopidine and Clopidogrel: Concomitant treatment with these
384
drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on
385
clinical response, dosage adjustment of WELLBUTRIN SR may be necessary when
386
coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical
387
Pharmacology (12.3)].
388
Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment
389
with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of
390
WELLBUTRIN SR may be necessary when coadministered with ritonavir, lopinavir, or
391
efavirenz [see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended
392
dose.
393
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
394
these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see
395
Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may
396
be necessary to increase the dose of bupropion, but the maximum recommended dose should not
397
be exceeded.
398
7.2
Potential for WELLBUTRIN SR to Affect Other Drugs
399
Drugs Metabolized by CYP2D6: Bupropion and its metabolites
400
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors.
401
Therefore, coadministration of WELLBUTRIN SR with drugs that are metabolized by CYP2D6
402
can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain
403
antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine,
404
and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g.,
405
metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used
406
concomitantly with WELLBUTRIN SR, it may be necessary to decrease the dose of these
407
CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
408
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen)
409
theoretically could have reduced efficacy when administered concomitantly with inhibitors of
410
CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN SR and such
411
drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].
412
7.3
Drugs that Lower Seizure Threshold
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Reference ID: 3674083
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413
Use extreme caution when coadministering WELLBUTRIN SR with other drugs that
414
lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants,
415
theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually
416
[see Contraindications (4), Warnings and Precautions (5.3)].
417
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
418
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has
419
been reported when bupropion was coadministered with levodopa or amantadine. Adverse
420
reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and
421
dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use
422
caution when administering WELLBUTRIN SR concomitantly with these drugs.
423
7.5
Use with Alcohol
424
In postmarketing experience, there have been rare reports of adverse neuropsychiatric
425
events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with
426
WELLBUTRIN SR. The consumption of alcohol during treatment with WELLBUTRIN SR
427
should be minimized or avoided.
428
7.6
MAO Inhibitors
429
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of
430
MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive
431
reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that
432
the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days
433
should elapse between discontinuation of an MAOI intended to treat depression and initiation of
434
treatment with WELLBUTRIN SR. Conversely, at least 14 days should be allowed after
435
stopping WELLBUTRIN SR before starting an MAOI antidepressant [see Dosage and
436
Administration (2.4, 2.5), Contraindications (4)].
437
7.7
Drug-Laboratory Test Interactions
438
False-positive urine immunoassay screening tests for amphetamines have been reported
439
in patients taking bupropion. This is due to lack of specificity of some screening tests. False
440
positive test results may result even following discontinuation of bupropion therapy.
441
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion
442
from amphetamines.
443
8
USE IN SPECIFIC POPULATIONS
444
8.1
Pregnancy
445
Pregnancy Category C
446
Risk Summary: Data from epidemiological studies of pregnant women exposed to
447
bupropion in the first trimester indicate no increased risk of congenital malformations overall.
448
All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major
449
malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity
450
was found in reproductive developmental studies conducted in rats and rabbits; however, in
451
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
15
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
452
observed at doses approximately equal to the maximum recommended human dose (MRHD) and
453
greater and decreased fetal weights were seen at doses twice the MRHD and greater.
454
WELLBUTRIN SR should be used during pregnancy only if the potential benefit justifies the
455
potential risk to the fetus.
456
Clinical Considerations: Consider the risks of untreated depression when discontinuing
457
or changing treatment with antidepressant medications during pregnancy and postpartum.
458
Human Data: Data from the international bupropion Pregnancy Registry (675 first
459
trimester exposures) and a retrospective cohort study using the United Healthcare database
460
(1,213 first trimester exposures) did not show an increased risk for malformations overall.
461
No increased risk for cardiovascular malformations overall has been observed after
462
bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular
463
malformations in pregnancies with exposure to bupropion in the first trimester from the
464
international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
465
maternal bupropion exposures), which is similar to the background rate of cardiovascular
466
malformations (approximately 1%). Data from the United Healthcare database and a case-control
467
study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular
468
malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an
469
increased risk for cardiovascular malformations overall after bupropion exposure during the first
470
trimester.
471
Study findings on bupropion exposure during the first trimester and risk for left
472
ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions
473
regarding a possible association. The United Healthcare database lacked sufficient power to
474
evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
475
2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk
476
for LVOTO.
477
Study findings on bupropion exposure during the first trimester and risk for ventricular
478
septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible
479
association. The Slone Epidemiology Study found an increased risk for VSD following first
480
trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not
481
find increased risk for any other cardiovascular malformations studied (including LVOTO as
482
above). The NBDPS and United Healthcare database study did not find an association between
483
first trimester maternal bupropion exposure and VSD.
484
For the findings of LVOTO and VSD, the studies were limited by the small number of
485
exposed cases, inconsistent findings among studies, and the potential for chance findings from
486
multiple comparisons in case control studies.
487
Animal Data: In studies conducted in rats and rabbits, bupropion was administered
488
orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively
489
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis). No clear evidence of
490
teratogenic activity was found in either species; however, in rabbits, slightly increased incidences
491
of fetal malformations and skeletal variations were observed at the lowest dose tested (25
16
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
492
mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal
493
weights were observed at 50 mg/kg and greater.
494
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
495
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
496
and lactation, there were no apparent adverse effects on offspring development.
497
8.3
Nursing Mothers
498
Bupropion and its metabolites are present in human milk. In a lactation study of 10
499
women, levels of orally dosed bupropion and its active metabolites were measured in expressed
500
milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion
501
and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when
502
WELLBUTRIN SR is administered to a nursing woman.
503
8.4
Pediatric Use
504
Safety and effectiveness in the pediatric population have not been established [see Boxed
505
Warning, Warnings and Precautions (5.1)].
506
8.5
Geriatric Use
507
Of the approximately 6,000 subjects who participated in clinical trials with bupropion
508
sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and
509
47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in
510
clinical trials using the immediate-release formulation of bupropion (depression trials). No
511
overall differences in safety or effectiveness were observed between these subjects and younger
512
subjects. Reported clinical experience has not identified differences in responses between the
513
elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
514
out.
515
Bupropion is extensively metabolized in the liver to active metabolites, which are further
516
metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients
517
with impaired renal function. Because elderly patients are more likely to have decreased renal
518
function, it may be necessary to consider this factor in dose selection; it may be useful to monitor
519
renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), Clinical
520
Pharmacology (12.3)].
521
8.6
Renal Impairment
522
Consider a reduced dose and/or dosing frequency of WELLBUTRIN SR in patients with
523
renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are
524
cleared renally and may accumulate in such patients to a greater extent than usual. Monitor
525
closely for adverse reactions that could indicate high bupropion or metabolite exposures [see
526
Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
527
8.7
Hepatic Impairment
528
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
529
maximum dose of WELLBUTRIN SR is 100 mg per day or 150 mg every other day. In patients
530
with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or
531
frequency of dosing [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
17
Reference ID: 3674083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
532
9
DRUG ABUSE AND DEPENDENCE
533
9.1
Controlled Substance
534
Bupropion is not a controlled substance.
535
9.2
Abuse
536
Humans: Controlled clinical trials conducted in normal volunteers, in subjects with a
537
history of multiple drug abuse, and in depressed subjects showed some increase in motor activity
538
and agitation/excitement, often typical of central stimulant activity.
539
In a population of individuals experienced with drugs of abuse, a single oral dose of
540
400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the
541
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
542
score greater than placebo but less than 15mg of the Schedule II stimulant dextroamphetamine
543
on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug
544
liking which are often associated with abuse potential.
545
Findings in clinical trials, however, are not known to reliably predict the abuse potential
546
of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily
547
dosage of bupropion when administered orally in divided doses is not likely to be significantly
548
reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be
549
tested because of the risk of seizure) might be modestly attractive to those who abuse CNS
550
stimulant drugs.
551
WELLBUTRIN SR is intended for oral use only. The inhalation of crushed tablets or
552
injection of dissolved bupropion has been reported.. Seizures and/or cases of death have been
553
reported when bupropion has been administered intranasally or by parenteral injection.
554
Animals: Studies in rodents and primates demonstrated that bupropion exhibits some
555
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
556
locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding
557
in several schedule-controlled behavior paradigms. In primate models assessing the positive
558
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
559
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
560
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
561
10
OVERDOSAGE
562
10.1 Human Overdose Experience
563
Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was
564
reported in approximately one-third of all cases. Other serious reactions reported with overdoses
565
of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG
566
changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever,
567
muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been
568
reported mainly when bupropion was part of multiple drug overdoses.
569
Although most patients recovered without sequelae, deaths associated with overdoses of
570
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
18
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
571
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
572
in these patients.
573
10.2 Overdosage Management
574
Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone
575
numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR).
576
Call 1-800-222-1222 or refer to www.poison.org.
577
There are no known antidotes for bupropion. In case of an overdose, provide supportive
578
care, including close medical supervision and monitoring. Consider the possibility of multiple
579
drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm
580
and vital signs. Induction of emesis is not recommended.
581
11
DESCRIPTION
582
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone
583
class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or
584
other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is
585
related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1
586
dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular
587
formula is C13 H18 ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly
588
soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral
589
mucosa. The structural formula is: structural formula
590
591
592
WELLBUTRIN SR is supplied for oral administration as 100-mg (blue), 150-mg
593
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
594
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
595
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
596
glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the
597
100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
598
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
599
12
CLINICAL PHARMACOLOGY
600
12.1 Mechanism of Action
601
The exact mechanism of the antidepressant action of bupropion is not known, but is
602
presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a
603
relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not
604
inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.
605
12.3 Pharmacokinetics
19
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
606
Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of
607
the individual enantiomers have not been studied. The mean elimination half-life (±SD) of
608
bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of
609
bupropion are reached within 8 days.
610
Absorption: The absolute bioavailability of WELLBUTRIN SR in humans has not been
611
determined because an intravenous formulation for human use is not available. However, it
612
appears likely that only a small proportion of any orally administered dose reaches the systemic
613
circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to
614
20%.
615
In humans, following oral administration of WELLBUTRIN SR, peak plasma
616
concentration (C max ) of bupropion is usually achieved within 3 hours.
617
In a trial comparing chronic dosing with WELLBUTRIN SR 150 mg twice daily to
618
bupropion immediate-release formulation 100 mg 3 times daily, the steady state C max for
619
bupropion after WELLBUTRIN SR administration was approximately 85% of those achieved
620
after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion
621
was equivalent for both formulations. Bioequivalence was also demonstrated for all three major
622
active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion)
623
for both Cmax and AUC. Thus, at steady state, WELLBUTRIN SR given twice daily, and the
624
immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for
625
both bupropion and the 3 quantitatively important metabolites.
626
WELLBUTRIN SR can be taken with or without food. Bupropion Cmax and AUC was
627
increased by 11% to 35% and 16% to 19%, respectively, when WELLBUTRIN SR was
628
administered with food to healthy volunteers in three trials. The food effect is not considered
629
clinically significant.
630
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins
631
at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
632
metabolite is similar to that for bupropion; whereas, the extent of protein binding of the
633
threohydrobupropion metabolite is about half that seen with bupropion.
634
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are
635
active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of
636
bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion,
637
which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is
638
the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450
639
enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion
640
side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is
641
then excreted as the major urinary metabolite. The potency and toxicity of the metabolites
642
relative to bupropion have not been fully characterized. However, it has been demonstrated in an
643
antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion,
644
while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion.
20
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
645
This may be of clinical importance because the plasma concentrations of the metabolites are as
646
high as or higher than those of bupropion.
647
Following a single dose administration of WELLBUTRIN SR in humans, Cmax of
648
hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the
649
peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is
650
approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The
651
times to peak concentrations for the erythrohydrobupropion and threohydrobupropion
652
metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination
653
half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5
654
and 7 times that of bupropion, respectively.
655
Bupropion and its metabolites exhibit linear kinetics following chronic administration of
656
300 to 450 mg per day.
657
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87%
658
and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5%
659
of the oral dose was excreted as unchanged bupropion.
660
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
661
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
662
be expected to influence the degree and extent of accumulation of the active metabolites of
663
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
664
renal or hepatic function because they are moderately polar compounds and are likely to undergo
665
further metabolism or conjugation in the liver prior to urinary excretion.
666
Renal Impairment: There is limited information on the pharmacokinetics of
667
bupropion in patients with renal impairment. An inter-trial comparison between normal subjects
668
and subjects with end-stage renal failure demonstrated that the parent drug C max and AUC values
669
were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
670
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage
671
renal failure. A second trial, comparing normal subjects and subjects with moderate-to-severe
672
renal impairment (GFR 30.9 ± 10.8 mL/min), showed that after a single 150-mg dose of
673
sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects
674
with impaired renal function, while levels of the hydroxybupropion and
675
threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is
676
extensively metabolized in the liver to active metabolites, which are further metabolized and
677
subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion
678
may be reduced by impaired renal function. WELLBUTRIN SR should be used with caution in
679
patients with renal impairment and a reduced frequency and/or dose should be considered [see
680
Use in Specific Populations (8.6)].
681
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of
682
bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease
683
and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half-life of
684
hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in
21
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
685
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
686
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
687
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
688
for bupropion and the other metabolites in the 2 groups were minimal.
689
The second trial demonstrated no statistically significant differences in the
690
pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild–to-moderate
691
hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in
692
some of the pharmacokinetic parameters for bupropion (AUC, Cmax , and Tmax ) and its active
693
metabolites (t½) in subjects with mild–to-moderate hepatic cirrhosis. In subjects with severe
694
hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites
695
were seen (Table 5).
696
697
Table 5. Pharmacokinetics of Bupropion and Metabolites in Patients with Severe Hepatic
698
Cirrhosis: Ratio Relative to Healthy Matched Controls
Cmax
AUC
t½
Tmax
a
Bupropion
1.69
3.12
1.43
0.5 h
Hydroxybupropion
0.31
1.28
3.88
19 h
Threo/erythrohydrobupropion
amino alcohol
0.69
2.48
1.96
20 h
699
a = Difference.
700
701
Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14
702
depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x
703
ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites,
704
compared with healthy volunteers.
705
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have
706
not been fully characterized, but an exploration of steady-state bupropion concentrations from
707
several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day,
708
on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
709
concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the
710
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
711
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
712
however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are
713
at increased risk for accumulation of bupropion and its metabolites [see Use in Specific
714
Populations (8.5)].
715
Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male
716
and 90 healthy female volunteers revealed no sex-related differences in the peak plasma
717
concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13%
718
higher in male volunteers compared with female volunteers. The clinical significance of this
719
finding is unknown.
22
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
720
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion
721
were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and
722
17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
723
were no statistically significant differences in C max , half-life, Tmax , AUC, or clearance of
724
bupropion or its active metabolites between smokers and nonsmokers.
725
Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN SR: In vitro
726
studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6.
727
Therefore, the potential exists for drug interactions between WELLBUTRIN SR and drugs that
728
are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine,
729
sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.
730
Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male
731
volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures
732
(Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for
733
ticlopidine, respectively. The exposures (C max and AUC) of hydroxybupropion were decreased
734
50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This
735
effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.
736
Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects,
737
prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and
738
decreased C max and AUC values of hydroxybupropion, an active metabolite of bupropion, by
739
32% and 24%, respectively.
740
Cimetidine: The threohydrobupropion metabolite of bupropion does not appear
741
to be produced by cytochrome P450 enzymes. The effects of concomitant administration of
742
cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24
743
healthy young male volunteers. Following oral administration of bupropion 300 mg with and
744
without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were
745
unaffected. However, there were 16% and 32% increases in the AUC and Cmax , respectively, of
746
the combined moieties of threohydrobupropion and erythrohydrobupropion.
747
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its
748
three metabolites.
749
Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial,
750
ritonavir 100 mg twice daily reduced the AUC and C max of bupropion by 22% and 21%,
751
respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the
752
threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
753
In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and
754
the C max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion
755
metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the
756
erythrohydrobupropion decreased by 68%.
757
In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily
758
decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were
759
decreased by 50% and 31%, respectively.
23
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
760
Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for
761
2 weeks reduced the AUC and C max of bupropion by approximately 55% and 34%, respectively.
762
The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was
763
increased by 50%.
764
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
765
these drugs may induce the metabolism of bupropion.
766
Potential for WELLBUTRIN SR to Affect Other Drugs: Animal data indicated that
767
bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following
768
chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14
769
days, there was no evidence of induction of its own metabolism. Nevertheless, there may be
770
potential for clinically important alterations of blood levels of co-administered drugs.
771
Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites
772
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a
773
clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of
774
CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased
775
the C max , AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold,
776
respectively. The effect was present for at least 7 days after the last dose of bupropion.
777
Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally
778
studied.
779
Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in
780
one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.
781
Lamotrigine: Multiple oral doses of bupropion had no statistically significant
782
effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
783
13
NONCLINICAL TOXICOLOGY
784
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
785
Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up
786
to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the
787
MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular
788
proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the
789
MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such
790
lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions
791
were not seen in the mouse study, and no increase in malignant tumors of the liver and other
792
organs was seen in either study.
793
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of
794
5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in
795
chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
796
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
797
fertility.
24
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
798
14
CLINICAL STUDIES
799
The efficacy of the immediate-release formulation of bupropion in the treatment of major
800
depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients
801
with MDD (Trials 1 and 2 in Table 6) and in one 6-week, placebo-controlled trial in adult
802
outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range of bupropion was 300
803
mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of
804
300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate-release
805
formulation of bupropion by the Hamilton Depression Rating Scale (HDRS) total score, the
806
HDRS depressed mood item (item 1), and the Clinical Global Impressions severity score (CGI
807
S). The second trial included 2 doses of the immediate-release formulation of bupropion (300
808
and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the
809
immediate-release formulation of bupropion, but only at the 450-mg-per-day dose. The efficacy
810
results were significant for the HDRS total score and the CGI-S score, but not for HDRS item 1.
811
In the third trial, outpatients were treated with 300 mg per day of the immediate-release
812
formulation of bupropion. This trial demonstrated the efficacy of the immediate-release
813
formulation of bupropion as measured by the HDRS total score, the HDRS item 1, the
814
Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI
815
Improvement Scale (CGI-I) score.
816
817
Table 6. Efficacy of Immediate-Release Bupropion for the Treatment of Major Depressive
818
Disorder
Trial
Number
Treatment Group
Primary Efficacy Measure: HDRS
Mean Baseline
Score (SD)
LS Mean Score at
Endpoint Visit
(SE)
Placebo-subtracted
Differencea (95%
CI)
Trial 1
Immediate-Release
Bupropion 300
600 mg/dayb
(n = 48)
28.5 (5.1)
14.9 (1.3)
-4.7 (-8.8, -0.6)
Placebo (n = 27)
29.3 (7.0)
19.6 (1.6)
-
Mean Baseline
Score (SD)
LS Mean Change
from Baseline (SE)
Placebo-subtracted
Differencea (95%
CI)
Trial 2
Immediate-Release
Bupropion 300
mg/day (n = 36)
32.4 (5.9)
-15.5 (1.7)
-4.1
Immediate-Release
Bupropion 450
mg/dayb (n = 34)
34.8 (4.6)
-17.4 (1.7)
-5.9 (-10.5, -1.4)
Placebo (n = 39)
32.9 (5.4)
-11.5 (1.6)
-
25
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Trial 3
Immediate-Release
Bupropion 300
mg/dayb (n = 110)
26.5 (4.3)
-12.0 (NA)
-3.9 (-5.7, -1.0)
Placebo (n = 106)
27.0 (3.5)
-8.7 (NA)
-
819
n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI:
820
unadjusted confidence interval included for doses that were demonstrated to be effective; NA:
821
not available.
822
a Difference (drug minus placebo) in least-squares estimates with respect to the primary efficacy
823
parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2 and 3, it
824
refers to the mean change from baseline to the endpoint visit.
825
b Doses that are demonstrated to be statistically significantly superior to placebo.
826
827
Although there are not as yet independent trials demonstrating the antidepressant
828
effectiveness of the sustained-release formulation of bupropion, trials have demonstrated the
829
bioequivalence of the immediate-release and sustained-release forms of bupropion under
830
steady-state conditions, i.e., bupropion sustained-release 150 mg twice daily was shown to be
831
bioequivalent to 100 mg 3 times daily of the immediate-release formulation of bupropion, with
832
regard to both rate and extent of absorption, for parent drug and metabolites.
833
In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder,
834
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
835
twice daily) were randomized to continuation of their same dose of WELLBUTRIN SR or
836
placebo for up to 44 weeks of observation for relapse. Response during the open phase was
837
defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of
838
the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s
839
judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving
840
continued treatment with WELLBUTRIN SR experienced significantly lower relapse rates over
841
the subsequent 44 weeks compared with those receiving placebo.
842
16
HOW SUPPLIED/STORAGE AND HANDLING
843
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are
844
blue, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
845
(NDC 0173-0947-55) tablets.
846
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
847
purple, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 150” in bottles of
848
60 (NDC 0173-0135-55) tablets.
849
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are
850
light pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles
851
of 60 (NDC 0173-0722-00) tablets.
26
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
852
Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between
853
15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from light
854
and moisture.
855
17
PATIENT COUNSELING INFORMATION
856
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
857
Inform patients, their families, and their caregivers about the benefits and risks associated
858
with treatment with WELLBUTRIN SR and counsel them in its appropriate use.
859
A patient Medication Guide about “Antidepressant Medicines, Depression and Other
860
Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking
861
Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or
862
Actions,” and “What Other Important Information Should I Know About WELLBUTRIN SR?”
863
is available for WELLBUTRIN SR. Instruct patients, their families, and their caregivers to read
864
the Medication Guide and assist them in understanding its contents. Patients should be given the
865
opportunity to discuss the contents of the Medication Guide and to obtain answers to any
866
questions they may have. The complete text of the Medication Guide is reprinted at the end of
867
this document.
868
Advise patients regarding the following issues and to alert their prescriber if these occur
869
while taking WELLBUTRIN SR.
870
Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their
871
caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
872
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
873
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
874
early during antidepressant treatment and when the dose is adjusted up or down. Advise families
875
and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis,
876
since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or
877
healthcare professional, especially if they are severe, abrupt in onset, or were not part of the
878
patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk
879
for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
880
changes in the medication.
881
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
882
Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it contains the
883
same active ingredient as ZYBAN which is approved for this use. Advise patients, families and
884
caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal
885
symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness.
886
Some patients have experienced changes in mood (including depression and mania), psychosis,
887
hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as
888
suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while
889
taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking
27
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
890
or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they
891
should be urged to report these symptoms to their healthcare provider immediately.
892
Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and
893
to discontinue WELLBUTRIN SR if they have a severe allergic reaction.
894
Seizure: Instruct patients to discontinue and not restart WELLBUTRIN SR if they
895
experience a seizure while on treatment. Advise patients that the excessive use or abrupt
896
discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can
897
increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.
898
As the dose is increased during initial titration to doses above 150 mg per day, instruct
899
patients to take WELLBUTRIN SR in 2 divided doses, preferably with at least 8 hours between
900
successive doses, to minimize the risk of seizures.
901
Angle-Closure Glaucoma: Patients should be advised that taking WELLBUTRIN SR
902
can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of
903
angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because
904
angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open
905
angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be
906
examined to determine whether they are susceptible to angle closure, and have a prophylactic
907
procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.7)].
908
Bupropion-Containing Products: Educate patients that WELLBUTRIN SR contains
909
the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid
910
to smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination
911
with ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN®, the
912
immediate-release formulation and WELLBUTRIN XL® or FORFIVO XL™, the extended
913
release formulations, and APLENZIN®, the extended-release formulation of bupropion
914
hydrobromide). In addition, there are a number of generic bupropion HCl products for the
915
immediate-, sustained-, and extended-release formulations.
916
Potential for Cognitive and Motor Impairment: Advise patients that any CNS-active
917
drug like WELLBUTRIN SR may impair their ability to perform tasks requiring judgment or
918
motor and cognitive skills. Advise patients that until they are reasonably certain that
919
WELLBUTRIN SR does not adversely affect their performance, they should refrain from driving
920
an automobile or operating complex, hazardous machinery. WELLBUTRIN SR may lead to
921
decreased alcohol tolerance.
922
Concomitant Medications: Counsel patients to notify their healthcare provider if they
923
are taking or plan to take any prescription or over-the-counter drugs because WELLBUTRIN SR
924
Sustained-Release Tablets and other drugs may affect each others’ metabolisms.
925
Pregnancy: Advise patients to notify their healthcare provider if they become pregnant
926
or intend to become pregnant during therapy.
927
Precautions for Nursing Mothers: Advise patients that WELLBUTRIN SR is present
928
in human milk in small amounts.
28
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
929
Storage Information: Instruct patients to store WELLBUTRIN SR at room temperature,
930
between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.
931
Administration Information: Instruct patients to swallow WELLBUTRIN SR Tablets
932
whole so that the release rate is not altered. Do not chew, divide, or crush tablets; they are
933
designed to slowly release drug in the body. When patients take more than 150 mg per day,
934
instruct them to take WELLBUTRIN SR in 2 doses at least 8 hours apart, to minimize the risk of
935
seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the
936
missed dose and to take the next tablet at the regular time because of the dose-related risk of
937
seizure. Instruct patients that WELLBUTRIN SR Tablets may have an odor. WELLBUTRIN SR
938
can be taken with or without food.
939
940
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
941
trademarks of the GSK group of companies. The other brands listed are trademarks of their
942
respective owners and are not trademarks of the GSK group of companies. The makers of these
943
brands are not affiliated with and do not endorse the GSK group of companies or its products.
944
945 company logo
946
GlaxoSmithKline
947
Research Triangle Park, NC 27709
948
949
©Year, the GSK group of companies. All rights reserved.
950
951
WLS:XXPIxPI
952
953
MEDICATION GUIDE
954
WELLBUTRIN® SR (WELL byu-trin)
955
(bupropion hydrochloride) Sustained-Release Tablets
956
957
Read this Medication Guide carefully before you start taking WELLBUTRIN SR and
958
each time you get a refill. There may be new information. This information does not
959
take the place of talking with your healthcare provider about your medical condition
960
or your treatment. If you have any questions about WELLBUTRIN SR, ask your
961
healthcare provider or pharmacist.
962
963
IMPORTANT: Be sure to read the three sections of this Medication Guide.
964
The first section is about the risk of suicidal thoughts and actions with
965
antidepressant medicines; the second section is about the risk of changes
966
in thinking and behavior, depression and suicidal thoughts or actions with
29
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
967
medicines used to quit smoking; and the third section is entitled “What
968
Other Important Information Should I Know About WELLBUTRIN SR?”
969
970
Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
971
and Suicidal Thoughts or Actions
972
973
This section of the Medication Guide is only about the risk of suicidal thoughts and
974
actions with antidepressant medicines. Talk to your healthcare provider or your
975
family member’s healthcare provider about:
976
•
all risks and benefits of treatment with antidepressant medicines
977
•
all treatment choices for depression or other serious mental illness
978
979
What is the most important information I should know about
980
antidepressant medicines, depression and other serious mental illnesses,
981
and suicidal thoughts or actions?
982
1. Antidepressant medicines may increase suicidal thoughts or actions in
983
some children, teenagers, or young adults within the first few months of
984
treatment.
985
2. Depression or other serious mental illnesses are the most important
986
causes of suicidal thoughts and actions. Some people may have a
987
particularly high risk of having suicidal thoughts or actions. These include
988
people who have (or have a family history of) bipolar illness (also called manic
989
depressive illness) or suicidal thoughts or actions.
990
3. How can I watch for and try to prevent suicidal thoughts and actions in
991
myself or a family member?
992
•
Pay close attention to any changes, especially sudden changes, in mood,
993
behaviors, thoughts, or feelings. This is very important when an antidepressant
994
medicine is started or when the dose is changed.
995
•
Call your healthcare provider right away to report new or sudden changes in
996
mood, behavior, thoughts, or feelings.
997
•
Keep all follow-up visits with your healthcare provider as scheduled. Call the
998
healthcare provider between visits as needed, especially if you have concerns
999
about symptoms.
1000
1001
Call your healthcare provider right away if you or your family member has
1002
any of the following symptoms, especially if they are new, worse, or worry
1003
you:
1004
30
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
thoughts about suicide or dying
•
trouble sleeping (insomnia)
•
attempts to commit suicide
•
new or worse irritability
•
new or worse depression
•
acting aggressive, being angry, or violent
•
new or worse anxiety
•
acting on dangerous impulses
•
feeling very agitated or restless
•
an extreme increase in activity and talking (mania)
•
panic attacks
•
other unusual changes in behavior or mood
1005
1006
What else do I need to know about antidepressant medicines?
1007
•
Never stop an antidepressant medicine without first talking to a
1008
healthcare provider. Stopping an antidepressant medicine suddenly can cause
1009
other symptoms.
1010
•
Antidepressants are medicines used to treat depression and other
1011
illnesses. It is important to discuss all the risks of treating depression and also
1012
the risks of not treating it. Patients and their families or other caregivers should
1013
discuss all treatment choices with the healthcare provider, not just the use of
1014
antidepressants.
1015
•
Antidepressant medicines have other side effects. Talk to the healthcare
1016
provider about the side effects of the medicine prescribed for you or your family
1017
member.
1018
•
Antidepressant medicines can interact with other medicines. Know all of
1019
the medicines that you or your family member takes. Keep a list of all medicines
1020
to show the healthcare provider. Do not start new medicines without first
1021
checking with your healthcare provider.
1022
1023
It is not known if WELLBUTRIN SR is safe and effective in children under the age of
1024
18.
1025
1026
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and
1027
Behavior, Depression, and Suicidal Thoughts or Actions
1028
1029
This section of the Medication Guide is only about the risk of changes in thinking
1030
and behavior, depression and suicidal thoughts or actions with drugs used to quit
1031
smoking.
1032
1033
Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the
1034
same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help
1035
patients quit smoking.
1036
1037
Some people have had changes in behavior, hostility, agitation, depression, suicidal
1038
thoughts or actions while taking bupropion to help them quit smoking. These
31
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1039
symptoms can develop during treatment with bupropion or after stopping treatment
1040
with bupropion.
1041
1042
If you, your family member, or your caregiver notice agitation, hostility,
1043
depression, or changes in thinking or behavior that are not typical for you, or you
1044
have any of the following symptoms, stop taking bupropion and call your healthcare
1045
provider right away:
1046
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• panic attacks
• feeling very agitated or restless
• acting aggressive, being angry, or
violent
• acting on dangerous impulses
1047
• an extreme increase in activity and talking
(mania)
• abnormal thoughts or sensations
• seeing or hearing things that are not there
(hallucinations)
• feeling people are against you (paranoia)
•
feeling confused
•
other unusual changes in behavior or mood
1048
When you try to quit smoking, with or without bupropion, you may have symptoms
1049
that may be due to nicotine withdrawal, including urge to smoke, depressed mood,
1050
trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty
1051
concentrating, restlessness, decreased heart rate, and increased appetite or weight
1052
gain. Some people have even experienced suicidal thoughts when trying to quit
1053
smoking without medication. Sometimes quitting smoking can lead to worsening of
1054
mental health problems that you already have, such as depression.
1055
1056
Before taking bupropion, tell your healthcare provider if you have ever had
1057
depression or other mental illnesses. You should also tell your healthcare provider
1058
about any symptoms you had during other times you tried to quit smoking, with or
1059
without bupropion.
1060
1061
What Other Important Information Should I Know About WELLBUTRIN SR?
1062
1063
•
Seizures: There is a chance of having a seizure (convulsion, fit) with
1064
WELLBUTRIN SR, especially in people:
1065
•
with certain medical problems.
1066
•
who take certain medicines.
1067
1068
The chance of having seizures increases with higher doses of WELLBUTRIN SR.
1069
For more information, see the sections “Who should not take WELLBUTRIN SR?”
32
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1070
and “What should I tell my healthcare provider before taking WELLBUTRIN SR?”
1071
Tell your healthcare provider about all of your medical conditions and all the
1072
medicines you take. Do not take any other medicines while you are taking
1073
WELLBUTRIN SR unless your healthcare provider has said it is okay to
1074
take them.
1075
1076
If you have a seizure while taking WELLBUTRIN SR, stop taking the
1077
tablets and call your healthcare provider right away. Do not take
1078
WELLBUTRIN SR again if you have a seizure.
1079
1080
•
High blood pressure (hypertension). Some people get high blood
1081
pressure, that can be severe, while taking WELLBUTRIN SR. The chance
1082
of high blood pressure may be higher if you also use nicotine replacement
1083
therapy (such as a nicotine patch) to help you stop smoking.
1084
•
Manic episodes. Some people may have periods of mania while taking
1085
WELLBUTRIN SR, including:
1086
•
Greatly increased energy
1087
•
Severe trouble sleeping
1088
•
Racing thoughts
1089
•
Reckless behavior
1090
•
Unusually grand ideas
1091
•
Excessive happiness or irritability
1092
•
Talking more or faster than usual
1093
If you have any of the above symptoms of mania, call your healthcare provider.
1094
•
Unusual thoughts or behaviors. Some patients have unusual thoughts or
1095
behaviors while taking WELLBUTRIN, including delusions (believe you are
1096
someone else), hallucinations (seeing or hearing things that are not there),
1097
paranoia (feeling that people are against you), or feeling confused. If this
1098
happens to you, call your healthcare provider.
1099
•
Visual problems.
1100
•
eye pain
1101
•
changes in vision
1102
•
swelling or redness in or around the eye
1103
Only some people are at risk for these problems. You may want to undergo an
1104
eye examination to see if you are at risk and receive preventative treatment if
1105
you are.
1106
•
Severe allergic reactions. Some people can have severe allergic
1107
reactions to WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your
1108
healthcare provider right away if you get a rash, itching, hives, fever,
1109
swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
33
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1110
the lips or tongue, chest pain, or have trouble breathing. These could be signs of
1111
a serious allergic reaction.
1112
1113
What is WELLBUTRIN SR?
1114
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type
1115
of depression called major depressive disorder.
1116
1117
Who should not take WELLBUTRIN SR?
1118
Do not take WELLBUTRIN SR if you
1119
•
have or had a seizure disorder or epilepsy.
1120
•
have or had an eating disorder such as anorexia nervosa or bulimia.
1121
•
are taking any other medicines that contain bupropion, ZYBAN (used to
1122
help people stop smoking) APLENZIN®, FORFIVO XL™, WELLBUTRIN®, or
1123
WELLBUTRIN XL® . Bupropion is the same active ingredient that is in
1124
WELLBUTRIN SR.
1125
•
drink a lot of alcohol and abruptly stop drinking, or use medicines called
1126
sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines,
1127
and you stop using them all of a sudden.
1128
•
take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
1129
pharmacist if you are not sure if you take an MAOI, including the antibiotic
1130
linezolid.
1131
•
do not take an MAOI within 2 weeks of stopping WELLBUTRIN SR unless
1132
directed to do so by your healthcare provider.
1133
•
do not start WELLBUTRIN SR if you stopped taking an MAOI in the last 2
1134
weeks unless directed to do so by your healthcare provider.
1135
•
are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of
1136
the inactive ingredients. See the end of this Medication Guide for a complete list
1137
of ingredients in WELLBUTRIN SR.
1138
1139
What should I tell my healthcare provider before taking WELLBUTRIN SR?
1140
Tell your healthcare provider if you have ever had depression, suicidal thoughts or
1141
actions, or other mental health problems. See “Antidepressant Medicines,
1142
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”
1143
1144
Tell your healthcare provider about your other medical conditions including
1145
if you:
1146
•
have liver problems, especially cirrhosis of the liver.
1147
•
have kidney problems.
1148
•
have, or have had, an eating disorder, such as anorexia nervosa or bulimia.
1149
•
have had a head injury.
34
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1150
•
have had a seizure (convulsion, fit).
1151
•
have a tumor in your nervous system (brain or spine).
1152
•
have had a heart attack, heart problems, or high blood pressure.
1153
•
are a diabetic taking insulin or other medicines to control your blood sugar.
1154
•
drink alcohol.
1155
•
abuse prescription medicines or street drugs.
1156
•
are pregnant or plan to become pregnant.
1157
•
are breastfeeding. WELLBUTRIN passes into your milk in small amounts.
1158
1159
•
Tell your healthcare provider about all the medicines you take, including
1160
prescription, over-the-counter medicines, vitamins, and herbal supplements.
1161
Many medicines increase your chances of having seizures or other serious side
1162
effects if you take them while you are taking WELLBUTRIN SR.
1163
1164
How should I take WELLBUTRIN SR?
1165
•
Take WELLBUTRIN SR exactly as prescribed by your healthcare provider.
1166
•
Swallow WELLBUTRIN SR Tablets whole. Do not chew, cut, or crush
1167
WELLBUTRIN SR Tablets. If you do, the medicine will be released into your
1168
body too quickly. If this happens you may be more likely to get side effects
1169
including seizures. Tell your healthcare provider if you cannot swallow
1170
tablets.
1171
•
Take WELLBUTRIN SR at the same time each day.
1172
•
Take your doses of WELLBUTRIN SR at least 8 hours apart.
1173
•
You may take WELLBUTRIN SR with or without food.
1174
•
If you miss a dose, do not take an extra dose to make up for the dose you
1175
missed. Wait and take your next dose at the regular time. This is very
1176
important. Too much WELLBUTRIN SR can increase your chance of having a
1177
seizure.
1178
•
If you take too much WELLBUTRIN SR, or overdose, call your local emergency
1179
room or poison control center right away.
1180
•
Do not take any other medicines while taking WELLBUTRIN SR unless
1181
your healthcare provider has told you it is okay.
1182
•
If you are taking WELLBUTRIN SR for the treatment of major depressive
1183
disorder, it may take several weeks for you to feel that WELLBUTRIN SR is
1184
working. Once you feel better, it is important to keep taking WELLBUTRIN SR
1185
exactly as directed by your healthcare provider. Call your healthcare provider if
1186
you do not feel WELLBUTRIN SR is working for you.
1187
•
Do not change your dose or stop taking WELLBUTRIN SR without talking with
1188
your healthcare provider first.
1189
35
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1190
What should I avoid while taking WELLBUTRIN SR?
1191
•
Limit or avoid using alcohol during treatment with WELLBUTRIN SR. If you
1192
usually drink a lot of alcohol, talk with your healthcare provider before suddenly
1193
stopping. If you suddenly stop drinking alcohol, you may increase your chance
1194
of having seizures.
1195
•
Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR
1196
affects you. WELLBUTRIN SR can affect your ability to do these things safely.
1197
1198
What are possible side effects of WELLBUTRIN SR?
1199
See “What Other Important Information Should I Know About
1200
WELLBUTRIN SR?”
1201
WELLBUTRIN SR can cause serious side effects.
1202
1203
The most common side effects of WELLBUTRIN SR include:
1204
•
Headache
1205
•
Dry mouth
1206
•
Nausea
1207
•
Trouble sleeping
1208
•
Dizziness
1209
•
Sore throat
1210
•
Constipation
1211
1212
If you have nausea, take your medicine with food. If you have trouble sleeping, do
1213
not take your medicine too close to bedtime.
1214
1215
Tell your healthcare provider right away about any side effects that bother you.
1216
1217
These are not all the possible side effects of WELLBUTRIN SR. For more
1218
information, ask your healthcare provider or pharmacist.
1219
1220
Call your doctor for medical advice about side effects. You may report side effects
1221
to FDA at 1-800-FDA-1088.
1222
1223
You may also report side effects to GlaxoSmithKline at 1-888-825-5249.
1224
1225
How should I store WELLBUTRIN SR?
1226
•
Store WELLBUTRIN SR at room temperature between 59°F and 86°F (15°C to
1227
30°C).
1228
•
Keep WELLBUTRIN SR dry and out of the light.
1229
•
WELLBUTRIN SR Tablets may have an odor.
36
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1230
1231
Keep WELLBUTRIN SR and all medicines out of the reach of children.
1232
1233
General Information about WELLBUTRIN SR.
1234
Medicines are sometimes prescribed for purposes other than those listed in a
1235
Medication Guide. Do not use WELLBUTRIN SR for a condition for which it was not
1236
prescribed. Do not give WELLBUTRIN SR to other people, even if they have the
1237
same symptoms you have. It may harm them.
1238
1239
If you take a urine drug screening test, WELLBUTRIN SR may make the test result
1240
positive for amphetamines. If you tell the person giving you the drug screening test
1241
that you are taking WELLBUTRIN SR, they can do a more specific drug screening
1242
test that should not have this problem.
1243
1244
This Medication Guide summarizes important information about WELLBUTRIN SR. If
1245
you would like more information, talk with your healthcare provider. You can ask
1246
your healthcare provider or pharmacist for information about WELLBUTRIN SR that
1247
is written for healthcare professionals.
1248
1249
For more information about WELLBUTRIN SR, go to www.wellbutrin.com or call 1
1250
888-825-5249.
1251
1252
What are the ingredients in WELLBUTRIN SR?
1253
Active ingredient: bupropion hydrochloride.
1254
1255
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose,
1256
magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80,
1257
and titanium dioxide. In addition, the 100-mg tablet contains FD&C Blue No. 1
1258
Lake, the 150-mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake,
1259
and the 200-mg tablet contains FD&C Red No. 40 Lake. The tablets are printed with
1260
edible black ink.
1261
1262
This Medication Guide has been approved by the U.S. Food and Drug
1263
Administration.
1264
1265
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
1266
trademarks of the GSK group of companies. The other brands listed are
1267
trademarks of their respective owners and are not trademarks of the GSK group of
1268
companies. The makers of these brands are not affiliated with and do not endorse
1269
the GSK group of companies or its products.
37
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1270
1271 company logo
1272
1273
1274
GlaxoSmithKline
1275
Research Triangle Park, NC 27709
1276
1277
©2014, the GSK group of companies. All rights reserved.
1278
1279
December 2014
1280
WLS:11MG
1281
38
Reference ID: 3674083
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:31.580772
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018644s048,020358s055lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
12,477
|
T2006-71
Famvir®
(famciclovir)
Tablets
Rx only
PRESCRIBING INFORMATION
DESCRIPTION
Famvir® (famciclovir) contains famciclovir, an orally administered prodrug of the antiviral
agent penciclovir. Chemically, famciclovir is known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-
1,3-propanediol diacetate. Its molecular formula is C14H19N504; its molecular weight is 321.3.
It is a synthetic acyclic guanine derivative and has the following structure
famciclovir
Famciclovir is a white to pale yellow solid. It is freely soluble in acetone and
methanol, and sparingly soluble in ethanol and isopropanol. At 25°C famciclovir is freely
soluble (>25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2%-3%
w/v) monohydrate. Famciclovir is not hygroscopic below 85% relative humidity. Partition
coefficients are: octanol/water (pH 4.8) P=1.09 and octanol/phosphate buffer (pH 7.4)
P=2.08.
Tablets for Oral Administration: Each white, film-coated tablet contains famciclovir. The
125-mg and 250-mg tablets are round; the 500-mg tablets are oval. Inactive ingredients
consist of hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium
stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide.
MICROBIOLOGY
Mechanism of Antiviral Action: Famciclovir undergoes rapid biotransformation to the
active antiviral compound penciclovir, which has demonstrated inhibitory activity against
herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In
cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates
penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by
cellular kinases. In vitro studies demonstrate that penciclovir triphosphate inhibits HSV-2
DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes
viral DNA synthesis and, therefore, replication are selectively inhibited.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2
Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours
in HSV-2- and 7 hours in VZV-infected cells grown in culture; however, the clinical
significance is unknown.
Antiviral Activity: In cell culture studies, penciclovir is inhibitory to the following herpes
viruses (listed in decreasing order of potency): HSV-1, HSV-2 and VZV. Sensitivity test
results, expressed as the concentration of the drug required to inhibit the growth of the virus
by 50% (EC50) or 99% (EC99) in cell culture, vary greatly depending upon a number of
factors, including the assay protocols, and in particular the cell type used. See Table 1.
Table 1
Method of Assay
Virus Type
Cell Type
EC50
EC99
(mcg/mL)
Plaque Reduction
VZV (c.i.)
MRC-5
5.0 ± 3.0
VZV (c.i.)
Hs68
0.9 ± 0.4
HSV-1 (c.i.)
MRC-5
0.2 – 0.6
HSV-1 (c.i.)
WISH
0.04 – 0.5
HSV-2 (c.i.)
MRC-5
0.9 – 2.1
HSV-2 (c.i.)
WISH
0.1 – 0.8
Virus Yield
HSV-1 (c.i.)
MRC-5
0.4 – 0.5
Reduction
HSV-2 (c.i.)
MRC-5
0.6 – 0.7
DNA Synthesis
VZV (Ellen)
MRC-5
0.1
Inhibition
HSV-1 (SC16)
MRC-5
0.04
HSV-2 (MS)
MRC-5
0.05
(c.i.) = clinical isolates.
Resistance: Penciclovir-resistant mutants of HSV and VZV can result from mutations in the
viral thymidine kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may
lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial),
or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in
the ability to phosphorylate thymidine (TK altered). The most commonly encountered
acyclovir-resistant mutants that are TK negative are also resistant to penciclovir. The
possibility of viral resistance to penciclovir should be considered in patients who fail to
respond or experience recurrent viral shedding during therapy.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption and Bioavailability: Famciclovir is the diacetyl 6-deoxy analog of the active
antiviral compound penciclovir. Following oral administration, little or no famciclovir is
detected in plasma or urine.
The absolute bioavailability of penciclovir is 77±8% as determined following the
administration of a 500-mg famciclovir oral dose and a 400-mg penciclovir intravenous dose
to 12 healthy male subjects.
Penciclovir concentrations increased in proportion to dose over a famciclovir dose
range of 125 mg to 1000 mg administered as a single dose. Single oral-dose administration of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3
125-mg, 250-mg, 500-mg, or 1000-mg famciclovir to healthy male volunteers across 17
studies gave the following pharmacokinetic parameters:
Table 2
Dose
AUC (0-inf)† (mcg hr/mL)
Cmax
‡ (mcg/mL)
Tmax
§ (h)
125 mg
2.24
0.8
0.9
250 mg
4.48
1.6
0.9
500 mg
8.95
3.3
0.9
1000 mg
17.9
6.6
0.9
†AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity.
‡Cmax (mcg/mL)=maximum observed plasma concentration.
§Tmax (h)= time to Cmax.
Following oral single-dose administration of 500-mg famciclovir to seven patients
with herpes zoster, the mean ± SD AUC, Cmax, and Tmax were 12.1±1.7 mcg hr/mL,
4.0±0.7 mcg/mL, and 0.7±0.2 hours, respectively. The AUC of penciclovir was approximately
35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this
difference may be due to differences in renal function between the two groups.
There is no accumulation of penciclovir after the administration of 500-mg famciclovir
t.i.d. for 7 days.
Penciclovir Cmax decreased approximately 50% and Tmax was delayed by 1.5 hours
when a capsule formulation of famciclovir was administered with food (nutritional content
was approximately 910 Kcal and 26% fat). There was no effect on the extent of availability
(AUC) of penciclovir. There was an 18% decrease in Cmax and a delay in Tmax of about 1 hour
when famciclovir was given 2 hours after a meal as compared to its administration 2 hours
before a meal. Because there was no effect on the extent of systemic availability of
penciclovir, it appears that Famvir® (famciclovir) can be taken without regard to meals.
Distribution: The volume of distribution (Vdβ) was 1.08±0.17 L/kg in 12 healthy male
subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1-
hour intravenous infusion.
Penciclovir is <20% bound to plasma proteins over the concentration range of 0.1 to
20 mcg/mL. The blood/plasma ratio of penciclovir is approximately 1.
Metabolism: Following oral administration, famciclovir is deacetylated and oxidized to form
penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated
penciclovir, and 6-deoxy monoacetylated penciclovir (5%, <0.5% and <0.5% of the dose in
the urine, respectively). Little or no famciclovir is detected in plasma or urine.
An in vitro study using human liver microsomes demonstrated that cytochrome P450
does not play an important role in famciclovir metabolism. The conversion of 6-deoxy
penciclovir to penciclovir is catalyzed by aldehyde oxidase.
Elimination: Approximately 94% of administered radioactivity was recovered in urine over
24 hours (83% of the dose was excreted in the first 6 hours) after the administration of
5 mg/kg radiolabeled penciclovir as a 1-hour infusion to three healthy male volunteers.
Penciclovir accounted for 91% of the radioactivity excreted in the urine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4
Following the oral administration of a single 500-mg dose of radiolabeled famciclovir
to three healthy male volunteers, 73% and 27% of administered radioactivity were recovered
in urine and feces over 72 hours, respectively. Penciclovir accounted for 82% and 6-deoxy
penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately 60%
of the administered radiolabeled dose was collected in urine in the first 6 hours.
After intravenous administration of penciclovir in 48 healthy male volunteers, mean ±
S.D. total plasma clearance of penciclovir was 36.6±6.3 L/hr (0.48±0.09 L/hr/kg). Penciclovir
renal clearance accounted for 74.5±8.8% of total plasma clearance.
Renal clearance of penciclovir following the oral administration of a single 500-mg
dose of famciclovir to 109 healthy male volunteers was 27.7±7.6 L/hr.
The plasma elimination half-life of penciclovir was 2.0±0.3 hours after intravenous
administration of penciclovir to 48 healthy male volunteers and 2.3±0.4 hours after oral
administration of 500-mg famciclovir to 124 healthy male volunteers. The half-life in 17
patients with herpes zoster was 2.8±1.0 hours and 2.7±1.0 hours after single and repeated
doses, respectively. .
HIV-Infected Patients: Following oral administration of a single dose of 500-mg famciclovir
(the oral prodrug of penciclovir) to HIV-positive patients, the pharmacokinetic parameters of
penciclovir were comparable to those observed in healthy subjects.
Renal Insufficiency: Apparent plasma clearance, renal clearance, and the plasma-elimination
rate constant of penciclovir decreased linearly with reductions in renal function. After the
administration of a single 500-mg famciclovir oral dose (n=27) to healthy volunteers and to
volunteers with varying degrees of renal insufficiency (CLCR ranged from 6.4 to
138.8 mL/min.), the following results were obtained (Table 3):
Table 3
Parameter
CLCR
† ≥60
CLCR 40-59
CLCR 20-39
CLCR <20
(mean ± S.D.)
(mL/min.)
(mL/min.)
(mL/min.)
(mL/min.)
(n=15)
(n=5)
(n=4)
n=3)
CLCR (mL/min)
88.1 ± 20.6
49.3 ± 5.9
26.5 ± 5.3
12.7 ± 5.9
CLR (L/hr)
30.1 ± 10.6
13.0 ± 1.3
‡
4.2 ± 0.9
1.6 ± 1.0
CL/F§ (L/hr)
66.9 ± 27.5
27.3 ± 2.8
12.8 ± 1.3
5.8 ± 2.8
Half-life (hr)
2.3 ± 0.5
3.4 ± 0.7
6.2 ± 1.6
13.4 ± 10.2
†CLCR is measured creatinine clearance.
‡n=4.
§CL/F consists of bioavailability factor and famciclovir to penciclovir conversion factor.
In a multiple-dose study of famciclovir conducted in subjects with varying degrees of
renal impairment (n=18), the pharmacokinetics of penciclovir were comparable to those after
single doses.
A dosage adjustment is recommended for patients with renal insufficiency (see
DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency: Well-compensated chronic liver disease (chronic hepatitis [n=6],
chronic ethanol abuse [n=8], or primary biliary cirrhosis [n=1]) had no effect on the extent of
availability (AUC) of penciclovir following a single dose of 500-mg famciclovir. However,
there was a 44% decrease in penciclovir mean maximum plasma concentration and the time to
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maximum plasma concentration was increased by 0.75 hours in patients with hepatic
insufficiency compared to normal volunteers. No dosage adjustment is recommended for
patients with well-compensated hepatic impairment. The pharmacokinetics of penciclovir
have not been evaluated in patients with severe uncompensated hepatic impairment.
Elderly Subjects: Based on cross-study comparisons, mean penciclovir AUC was 40% larger
and penciclovir renal clearance was 22% lower after the oral administration of famciclovir in
elderly volunteers (n=18, age 65 to 79 years) compared to younger volunteers. Some of this
difference may be due to differences in renal function between the two groups.
Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18
healthy female volunteers after single-dose oral administration of 500-mg famciclovir. AUC
of penciclovir was 9.3±1.9 mcg hr/mL and 11.1±2.1 mcg hr/mL in males and females,
respectively. Penciclovir renal clearance was 28.5±8.9 L/hr and 21.8±4.3 L/hr, respectively.
These differences were attributed to differences in renal function between the two groups. No
famciclovir dosage adjustment based on gender is recommended.
Pediatric Patients: The pharmacokinetics of famciclovir or penciclovir have not been
evaluated in patients <18 years of age.
Race: The pharmacokinetics of famciclovir or penciclovir with respect to race have not been
evaluated.
Drug Interactions
Effects on penciclovir
No clinically significant alterations in penciclovir pharmacokinetics were observed following
single-dose administration of 500-mg famciclovir after pre-treatment with multiple doses of
allopurinol, cimetidine, theophylline, or zidovudine. No clinically significant effect on
penciclovir pharmacokinetics was observed following multiple-dose (t.i.d.) administration of
famciclovir (500 mg) with multiple doses of digoxin.
Effects of famciclovir on co-administered drugs
The steady-state pharmacokinetics of digoxin were not altered by concomitant administration
of multiple doses of famciclovir (500 mg t.i.d.). No clinically significant effect on the
pharmacokinetics of zidovudine or zidovudine glucuronide was observed following a single
oral dose of 500-mg famciclovir.
CLINICAL TRIALS
Herpes Zoster
Famvir® (famciclovir) was studied in a placebo-controlled, double-blind trial of 419
immunocompetent adults with uncomplicated herpes zoster. Comparisons included Famvir
500 mg t.i.d., Famvir 750 mg t.i.d., or placebo. Treatment was begun within 72 hours of
initial lesion appearance and therapy was continued for 7 days.
The median time to full crusting in Famvir-treated patients was 5 days compared to 7
days in placebo-treated patients. The times to full crusting, loss of vesicles, loss of ulcers, and
loss of crusts were shorter for Famvir 500 mg-treated patients than for placebo-treated
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patients in the overall study population. The effects of Famvir were greater when therapy was
initiated within 48 hours of rash onset; it was also more pronounced in patients 50 years of
age or older. Among the 65.2% of patients with at least one positive viral culture, Famvir-
treated patients had a shorter median duration of viral shedding than placebo-treated patients
(1 day and 2 days, respectively).
There were no overall differences in the duration of pain before rash healing between
Famvir- and placebo-treated groups. In addition, there was no difference in the incidence of
pain after rash healing (postherpetic neuralgia) between the treatment groups. In the 186
patients (44.4% of total study population) who did develop postherpetic neuralgia, the median
duration of postherpetic neuralgia was shorter in patients treated with Famvir 500 mg than in
those treated with placebo (63 days and 119 days, respectively). No additional efficacy was
demonstrated with higher doses of Famvir.
A double-blind controlled trial in 545 immunocompetent adults with uncomplicated
herpes zoster treated within 72 hours of initial lesion appearance compared three doses of
Famvir to acyclovir 800 mg 5 times per day. Times to full lesion crusting and times to loss of
acute pain were comparable for all groups and there were no statistically significant
differences in the time to loss of postherpetic neuralgia between Famvir- and acyclovir-treated
groups.
Herpes Simplex Infections
Recurrent Genital Herpes: In one placebo-controlled trial, 329 immunocompetent adults with
a recurrence of genital herpes were treated with Famvir 1000 mg b.i.d. (n=163) or placebo
(n=166) for 1 day. Treatment was initiated within 6 hours of either symptom onset or lesion
appearance. Among patients with non-aborted lesions, the median time to healing (from start
of therapy to re-epithelialization) in Famvir-treated patients (n=125) was 4.3 days compared
to 6.1 days in placebo-treated patients (n=145). The median difference in time to healing
between placebo and the Famvir treated groups was 1.2 days (95% CI: 0.5 – 2.0). Twenty-
three percent of Famvir-treated patients had aborted lesions (no development beyond
erythema) compared to 13% in placebo-treated patients. The median time to loss of all
symptoms (e.g.,burning, itching, pain, tenderness, tingling,), was 3.3 days in Famvir-treated
patients vs. 5.4 days in placebo-treated patients.
Suppression of Recurrent Genital Herpes: 934 immunocompetent adults with a history of 6
or more recurrences per year were randomized into two double-blind, 1-year, placebo-
controlled trials. Comparisons included Famvir 125 mg t.i.d., 250 mg b.i.d., 250 mg t.i.d. and
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placebo. At one year, 60% to 65% of patients were still receiving Famvir and 25% were
receiving placebo treatment. Patient reported recurrence rates for the 250 mg b.i.d. dose at 6
and 12 months as shown in Table 4.
Table 4
Recurrence Rates
Recurrence Rates
at 6 Months
at 12 Months
Famvir
®
Placebo
Famvir
®
Placebo
250 mg b.i.d.
250 mg b.i.d.
(n = 236)
(n=233)
(n=236)
(n=233)
Recurrence-free
39%
10%
29%
6%
Recurrences†
47%
74%
53%
78%
Lost to Follow-up‡
14%
16%
17%
16%
† Based on patient reported data; not necessarily confirmed by a physician.
‡ Patients recurrence-free at time of last contact prior to withdrawal.
Famvir-treated patients had approximately 1/5 the median number of recurrences as
compared to placebo-treated patients.
Higher doses of Famvir were not associated with an increase in efficacy.
Herpes Labialis (Cold Sores): In one placebo-controlled trial, 701 immunocompetent adults
with recurrent herpes labialis were treated with Famvir 1500 mg as a single dose (n=227),
Famvir 750 mg b.i.d. (n=220) or placebo (n=254) for 1 day. Treatment was initiated within 1
hour of symptom onset. Among patients with non-aborted lesions, the median time to healing
was 4.4 days in the Famvir 1500 mg single dose group (n=152) compared to 6.2 days in the
placebo-group (n=168). The median difference in time to healing between the placebo and
Famvir treated group was 1.3 days (95% CI: 0.6 – 2.0). No differences in aborted lesions
(beyond the papular stage) were observed between subjects receiving Famvir or placebo: 33%
for Famvir 1500 mg and 34% for placebo. The median time to loss of pain and tenderness
was 1.7 days in Famvir 1500 mg once-treated patients versus 2.9 days in placebo-treated
patients..
Recurrent Mucocutaneous Herpes Simplex Infection in HIV-Infected Patients: A
randomized, double-blind, multicenter study compared famciclovir 500 mg twice daily for 7
days (n=150) with oral acyclovir 400 mg 5 times daily for 7 days (n=143) in HIV-infected
patients with recurrent mucocutaneous HSV infection treated within 48 hours of lesion onset.
Approximately 40% of patients had a CD4 count below 200 cells/mm3, 54% of patients had
anogenital lesions and 35% had orolabial lesions. Famciclovir therapy was comparable to oral
acyclovir in reducing new lesion formation and in time to complete healing.
INDICATIONS AND USAGE
Herpes Zoster: Famvir® (famciclovir) is indicated for the treatment of acute herpes zoster
(shingles).
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Herpes Simplex Infections: Famvir is indicated for:
• treatment or suppression of recurrent genital herpes in immunocompetent patients.
• treatment of recurrent herpes labialis (cold sores) in immunocompetent patients.
• treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients.
CONTRAINDICATIONS
Famvir® (famciclovir) is contraindicated in patients with known hypersensitivity to the
product, its components, and Denavir
® (penciclovir cream).
PRECAUTIONS
General
The efficacy of Famvir® (famciclovir) has not been established for initial episode genital
herpes infection, ophthalmic zoster, disseminated zoster or in immunocompromised patients
with herpes zoster.
Dosage adjustment is recommended when administering Famvir to patients with
creatinine clearance values < 60 mL/min. (See DOSAGE AND ADMINISTRATION). In
patients with underlying renal disease who have received inappropriately high doses of
Famvir for their level of renal function, acute renal failure has been reported.
Famvir 125 mg, 250 mg and 500 mg tablets contain lactose (26.9 mg, 53.7 mg and
107.4 mg, respectively). Patients with rare hereditary problems of galactose intolerance, a
severelactase deficiency or glucose-galactose malabsorption should not take Famvir 125 mg,
250mg and 500 mg tablets.
Information for Patients
Patients should be informed that Famvir is not a cure for genital herpes. There are no data
evaluating whether Famvir will prevent transmission of infection to others. As genital herpes
is a sexually transmitted disease, patients should avoid contact with lesions or intercourse
when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also
be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical
management of recurrent episodes is indicated, patients should be advised to initiate therapy
at the first sign or symptom.
There is no evidence that Famvir will affect the ability of a patient to drive or to use
machines. However, patients who experience dizziness, somnolence, confusion or other
central nervous system disturbances while taking Famvir should refrain from driving or
operating machinery.
Drug Interactions
Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular
secretion may result in increased plasma concentrations of penciclovir.
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The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde
oxidase. Interactions with other drugs metabolized by this enzyme could potentially occur.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Famciclovir was administered orally unless otherwise stated.
Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in
rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in
animals of this strain) was seen in female rats receiving the high dose of 600 mg/kg/day (1.1
to 4.5x the human systemic exposure at the recommended total daily oral dose ranging
between 2000 mg and 500 mg, based on area under the plasma concentration curve
comparisons [24 hr AUC] for penciclovir). No increases in tumor incidence were reported in
male rats treated at doses up to 240 mg/kg/day (0.7 to 2.7x the human AUC), or in male and
female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).
Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested
for genotoxic potential in a battery of in vitro and in vivo assays. Famciclovir and penciclovir
were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and
unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses up to 10,000 and
5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse
lymphoma assay (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat
dominant lethal study (5000 mg/kg). Famciclovir induced increases in polyploidy in human
lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL). Penciclovir was
positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations,
with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir
caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL).
Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when
administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when
administered orally.
Impairment of Fertility: Testicular toxicity was observed in rats, mice, and dogs following
repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of
the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with
abnormal morphology or reduced motility. The degree of toxicity to male reproduction was
related to dose and duration of exposure. In male rats, decreased fertility was observed after
10 weeks of dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect
level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was
50 mg/kg/day (0.15 to 0.6x the human systemic exposure based on AUC comparisons).
Testicular toxicity was observed following chronic administration to mice (104 weeks) and
dogs (26 weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day
(1.3 to 5.1x the human AUC), respectively.
Famciclovir had no effect on general reproductive performance or fertility in female
rats at doses up to 1000 mg/kg/day (2.7 to 10.8x the human AUC).
Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal
sperm profile over an 8-week baseline period and recurrent genital herpes receiving oral
Famvir (250 mg b.i.d.) (n=66) or placebo (n=64) therapy for 18 weeks showed no evidence of
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significant effects on sperm count, motility or morphology during treatment or during an
8-week follow-up.
Pregnancy
Teratogenic Effects–Pregnancy Category B: Famciclovir was tested for effects on embryo-
fetal development in rats and rabbits at oral doses up to 1000 mg/kg/day (approximately 2.7 to
10.8x and 1.4 to 5.4x the human systemic exposure to penciclovir based on AUC comparisons
for the rat and rabbit, respectively) and intravenous doses of 360 mg/kg/day in rats (1.5 to 6x
the human dose based on body surface area [BSA] comparisons) or 120 mg/kg/day in rabbits
(1.1 to 4.5x the human dose [BSA]). No adverse effects were observed on embryo-fetal
development. Similarly, no adverse effects were observed following intravenous
administration of penciclovir to rats (80 mg/kg/day, 0.3 to 1.3x the human dose [BSA]) or
rabbits (60 mg/kg/day, 0.5 to 2.1x the human dose [BSA]). There are, however, no adequate
and well-controlled studies in pregnant women. Because animal reproduction studies are not
always predictive of human response, famciclovir should be used during pregnancy only if the
benefit to the patient clearly exceeds the potential risk to the fetus.
Pregnancy Exposure Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to Famvir, Novartis Pharmaceuticals Corporation maintains a Famvir Pregnancy
Registry. Physicians are encouraged to register their patients by calling (888) 669-6682.
Nursing Mothers
Following oral administration of famciclovir to lactating rats, penciclovir was excreted in
breast milk at concentrations higher than those seen in the plasma. It is not known whether it
is excreted in human milk. There are no data on the safety of Famvir in infants.
Usage in Children
Safety and efficacy in children under the age of 18 years have not been established.
Geriatric Use
Of 816 patients with herpes zoster in clinical studies who were treated with Famvir, 248
(30.4%) were ≥65 years of age and 103 (13%) were ≥75 years of age. No overall differences
were observed in the incidence or types of adverse events between younger and older patients.
Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who
were treated with Famvir, 26 (4.3%) were > 65 years of age and 7 (1.1%) were > 75 years of
age. Clinical studies of Famvir did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects.
In general, appropriate caution should be exercised in the administration and
monitoring of FAMVIR in elderly patients reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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ADVERSE REACTIONS
Immunocompetent Patients
The safety of Famvir® (famciclovir) has been evaluated in clinical studies involving 816
Famvir-treated patients with herpes zoster (Famvir, 250 mg t.i.d. to 750 mg t.i.d.); 163
Famvir-treated patients with recurrent genital herpes (Famvir, 1000 mg b.i.d.); 1,197 patients
with recurrent genital herpes treated with Famvir as suppressive therapy (125 mg q.d. to 250
mg t.i.d.) of which 570 patients received Famvir (open-labeled and/or double-blind) for at
least 10 months; and 447 Famvir-treated patients with herpes labialis (Famvir, 1500 mg once
or 750 mg b.i.d.). Table 5 lists selected adverse events.
Table 5
Selected Adverse Events (all grades and without regard to causality) Reported by ≥2% of
Patients in Placebo-controlled Famvir® (famciclovir) Trials*
Incidence
Recurrent
Genital Herpes-
Herpes Zoster†
Genital Herpes‡
Suppression§
Herpes Labialis‡
Event
Famvir®
Placebo
Famvir® Placebo
Famvir® Placebo
Famvir® Placebo
(n=273)
(n=146)
(n=163)
(n=166)
(n=458)
(n=63)
(n=227)
(n=254)
%
%
%
%
%
%
%
%
Nervous System
Headache
22.7
17.8
13.5
5.4
39.3
42.9
9.7
6.7
Paresthesia
2.6
0.0
0.0
0.0
0.9
0.0
0.0
0.0
Migraine
0.7
0.7
0.6
0.6
3.1
0.0
0.0
0.0
Gastrointestinal
Nausea
12.5
11.6
2.5
3.6
7.2
9.5
2.2
3.9
Diarrhea
7.7
4.8
4.9
1.2
9.0
9.5
1.8
0.8
Vomiting
4.8
3.4
1.2
0.6
3.1
1.6
0.0
0.0
Flatulence
1.5
0.7
0.6
0.0
4.8
1.6
0.0
0.0
Abdominal Pain
1.1
3.4
0.0
1.2
7.9
7.9
0.0
0.4
Body as a Whole
Fatigue
4.4
3.4
0.6
0.0
4.8
3.2
1.3
0.4
Skin and Appendages
Pruritus
3.7
2.7
0.0
0.6
2.2
0.0
0.0
0.0
Rash
0.4
0.7
0.0
0.0
3.3
1.6
0.0
0.0
Reproductive Female
Dysmenorrhea
0.0
0.7
1.8
0.6
7.6
6.3
0.9
0.0
*Patients may have entered into more than one clinical trial.
†7 days of treatment
‡1 day of treatment
§daily treatment
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The following adverse events have been reported during post-approval use of Famvir:
urticaria, hallucinations and confusion (including delirium, disorientation, confusional state,
occurring predominantly in the elderly). Because these adverse events are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. Table 6 lists
selected laboratory abnormalities in genital herpes suppression trials.
Table 6
Selected Laboratory Abnormalities in Genital Herpes Suppression Studies*
Parameter
Famvir
®
Placebo
(n = 660)
†
(n = 210)
†
%
%
Anemia (<0.8 x NRL)
0.1
0.0
Leukopenia (<0.75 x NRL)
1.3
0.9
Neutropenia (<0.8 x NRL)
3.2
1.5
AST (SGOT) (>2 x NRH)
2.3
1.2
ALT (SGPT) (>2 x NRH)
3.2
1.5
Total Bilirubin (>1.5 x NRH)
1.9
1.2
Serum Creatinine (>1.5 x NRH)
0.2
0.3
Amylase (>1.5 x NRH)
1.5
1.9
Lipase (>1.5 x NRH)
4.9
4.7
*Percentage of patients with laboratory abnormalities that were increased or decreased from baseline
and were outside of specified ranges.
†n values represent the minimum number of patients assessed for each laboratory parameter.
NRH = Normal Range High.
NRL = Normal Range Low.
HIV-Infected Patients
In HIV-infected patients, the most frequently reported adverse events for famciclovir (500 mg
twice daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache
(16.7% vs. 15.4%), nausea (10.7% vs. 12.6%), diarrhea (6.7% vs. 10.5%), vomiting (4.7% vs.
3.5%), fatigue (4.0% vs. 2.1%), and abdominal pain (3.3% vs. 5.6%).
Post Marketing Experience
The following adverse events have been reported during post-approval use of Famvir:
uticaria, serious skin reactions (e.g. erythema multiforme), jaundice, thrombocytopenia,
hallucinations, dizziness, somnolence and confusion (including delirium, disorientation,
confusional state, occurring predominantly in the elderly). Because these adverse events are
reported voluntarily from a population of unknown size, estimates of frequency cannot be
made.
OVERDOSAGE
Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by
hemodialysis (see PRECAUTIONS, General).
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DOSAGE AND ADMINISTRATION
Herpes Zoster
The recommended dosage is 500 mg every 8 hours for 7 days. Therapy should be initiated
promptly as soon as herpes zoster is diagnosed. No data are available on efficacy of treatment
started greater than 72 hours after rash onset.
Herpes Simplex Infections
Recurrent genital herpes: The recommended dosage is 1000 mg twice daily for 1 day.
Initiate therapy at the first sign or symptom if medical management of a genital herpes
recurrence is indicated. The efficacy of Famvir® (famciclovir) has not been established when
treatment is initiated more than 6 hours after onset of symptoms or lesions.
Suppression of recurrent genital herpes: The recommended dosage is 250 mg twice daily for
up to 1 year. The safety and efficacy of Famvir therapy beyond 1 year of treatment have not
been established.
Recurrent herpes labialis (cold sores): The recommended dosage is 1500 mg as a single
dose. Initiate therapy at the earliest sign or symptom of a cold sore (e.g. tingling, itching or
burning).
HIV-Infected Patients
For recurrent orolabial or genital herpes simplex infection, the recommended dosage is
500 mg twice daily for 7 days.
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Patients with Reduced Renal Function
In patients with reduced renal function, dosage reduction is recommended (see
PRECAUTIONS, General).
Table 7
Adjusted
Indication and
Creatinine
Dosage
Normal Dosage
Clearance
Regimen
Regimen
(mL/min.)
Dose (mg)
Dosing Interval
Single-Day Dosing Regimens
Recurrent Genital Herpes
1000 mg every 12 hours for 1 day
≥60
1000
every 12 hours for 1 day
40-59
500
every 12 hours for 1 day
20-39
500
single dose
<20
250
single dose
HD*
250
single dose following
Dialysis
Recurrent herpes labialis
1500 mg single dose
≥60
1500
single dose
40-59
750
single dose
20-39
500
single dose
<20
250
single dose
HD*
250
single dose following
dialysis
Multiple-Day Dosing Regimens
Herpes Zoster
500 mg every 8 hours
≥60
500
every 8 hours
40–59
500
every 12 hours
20–39
500
every 24 hours
<20
250
every 24 hours
HD*
250
following each dialysis
Suppression of Recurrent
Genital Herpes
250 mg every 12 hours
≥40
250
every 12 hours
20–39
125
every 12 hours
<20
125
every 24 hours
HD*
125
following each dialysis
Recurrent Orolabial
and Genital Herpes
Simplex Infection in
HIV-Infected Patients
500 mg every 12 hours
≥40
500
every 12 hours
20–39
500
every 24 hours
<20
250
every 24 hours
HD*
250
following each dialysis
*Hemodialysis
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Administration with Food
When famciclovir was administered with food, penciclovir Cmax decreased approximately
50%. Because the systemic availability of penciclovir (AUC) was not altered, it appears that
Famvir may be taken without regard to meals.
HOW SUPPLIED
Famvir® (famciclovir) is supplied as film-coated tablets as follows: 125 mg in bottles of 30;
250 mg in bottles of 30; and 500 mg in bottles of 30 and Single Unit Packages of 50 (intended
for institutional use only).
Famvir 125 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side
and “125” on the other.
125 mg 30’s ..................................................................................................NDC 0078-0366-15
Famvir 250 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side
and “250” on the other.
250 mg 30’s ..................................................................................................NDC 0078-0367-15
Famvir 500 mg tablet:
White, oval film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and
“500” on the other.
500 mg 30’s ..................................................................................................NDC 0078-0368-15
500 mg SUP 50’s..........................................................................................NDC 0078-0368-64
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
REV: JULY 2006
T2006-71
Distributed by:
Novartis Pharmaceuticals Corp.
East Hanover, NJ 07936
©Novartis
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020363s027s028lbl.pdf', 'application_number': 20363, 'submission_type': 'SUPPL ', 'submission_number': 27}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
WELLBUTRIN SR safely and effectively. See full prescribing
information for WELLBUTRIN SR.
WELLBUTRIN SR (bupropion hydrochloride) Sustained-Release
Tablets, for oral use
Initial U.S. Approval: 1985
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
See full prescribing information for complete boxed warning.
Increased risk of suicidal thinking and behavior in children,
adolescents and young adults taking antidepressants. (5.1)
Monitor for worsening and emergence of suicidal thoughts and
behaviors. (5.1)
Serious neuropsychiatric events have been reported in patients
taking bupropion for smoking cessation. (5.2)
--------------------------- RECENT MAJOR CHANGES ---------------------------
Warnings and Precautions (5.7)
mm/2014
----------------------------INDICATIONS AND USAGE ----------------------------
WELLBUTRIN SR is an aminoketone antidepressant, indicated for the
treatment of major depressive disorder (MDD). (1)
----------------------- DOSAGE AND ADMINISTRATION -----------------------
Starting dose: 150 mg per day (2.1)
General: Increase dose gradually to reduce seizure risk. (2.1, 5.3)
After 3 days, may increase the dose to 300 mg per day, given as 150 mg
twice daily at an interval of at least 8 hours. (2.1)
Usual target dose: 300 mg per day as 150 mg twice daily. (2.1)
Maximum dose: 400 mg per day, given as 200 mg twice daily, for
patients not responding to 300 mg per day. (2.1)
Periodically reassess the dose and need for maintenance treatment. (2.1)
Moderate to severe hepatic impairment: 100 mg daily or 150 mg every
other day. (2.2, 8.7)
Mild hepatic impairment: Consider reducing the dose and/or frequency of
dosing. (2.2, 8.7)
Renal impairment: Consider reducing the dose and/or frequency. (2.3,
8.6)
---------------------DOSAGE FORMS AND STRENGTHS ---------------------
Tablets: 100 mg, 150 mg, 200 mg. (3)
------------------------------- CONTRAINDICATIONS-------------------------------
Seizure disorder. (4, 5.3)
Current or prior diagnosis of bulimia or anorexia nervosa. (4, 5.3)
Abrupt discontinuation of alcohol, benzodiazepines, barbiturates,
antiepileptic drugs. (4, 5.3)
Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to
treat psychiatric disorders with WELLBUTRIN SR or within 14 days of
stopping treatment with WELLBUTRIN SR. Do not use WELLBUTRIN
SR within 14 days of stopping an MAOI intended to treat psychiatric
disorders. In addition, do not start WELLBUTRIN SR in a patient who is
being treated with linezolid or intravenous methylene blue. (4, 7.6)
Known hypersensitivity to bupropion or other ingredients of
WELLBUTRIN SR. (4, 5.8)
----------------------- WARNINGS AND PRECAUTIONS -----------------------
Seizure risk: The risk is dose-related. Can minimize risk by gradually
increasing the dose and limiting daily dose to 400 mg. Discontinue if
seizure occurs. (4, 5.3, 7.3)
Hypertension: WELLBUTRIN SR can increase blood pressure. Monitor
blood pressure before initiating treatment and periodically during
treatment. (5.4)
Activation of mania/hypomania: Screen patients for bipolar disorder and
monitor for these symptoms. (5.5)
Psychosis and other neuropsychiatric reactions: Instruct patients to
contact a healthcare professional if such reactions occur. (5.6)
Angle-closure glaucoma: Angle-closure glaucoma has occurred in
patients with untreated anatomically narrow angles treated with
antidepressants. (5.7)
------------------------------ ADVERSE REACTIONS ------------------------------
Most common adverse reactions (incidence ≥5% and ≥2% more than placebo
rate) are: headache, dry mouth, nausea, insomnia, dizziness, pharyngitis,
constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitation,
myalgia, sweating, rash, and anorexia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS -------------------------------
CYP2B6 inducers: Dose increase may be necessary if coadministered
with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz,
carbamazepine, phenobarbital, and phenytoin) based on clinical response,
but should not exceed the maximum recommended dose. (7.1)
Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can
increase concentrations of: antidepressants (e.g., venlafaxine,
nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline),
antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers
(e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone,
flecainide). Consider dose reduction when using with bupropion. (7.2)
Drugs that lower seizure threshold: Dose WELLBUTRIN SR with
caution. (5.3, 7.3)
Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur
when used concomitantly with WELLBUTRIN SR. (7.4)
MAOIs: Increased risk of hypertensive reactions can occur when used
concomitantly with WELLBUTRIN SR. (7.6)
Drug-laboratory test interactions: WELLBUTRIN SR can cause false-
positive urine test results for amphetamines. (7.7)
----------------------- USE IN SPECIFIC POPULATIONS -----------------------
Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: month/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
2.2
Dose Adjustment in Patients With Hepatic Impairment
2.3 Dose Adjustment in Patients With Renal Impairment
2.4
Switching a Patient To or From a Monoamine Oxidase
Inhibitor (MAOI) Antidepressant
2.5
Use of WELLBUTRIN SR With Reversible MAOIs
Such as Linezolid or Methylene Blue
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children,
Adolescents, and Young Adults
5.2
Neuropsychiatric Symptoms and Suicide Risk in
Smoking Cessation Treatment
5.3
Seizure
5.4
Hypertension
5.5
Activation of Mania/Hypomania
5.6
Psychosis and Other Neuropsychiatric Reactions
5.7
Angle-Closure Glaucoma
5.8
Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN SR
7.2
Potential for WELLBUTRIN SR to Affect Other Drugs
7.3
Drugs That Lower Seizure Threshold
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
7.5
Use With Alcohol
7.6
MAO Inhibitors
1
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.7
Drug-Laboratory Test Interactions
10.2 Overdosage Management
8
USE IN SPECIFIC POPULATIONS
11 DESCRIPTION
8.1
Pregnancy
12 CLINICAL PHARMACOLOGY
8.3
Nursing Mothers
12.1 Mechanism of Action
8.4
Pediatric Use
12.3 Pharmacokinetics
8.5
Geriatric Use
13 NONCLINICAL TOXICOLOGY
8.6
Renal Impairment
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
8.7
Hepatic Impairment
14 CLINICAL STUDIES
9
DRUG ABUSE AND DEPENDENCE
16 HOW SUPPLIED/STORAGE AND HANDLING
9.1
Controlled Substance
17 PATIENT COUNSELING INFORMATION
9.2
Abuse
*Sections or subsections omitted from the full prescribing information are not
10 OVERDOSAGE
listed.
10.1 Human Overdose Experience
FULL PRESCRIBING INFORMATION
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC
REACTIONS
SUICIDALITY AND ANTIDEPRESSANT DRUGS
Antidepressants increased the risk of suicidal thoughts and behavior in children,
adolescents, and young adults in short-term trials. These trials did not show an increase in
the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24;
there was a reduction in risk with antidepressant use in subjects aged 65 and older [see
Warnings and Precautions (5.1)].
In patients of all ages who are started on antidepressant therapy, monitor closely for
worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
caregivers of the need for close observation and communication with the prescriber [see
Warnings and Precautions (5.1)].
NEUROPSYCHIATRIC REACTIONS IN PATIENTS TAKING BUPROPION FOR
SMOKING CESSATION
Serious neuropsychiatric reactions have occurred in patients taking bupropion for
smoking cessation [see Warnings and Precautions (5.2)]. The majority of these reactions
occurred during bupropion treatment, but some occurred in the context of discontinuing
treatment. In many cases, a causal relationship to bupropion treatment is not certain,
because depressed mood may be a symptom of nicotine withdrawal. However, some of the
cases occurred in patients taking bupropion who continued to smoke. Although
WELLBUTRIN® SR is not approved for smoking cessation, observe all patients for
neuropsychiatric reactions. Instruct the patient to contact a healthcare provider if such
reactions occur [see Warnings and Precautions (5.2)].
1
INDICATIONS AND USAGE
WELLBUTRIN SR (bupropion hydrochloride) is indicated for the treatment of major
depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of bupropion in the treatment of a major depressive episode was established
in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult
subjects with MDD [see Clinical Studies (14)].
2
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
[see Clinical Studies (14)].
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
To minimize the risk of seizure, increase the dose gradually [see Warnings and
Precautions (5.3)]. WELLBUTRIN SR Tablets should be swallowed whole and not crushed,
divided, or chewed. WELLBUTRIN SR may be taken with or without food.
The usual adult target dose for WELLBUTRIN SR is 300 mg per day, given as 150 mg
twice daily. Initiate dosing with 150 mg per day given as a single daily dose in the morning.
After 3 days of dosing, the dose may be increased to the 300-mg-per-day target dose, given as
150 mg twice daily. There should be an interval of at least 8 hours between successive doses. A
maximum of 400 mg per day, given as 200 mg twice daily, may be considered for patients in
whom no clinical improvement is noted after several weeks of treatment at 300 mg per day. To
avoid high peak concentrations of bupropion and/or its metabolites, do not exceed 200 mg in any
single dose.
It is generally agreed that acute episodes of depression require several months or longer
of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether
the dose of WELLBUTRIN SR needed for maintenance treatment is identical to the dose that
provided an initial response. Periodically reassess the need for maintenance treatment and the
appropriate dose for such treatment.
2.2
Dose Adjustment in Patients With Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
maximum dose of WELLBUTRIN SR is 100 mg per day or 150 mg every other day. In patients
with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or
frequency of dosing [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
2.3 Dose Adjustment in Patients With Renal Impairment
Consider reducing the dose and/or frequency of WELLBUTRIN SR in patients with renal
impairment (Glomerular Filtration Rate <90 mL/min) [see Use in Specific Populations (8.6),
Clinical Pharmacology (12.3)].
2.4
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI)
Antidepressant
At least 14 days should elapse between discontinuation of an MAOI intended to treat
depression and initiation of therapy with WELLBUTRIN SR. Conversely, at least 14 days
should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant
[see Contraindications (4), Drug Interactions (7.6)].
2.5
Use of WELLBUTRIN SR With Reversible MAOIs Such as Linezolid or
Methylene Blue
3
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not start WELLBUTRIN SR in a patient who is being treated with a reversible MAOI
such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of
hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric
condition, non-pharmacological interventions, including hospitalization, should be considered
[see Contraindications (4), Drug Interactions (7.6)].
In some cases, a patient already receiving therapy with WELLBUTRIN SR may require
urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential benefits of
linezolid or intravenous methylene blue treatment are judged to outweigh the risks of
hypertensive reactions in a particular patient, WELLBUTRIN SR should be stopped promptly,
and linezolid or intravenous methylene blue can be administered. The patient should be
monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene
blue, whichever comes first. Therapy with WELLBUTRIN SR may be resumed 24 hours after
the last dose of linezolid or intravenous methylene blue.
The risk of administering methylene blue by non-intravenous routes (such as oral tablets
or by local injection) or in intravenous doses much lower than 1 mg/kg with WELLBUTRIN SR
is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction
with such use [see Contraindications (4), Drug Interactions (7.6)].
3
DOSAGE FORMS AND STRENGTHS
100 mg – blue, round, biconvex, film-coated, sustained-release tablets printed with
“WELLBUTRIN SR 100”.
150 mg – purple, round, biconvex, film-coated, sustained-release tablets printed with
“WELLBUTRIN SR 150”.
200 mg – light pink, round, biconvex, film-coated, sustained-release tablets printed with
“WELLBUTRIN SR 200”.
4
CONTRAINDICATIONS
WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia
or anorexia nervosa as a higher incidence of seizures was observed in such patients treated
with the immediate-release formulation of bupropion [see Warnings and Precautions (5.3)].
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and
Precautions (5.3), Drug Interactions (7.3)].
The use of MAOIs (intended to treat psychiatric disorders) concomitantly with
WELLBUTRIN SR or within 14 days of discontinuing treatment with WELLBUTRIN SR is
contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN
SR is used concomitantly with MAOIs. The use of WELLBUTRIN SR within 14 days of
discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN SR
in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is
4
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
contraindicated [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.4),
Drug Interactions (7.6)].
WELLBUTRIN SR is contraindicated in patients with known hypersensitivity to bupropion
or other ingredients of WELLBUTRIN SR. Anaphylactoid/anaphylactic reactions and
Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.8)].
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young
Adults
Patients with MDD, both adult and pediatric, may experience worsening of their
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early
phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective
serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to
24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase
in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24;
there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
subjects. There was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger subjects for almost all drugs studied. There were differences in
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs. placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of cases of
suicidality per 1,000 subjects treated) are provided in Table 1.
5
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled
Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1,000 Subjects Treated
Increases Compared With Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared With Placebo
25-64
1 fewer case
65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality, and
unusual changes in behavior, especially during the initial few months of a course of drug
therapy, or at times of dose changes, either increases or decreases [see Boxed Warning].
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or
other indications, both psychiatric and nonpsychiatric, should be alerted about the need to
monitor patients for the emergence of agitation, irritability, unusual changes in behavior,
and the other symptoms described above, as well as the emergence of suicidality, and to
report such symptoms immediately to healthcare providers. Such monitoring should
include daily observation by families and caregivers. Prescriptions for WELLBUTRIN SR
should be written for the smallest quantity of tablets consistent with good patient
management, in order to reduce the risk of overdose.
6
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment
WELLBUTRIN SR is not approved for smoking cessation treatment; however, ZYBAN®
is approved for this use. Serious neuropsychiatric symptoms have been reported in patients
taking bupropion for smoking cessation. These have included changes in mood (including
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt,
and completed suicide [see Boxed Warning, Adverse Reactions (6.2)]. Observe patients for the
occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if
such reactions occur.
In many of these cases, a causal relationship to bupropion treatment is not certain,
because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases
occurred in patients taking bupropion who continued to smoke.
5.3
Seizure
WELLBUTRIN SR can cause seizure. The risk of seizure is dose-related. The dose
should not exceed 400 mg per day. Increase the dose gradually. Discontinue WELLBUTRIN SR
and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant
medications that lower the seizure threshold. Consider these risks before initiating treatment with
WELLBUTRIN SR. WELLBUTRIN SR is contraindicated in patients with a seizure disorder,
current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation
of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4),
Drug Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe
head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke;
concomitant use of other medications that lower the seizure threshold (e.g., other bupropion
products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids);
metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and
hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as
CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral
hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol,
benzodiazepines, sedative/hypnotics, or opiates.
Incidence of Seizure With Bupropion Use: When WELLBUTRIN SR is dosed up to
300 mg per day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to
approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.
The risk of seizure can be reduced if the dose of WELLBUTRIN SR does not exceed
400 mg per day, given as 200 mg twice daily, and the titration rate is gradual.
5.4
Hypertension
Treatment with WELLBUTRIN SR can result in elevated blood pressure and
hypertension. Assess blood pressure before initiating treatment with WELLBUTRIN SR, and
monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN
7
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SR is used concomitantly with MAOIs or other drugs that increase dopaminergic or
noradrenergic activity [see Contraindications (4)].
Data from a comparative trial of the sustained-release formulation of bupropion HCl,
nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS,
and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent
hypertension in patients treated with the combination of sustained-release bupropion and NTS. In
this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS
had treatment-emergent hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated
with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects
had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of
sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study
medication discontinued due to hypertension compared with none of the subjects treated with
sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in
patients who receive the combination of bupropion and nicotine replacement.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive
heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing
hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no
controlled trials assessing the safety of bupropion in patients with a recent history of myocardial
infarction or unstable cardiac disease.
5.5
Activation of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode.
The risk appears to be increased in patients with bipolar disorder or who have risk factors for
bipolar disorder. Prior to initiating WELLBUTRIN SR, screen patients for a history of bipolar
disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar
disorder, suicide, or depression). WELLBUTRIN SR is not approved for use in treating bipolar
depression.
5.6
Psychosis and Other Neuropsychiatric Reactions
Depressed patients treated with WELLBUTRIN SR have had a variety of
neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis,
concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of
bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal
of treatment. Instruct patients to contact a healthcare professional if such reactions occur.
5.7
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including
WELLBUTRIN SR may trigger an angle-closure attack in a patient with anatomically narrow
angles who does not have a patent iridectomy.
5.8
Hypersensitivity Reactions
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion.
Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring
medical treatment. In addition, there have been rare, spontaneous postmarketing reports of
8
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with
bupropion. Instruct patients to discontinue WELLBUTRIN SR and consult a healthcare provider
if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives,
chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like
symptoms suggestive of delayed hypersensitivity.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning,
Warnings and Precautions (5.1)]
Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed
Warning, Warnings and Precautions (5.2)]
Seizure [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Activation of mania or hypomania [see Warnings and Precautions (5.5)]
Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6)]
Angle-closure glaucoma [see Warnings and Precautions (5.7)]
Hypersensitivity reactions [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Leading to Discontinuation of Treatment: In placebo-controlled
clinical trials, 4%, 9%, and 11% of the placebo, 300-mg-per-day, and 400-mg-per-day groups,
respectively, discontinued treatment due to adverse reactions. The specific adverse reactions
leading to discontinuation in at least 1% of the 300-mg-per-day or 400-mg-per-day groups and at
a rate at least twice the placebo rate are listed in Table 2.
Table 2. Treatment Discontinuations Due to Adverse Reactions in Placebo-Controlled
Trials
WELLBUTRIN SR
WELLBUTRIN SR
Placebo
300 mg/day
400 mg/day
Adverse Reaction
(n = 385)
(n = 376)
(n = 114)
Rash
0.0%
2.4%
0.9%
Nausea
0.3%
0.8%
1.8%
Agitation
0.3%
0.3%
1.8%
Migraine
0.3%
0.0%
1.8%
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Commonly Observed Adverse Reactions: Adverse reactions from Table 3 occurring
in at least 5% of subjects treated with WELLBUTRIN SR and at a rate at least twice the placebo
rate are listed below for the 300- and 400-mg-per-day dose groups.
WELLBUTRIN SR 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus,
and tremor.
WELLBUTRIN SR 400 mg per day: Abdominal pain, agitation, anxiety, dizziness,
dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
frequency.
Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported
adverse reactions were classified using a COSTART-based Dictionary.
Table 3. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater
Frequency Than Placebo in Controlled Clinical Trials
Body System/
Adverse Reaction
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
Arthralgia
2%
1%
6%
4%
3%
1%
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Arthritis
Twitch
0%
1%
2%
2%
0%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous system
2%
1%
1%
stimulation
Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Blurred vision or
diplopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal hemorrhagea
0%
2%
—
Urinary tract infection
1%
0%
—
a Incidence based on the number of female subjects.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects.
Other Adverse Reactions Observed During the Clinical Development of
Bupropion: In addition to the adverse reactions noted above, the following adverse reactions
have been reported in clinical trials with the sustained-release formulation of bupropion in
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depressed subjects and in nondepressed smokers, as well as in clinical trials with the
immediate-release formulation of bupropion.
Adverse reaction frequencies represent the proportion of subjects who experienced a
treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for
depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse
reaction requiring discontinuation of treatment in an open-label surveillance trial with
WELLBUTRIN SR (n = 3,100). All treatment-emergent adverse reactions are included except
those listed in Table 3, those listed in other safety-related sections of the prescribing information,
those subsumed under COSTART terms that are either overly general or excessively specific so
as to be uninformative, those not reasonably associated with the use of the drug, and those that
were not serious and occurred in fewer than 2 subjects.
Adverse reactions are further categorized by body system and listed in order of
decreasing frequency according to the following definitions of frequency: Frequent adverse
reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions
are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than
1/1,000 subjects.
Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was
malaise.
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
vasodilation. Rare were syncope and myocardial infarction.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.
Hemic and Lymphatic: Infrequent was ecchymosis.
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
Musculoskeletal: Infrequent were leg cramps.
Nervous System: Infrequent were abnormal coordination, decreased libido,
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.
Respiratory: Rare was bronchospasm.
Special Senses: Infrequent were accommodation abnormality and dry eye.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder.
Changes in Body Weight: In placebo-controlled trials, subjects experienced weight
gain or weight loss as shown in Table 4.
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Table 4. Incidence of Weight Gain and Weight Loss (≥5 lbs.) in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
Lost >5 lbs
3%
14%
2%
19%
4%
6%
In clinical trials conducted with the immediate-release formulation of bupropion, 35% of
subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated
with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of
a patient’s depressive illness, the anorectic and/or weight-reducing potential of
WELLBUTRIN SR should be considered.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
WELLBUTRIN SR and are not described elsewhere in the label. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Body (General): Arthralgia, myalgia, and fever with rash and other symptoms
suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see
Warnings and Precautions (5.8)].
Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension,
hypertension (in some cases severe), phlebitis, and pulmonary embolism.
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis,
intestinal perforation, pancreatitis, and stomach ulcer.
Endocrine: Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic
hormone.
Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy,
pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with
hemorrhagic or thrombotic complications, were observed when bupropion was coadministered
with warfarin.
Metabolic and Nutritional: Glycosuria.
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia,
aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria,
extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction,
neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive
dyskinesia.
Respiratory: Pneumonia.
Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson
syndrome.
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Special Senses: Deafness, increased intraocular pressure, and mydriasis.
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia,
menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
7
DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN SR
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the
potential exists for drug interactions between WELLBUTRIN SR and drugs that are inhibitors or
inducers of CYP2B6.
Inhibitors of CYP2B6: Ticlopidine and Clopidogrel: Concomitant treatment with these
drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on
clinical response, dosage adjustment of WELLBUTRIN SR may be necessary when
coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical
Pharmacology (12.3)].
Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment
with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of
WELLBUTRIN SR may be necessary when coadministered with ritonavir, lopinavir, or
efavirenz [see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended
dose.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see
Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may
be necessary to increase the dose of bupropion, but the maximum recommended dose should not
be exceeded.
7.2
Potential for WELLBUTRIN SR to Affect Other Drugs
Drugs Metabolized by CYP2D6: Bupropion and its metabolites
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors.
Therefore, coadministration of WELLBUTRIN SR with drugs that are metabolized by CYP2D6
can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain
antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine,
and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g.,
metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used
concomitantly with WELLBUTRIN SR, it may be necessary to decrease the dose of these
CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen)
theoretically could have reduced efficacy when administered concomitantly with inhibitors of
CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN SR and such
drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].
7.3
Drugs That Lower Seizure Threshold
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Use extreme caution when coadministering WELLBUTRIN SR with other drugs that
lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants,
theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually
[see Contraindications (4), Warnings and Precautions (5.3)].
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has
been reported when bupropion was coadministered with levodopa or amantadine. Adverse
reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and
dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use
caution when administering WELLBUTRIN SR concomitantly with these drugs.
7.5
Use With Alcohol
In postmarketing experience, there have been rare reports of adverse neuropsychiatric
events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with
WELLBUTRIN SR. The consumption of alcohol during treatment with WELLBUTRIN SR
should be minimized or avoided.
7.6
MAO Inhibitors
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of
MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive
reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that
the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days
should elapse between discontinuation of an MAOI intended to treat depression and initiation of
treatment with WELLBUTRIN SR. Conversely, at least 14 days should be allowed after
stopping WELLBUTRIN SR before starting an MAOI antidepressant [see Dosage and
Administration (2.4, 2.5), Contraindications (4)].
7.7
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for amphetamines have been reported
in patients taking bupropion. This is due to lack of specificity of some screening tests. False-
positive test results may result even following discontinuation of bupropion therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion
from amphetamines.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary: Data from epidemiological studies of pregnant women exposed to
bupropion in the first trimester indicate no increased risk of congenital malformations overall.
All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major
malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity
was found in reproductive developmental studies conducted in rats and rabbits; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
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observed at doses approximately equal to the maximum recommended human dose (MRHD) and
greater and decreased fetal weights were seen at doses twice the MRHD and greater.
WELLBUTRIN SR should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Clinical Considerations: Consider the risks of untreated depression when discontinuing
or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data: Data from the international bupropion Pregnancy Registry (675 first
trimester exposures) and a retrospective cohort study using the United Healthcare database
(1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after
bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular
malformations in pregnancies with exposure to bupropion in the first trimester from the
international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
maternal bupropion exposures), which is similar to the background rate of cardiovascular
malformations (approximately 1%). Data from the United Healthcare database and a case-control
study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular
malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an
increased risk for cardiovascular malformations overall after bupropion exposure during the first
trimester.
Study findings on bupropion exposure during the first trimester and risk for left
ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions
regarding a possible association. The United Healthcare database lacked sufficient power to
evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk
for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular
septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible
association. The Slone Epidemiology Study found an increased risk for VSD following first
trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not
find increased risk for any other cardiovascular malformations studied (including LVOTO as
above). The NBDPS and United Healthcare database study did not find an association between
first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of
exposed cases, inconsistent findings among studies, and the potential for chance findings from
multiple comparisons in case control studies.
Animal Data: In studies conducted in rats and rabbits, bupropion was administered
orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis). No clear evidence of
teratogenic activity was found in either species; however, in rabbits, slightly increased incidences
of fetal malformations and skeletal variations were observed at the lowest dose tested (25
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mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal
weights were observed at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
and lactation, there were no apparent adverse effects on offspring development.
8.3
Nursing Mothers
Bupropion and its metabolites are present in human milk. In a lactation study of 10
women, levels of orally dosed bupropion and its active metabolites were measured in expressed
milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion
and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when
WELLBUTRIN SR is administered to a nursing woman.
8.4
Pediatric Use
Safety and effectiveness in the pediatric population have not been established [see Boxed
Warning, Warnings and Precautions (5.1)].
8.5
Geriatric Use
Of the approximately 6,000 subjects who participated in clinical trials with bupropion
sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and
47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in
clinical trials using the immediate-release formulation of bupropion (depression trials). No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects. Reported clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients
with impaired renal function. Because elderly patients are more likely to have decreased renal
function, it may be necessary to consider this factor in dose selection; it may be useful to monitor
renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), Clinical
Pharmacology (12.3)].
8.6
Renal Impairment
Consider a reduced dose and/or dosing frequency of WELLBUTRIN SR in patients with
renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are
cleared renally and may accumulate in such patients to a greater extent than usual. Monitor
closely for adverse reactions that could indicate high bupropion or metabolite exposures [see
Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
maximum dose of WELLBUTRIN SR is 100 mg per day or 150 mg every other day. In patients
with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or
frequency of dosing [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
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9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
Bupropion is not a controlled substance.
9.2
Abuse
Humans: Controlled clinical trials of bupropion (immediate-release formulation)
conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in
depressed subjects showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg
of bupropion produced mild amphetamine-like activity as compared with placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential
of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be significantly
reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be
tested because of the risk of seizure) might be modestly attractive to those who abuse CNS
stimulant drugs.
Animals: Studies in rodents and primates demonstrated that bupropion exhibits some
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding
in several schedule-controlled behavior paradigms. In primate models assessing the positive
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
10
OVERDOSAGE
10.1 Human Overdose Experience
Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was
reported in approximately one-third of all cases. Other serious reactions reported with overdoses
of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG
changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever,
muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been
reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
in these patients.
10.2 Overdosage Management
18
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Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone
numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR).
Call 1-800-222-1222 or refer to www.poison.org.
There are no known antidotes for bupropion. In case of an overdose, provide supportive
care, including close medical supervision and monitoring. Consider the possibility of multiple
drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm
and vital signs. Induction of emesis is not recommended.
11
DESCRIPTION
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone
class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or
other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is
related to phenylethylamines. It is designated as ()-1-(3-chlorophenyl)-2-[(1,1
dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular
formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly
soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral
mucosa. The structural formula is: structural formula
WELLBUTRIN SR is supplied for oral administration as 100-mg (blue), 150-mg
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the
100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The exact mechanism of the antidepressant action of bupropion is not known, but is
presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a
relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not
inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.
12.3 Pharmacokinetics
Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of
the individual enantiomers have not been studied. The mean elimination half-life (SD) of
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bupropion after chronic dosing is 21 (9) hours, and steady-state plasma concentrations of
bupropion are reached within 8 days.
Absorption: The absolute bioavailability of WELLBUTRIN SR in humans has not been
determined because an intravenous formulation for human use is not available. However, it
appears likely that only a small proportion of any orally administered dose reaches the systemic
circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to
20%.
In humans, following oral administration of WELLBUTRIN SR, peak plasma
concentration (Cmax) of bupropion is usually achieved within 3 hours.
In a trial comparing chronic dosing with WELLBUTRIN SR 150 mg twice daily to
bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for
bupropion after WELLBUTRIN SR administration was approximately 85% of those achieved
after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion
was equivalent for both formulations. Bioequivalence was also demonstrated for all three major
active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion)
for both Cmax and AUC. Thus, at steady state, WELLBUTRIN SR given twice daily, and the
immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for
both bupropion and the 3 quantitatively important metabolites.
WELLBUTRIN SR can be taken with or without food. Bupropion Cmax and AUC was
increased by 11% to 35% and 16% to 19%, respectively, when WELLBUTRIN SR was
administered with food to healthy volunteers in three trials. The food effect is not considered
clinically significant.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins
at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion; whereas, the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are
active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of
bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion,
which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is
the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450
enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion
side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is
then excreted as the major urinary metabolite. The potency and toxicity of the metabolites
relative to bupropion have not been fully characterized. However, it has been demonstrated in an
antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion,
while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion.
This may be of clinical importance because the plasma concentrations of the metabolites are as
high as or higher than those of bupropion.
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Following a single dose administration of WELLBUTRIN SR in humans, Cmax of
hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the
peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is
approximately 20 (5) hours and its AUC at steady state is about 17 times that of bupropion. The
times to peak concentrations for the erythrohydrobupropion and threohydrobupropion
metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination
half-lives are longer, 33(10) and 37 (13) hours, respectively, and steady-state AUCs are 1.5
and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of
300 to 450 mg per day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87%
and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5%
of the oral dose was excreted as unchanged bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
be expected to influence the degree and extent of accumulation of the active metabolites of
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
renal or hepatic function because they are moderately polar compounds and are likely to undergo
further metabolism or conjugation in the liver prior to urinary excretion.
Renal Impairment: There is limited information on the pharmacokinetics of
bupropion in patients with renal impairment. An inter-trial comparison between normal subjects
and subjects with end-stage renal failure demonstrated that the parent drug Cmax and AUC values
were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage
renal failure. A second trial, comparing normal subjects and subjects with moderate-to-severe
renal impairment (GFR 30.9 10.8 mL/min), showed that after a single 150-mg dose of
sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects
with impaired renal function, while levels of the hydroxybupropion and
threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is
extensively metabolized in the liver to active metabolites, which are further metabolized and
subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion
may be reduced by impaired renal function. WELLBUTRIN SR should be used with caution in
patients with renal impairment and a reduced frequency and/or dose should be considered [see
Use in Specific Populations (8.6)].
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of
bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease
and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half-life of
hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in
8 healthy volunteers (32 14 hours versus 21 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
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greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
for bupropion and the other metabolites in the 2 groups were minimal.
The second trial demonstrated no statistically significant differences in the
pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild–to-moderate
hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in
some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active
metabolites (t½) in subjects with mild–to-moderate hepatic cirrhosis. In subjects with severe
hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites
were seen (Table 5).
Table 5. Pharmacokinetics of Bupropion and Metabolites in Patients With Severe Hepatic
Cirrhosis: Ratio Relative to Healthy Matched Controls
Cmax
AUC
t½
Tmax
a
Bupropion
1.69
3.12
1.43
0.5 h
Hydroxybupropion
0.31
1.28
3.88
19 h
Threo/erythrohydrobupropion
amino alcohol
0.69
2.48
1.96
20 h
a = Difference.
Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14
depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-
ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites,
compared with healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have
not been fully characterized, but an exploration of steady-state bupropion concentrations from
several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day,
on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are
at increased risk for accumulation of bupropion and its metabolites [see Use in Specific
Populations (8.5)].
Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male
and 90 healthy female volunteers revealed no sex-related differences in the peak plasma
concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13%
higher in male volunteers compared with female volunteers. The clinical significance of this
finding is unknown.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion
were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and
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17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
were no statistically significant differences in Cmax, half-life, Tmax, AUC, or clearance of
bupropion or its active metabolites between smokers and nonsmokers.
Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN SR: In vitro
studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6.
Therefore, the potential exists for drug interactions between WELLBUTRIN SR and drugs that
are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine,
sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.
Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male
volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures
(Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for
ticlopidine, respectively. The exposures (Cmax and AUC) of hydroxybupropion were decreased
50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This
effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.
Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects,
prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and
decreased Cmax and AUC values of hydroxybupropion, an active metabolite of bupropion, by
32% and 24%, respectively.
Cimetidine: The threohydrobupropion metabolite of bupropion does not appear
to be produced by cytochrome P450 enzymes. The effects of concomitant administration of
cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24
healthy young male volunteers. Following oral administration of bupropion 300 mg with and
without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were
unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of
the combined moieties of threohydrobupropion and erythrohydrobupropion.
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its
three metabolites.
Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial,
ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%,
respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the
threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and
the Cmax of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion
metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the
erythrohydrobupropion decreased by 68%.
In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily
decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were
decreased by 50% and 31%, respectively.
Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for
2 weeks reduced the AUC and Cmax of bupropion by approximately 55% and 34%, respectively.
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The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was
increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
these drugs may induce the metabolism of bupropion.
Potential for WELLBUTRIN SR to Affect Other Drugs: Animal data indicated that
bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following
chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14
days, there was no evidence of induction of its own metabolism. Nevertheless, there may be
potential for clinically important alterations of blood levels of co-administered drugs.
Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a
clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of
CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased
the Cmax, AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold,
respectively. The effect was present for at least 7 days after the last dose of bupropion.
Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally
studied.
Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in
one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.
Lamotrigine: Multiple oral doses of bupropion had no statistically significant
effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up
to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the
MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular
proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the
MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such
lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions
were not seen in the mouse study, and no increase in malignant tumors of the liver and other
organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of
5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in
chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
fertility.
14
CLINICAL STUDIES
The efficacy of the immediate-release formulation of bupropion in the treatment of major
depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients
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with MDD (Trials 1 and 2 in Table 6) and in one 6-week, placebo-controlled trial in adult
outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range of bupropion was 300
mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of
300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate-release
formulation of bupropion by the Hamilton Depression Rating Scale (HDRS) total score, the
HDRS depressed mood item (item 1), and the Clinical Global Impressions severity score (CGI
S). The second trial included 2 doses of the immediate-release formulation of bupropion (300
and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the
immediate-release formulation of bupropion, but only at the 450-mg-per-day dose. The efficacy
results were significant for the HDRS total score and the CGI-S score, but not for HDRS item 1.
In the third trial, outpatients were treated with 300 mg per day of the immediate-release
formulation of bupropion. This trial demonstrated the efficacy of the immediate-release
formulation of bupropion as measured by the HDRS total score, the HDRS item 1, the
Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-
Improvement Scale (CGI-I) score.
Table 6. Efficacy of Immediate-Release Bupropion for the Treatment of Major Depressive
Disorder
Primary Efficacy Measure: HDRS
LS Mean Score at
Placebo-subtracted
Trial
Mean Baseline
Endpoint Visit
Differencea (95%
Number
Treatment Group
Score (SD)
(SE)
CI)
Trial 1
Immediate-Release
28.5 (5.1)
14.9 (1.3)
-4.7 (-8.8, -0.6)
Bupropion 300
600 mg/dayb
(n = 48)
Placebo (n = 27)
29.3 (7.0)
19.6 (1.6)
--
Mean Baseline
Score (SD)
LS Mean Change
from Baseline (SE)
Placebo-subtracted
Differencea (95%
CI)
Trial 2
Immediate-Release
32.4 (5.9)
-15.5 (1.7)
-4.1
Bupropion 300
mg/day (n = 36)
Immediate-Release
34.8 (4.6)
-17.4 (1.7)
-5.9 (-10.5, -1.4)
Bupropion 450
mg/dayb (n = 34)
Placebo (n = 39)
32.9 (5.4)
-11.5 (1.6)
--
Trial 3
Immediate-Release
26.5 (4.3)
-12.0 (NA)
-3.9 (-5.7, -1.0)
Bupropion 300
mg/dayb (n = 110)
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Placebo (n = 106)
27.0 (3.5)
-8.7 (NA)
--
n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI:
unadjusted confidence interval included for doses that were demonstrated to be effective; NA:
not available.
a Difference (drug minus placebo) in least-squares estimates with respect to the primary efficacy
parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2 and 3, it
refers to the mean change from baseline to the endpoint visit.
b Doses that are demonstrated to be statistically significantly superior to placebo.
Although there are not as yet independent trials demonstrating the antidepressant
effectiveness of the sustained-release formulation of bupropion, trials have demonstrated the
bioequivalence of the immediate-release and sustained-release forms of bupropion under
steady-state conditions, i.e., bupropion sustained-release 150 mg twice daily was shown to be
bioequivalent to 100 mg 3 times daily of the immediate-release formulation of bupropion, with
regard to both rate and extent of absorption, for parent drug and metabolites.
In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder,
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
twice daily) were randomized to continuation of their same dose of WELLBUTRIN SR or
placebo for up to 44 weeks of observation for relapse. Response during the open phase was
defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of
the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s
judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving
continued treatment with WELLBUTRIN SR experienced significantly lower relapse rates over
the subsequent 44 weeks compared with those receiving placebo.
16
HOW SUPPLIED/STORAGE AND HANDLING
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are
blue, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
(NDC 0173-0947-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
purple, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 150” in bottles of
60 (NDC 0173-0135-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are
light pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles
of 60 (NDC 0173-0722-00) tablets.
Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between
15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from light
and moisture.
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17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated
with treatment with WELLBUTRIN SR and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other
Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking
Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or
Actions,” and “What Other Important Information Should I Know About WELLBUTRIN SR?”
is available for WELLBUTRIN SR. Instruct patients, their families, and their caregivers to read
the Medication Guide and assist them in understanding its contents. Patients should be given the
opportunity to discuss the contents of the Medication Guide and to obtain answers to any
questions they may have. The complete text of the Medication Guide is reprinted at the end of
this document.
Advise patients regarding the following issues and to alert their prescriber if these occur
while taking WELLBUTRIN SR.
Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their
caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
early during antidepressant treatment and when the dose is adjusted up or down. Advise families
and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis,
since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or
healthcare professional, especially if they are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk
for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it contains the
same active ingredient as ZYBAN which is approved for this use. Advise patients, families and
caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal
symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness.
Some patients have experienced changes in mood (including depression and mania), psychosis,
hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as
suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while
taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking
or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they
should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and
to discontinue WELLBUTRIN SR if they have a severe allergic reaction.
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Seizure: Instruct patients to discontinue and not restart WELLBUTRIN SR if they
experience a seizure while on treatment. Advise patients that the excessive use or abrupt
discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can
increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.
As the dose is increased during initial titration to doses above 150 mg per day, instruct
patients to take WELLBUTRIN SR in 2 divided doses, preferably with at least 8 hours between
successive doses, to minimize the risk of seizures.
Angle-Closure Glaucoma: Patients should be advised that taking WELLBUTRIN SR
can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of
angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because
angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-
angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be
examined to determine whether they are susceptible to angle closure, and have a prophylactic
procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.7)].
Bupropion-Containing Products: Educate patients that WELLBUTRIN SR contains
the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid
to smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination
with ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN®, the
immediate-release formulation and WELLBUTRIN XL® or FORFIVO XL™, the extended-
release formulations, and APLENZIN®, the extended-release formulation of bupropion
hydrobromide). In addition, there are a number of generic bupropion HCl products for the
immediate-, sustained-, and extended-release formulations.
Potential for Cognitive and Motor Impairment: Advise patients that any CNS-active
drug like WELLBUTRIN SR may impair their ability to perform tasks requiring judgment or
motor and cognitive skills. Advise patients that until they are reasonably certain that
WELLBUTRIN SR does not adversely affect their performance, they should refrain from driving
an automobile or operating complex, hazardous machinery. WELLBUTRIN SR may lead to
decreased alcohol tolerance.
Concomitant Medications: Counsel patients to notify their healthcare provider if they
are taking or plan to take any prescription or over-the-counter drugs because WELLBUTRIN SR
Sustained-Release Tablets and other drugs may affect each others’ metabolisms.
Pregnancy: Advise patients to notify their healthcare provider if they become pregnant
or intend to become pregnant during therapy.
Precautions for Nursing Mothers: Advise patients that WELLBUTRIN SR is present
in human milk in small amounts.
Storage Information: Instruct patients to store WELLBUTRIN SR at room temperature,
between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.
Administration Information: Instruct patients to swallow WELLBUTRIN SR Tablets
whole so that the release rate is not altered. Do not chew, divide, or crush tablets; they are
designed to slowly release drug in the body. When patients take more than 150 mg per day,
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instruct them to take WELLBUTRIN SR in 2 doses at least 8 hours apart, to minimize the risk of
seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the
missed dose and to take the next tablet at the regular time because of the dose-related risk of
seizure. Instruct patients that WELLBUTRIN SR Tablets may have an odor. WELLBUTRIN SR
can be taken with or without food.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of the GSK group of companies. The other brands listed are trademarks of their
respective owners and are not trademarks of the GSK group of companies. The makers of these
brands are not affiliated with and do not endorse the GSK group of companies or its products. company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
©2014, the GSK group of companies. All rights reserved.
WLS:XXPI
MEDICATION GUIDE
WELLBUTRIN® SR (WELL byu-trin)
(bupropion hydrochloride) Sustained-Release Tablets
Read this Medication Guide carefully before you start taking WELLBUTRIN SR and
each time you get a refill. There may be new information. This information does not
take the place of talking with your healthcare provider about your medical condition
or your treatment. If you have any questions about WELLBUTRIN SR, ask your
healthcare provider or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide.
The first section is about the risk of suicidal thoughts and actions with
antidepressant medicines; the second section is about the risk of changes
in thinking and behavior, depression and suicidal thoughts or actions with
medicines used to quit smoking; and the third section is entitled “What
Other Important Information Should I Know About WELLBUTRIN SR?”
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Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of suicidal thoughts and
actions with antidepressant medicines. Talk to your healthcare provider or your
family member’s healthcare provider about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental illness
What is the most important information I should know about
antidepressant medicines, depression and other serious mental illnesses,
and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in
some children, teenagers, or young adults within the first few months of
treatment.
2. Depression or other serious mental illnesses are the most important
causes of suicidal thoughts and actions. Some people may have a
particularly high risk of having suicidal thoughts or actions. These include
people who have (or have a family history of) bipolar illness (also called manic-
depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in
myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
Call your healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call your healthcare provider right away if you or your family member has
any of the following symptoms, especially if they are new, worse, or worry
you:
thoughts about suicide or dying
trouble sleeping (insomnia)
attempts to commit suicide
new or worse irritability
new or worse depression
acting aggressive, being angry, or violent
new or worse anxiety
acting on dangerous impulses
feeling very agitated or restless
an extreme increase in activity and talking (mania)
30
Reference ID: 3594816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
panic attacks
other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
Never stop an antidepressant medicine without first talking to a
healthcare provider. Stopping an antidepressant medicine suddenly can cause
other symptoms.
Antidepressants are medicines used to treat depression and other
illnesses. It is important to discuss all the risks of treating depression and also
the risks of not treating it. Patients and their families or other caregivers should
discuss all treatment choices with the healthcare provider, not just the use of
antidepressants.
Antidepressant medicines have other side effects. Talk to the healthcare
provider about the side effects of the medicine prescribed for you or your family
member.
Antidepressant medicines can interact with other medicines. Know all of
the medicines that you or your family member takes. Keep a list of all medicines
to show the healthcare provider. Do not start new medicines without first
checking with your healthcare provider.
It is not known if WELLBUTRIN SR is safe and effective in children under the age of
18.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and
Behavior, Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking
and behavior, depression and suicidal thoughts or actions with drugs used to quit
smoking.
Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the
same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help
patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression, suicidal
thoughts or actions while taking bupropion to help them quit smoking. These
31
Reference ID: 3594816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
symptoms can develop during treatment with bupropion or after stopping treatment
with bupropion.
If you, your family member, or your caregiver notice agitation, hostility,
depression, or changes in thinking or behavior that are not typical for you, or you
have any of the following symptoms, stop taking bupropion and call your healthcare
provider right away:
thoughts about suicide or dying
an extreme increase in activity and talking
attempts to commit suicide
(mania)
new or worse depression
abnormal thoughts or sensations
new or worse anxiety
seeing or hearing things that are not there
panic attacks
(hallucinations)
feeling very agitated or restless
feeling people are against you (paranoia)
acting aggressive, being angry, or
feeling confused
violent
other unusual changes in behavior or mood
acting on dangerous impulses
When you try to quit smoking, with or without bupropion, you may have symptoms
that may be due to nicotine withdrawal, including urge to smoke, depressed mood,
trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty
concentrating, restlessness, decreased heart rate, and increased appetite or weight
gain. Some people have even experienced suicidal thoughts when trying to quit
smoking without medication. Sometimes quitting smoking can lead to worsening of
mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had
depression or other mental illnesses. You should also tell your healthcare provider
about any symptoms you had during other times you tried to quit smoking, with or
without bupropion.
What Other Important Information Should I Know About WELLBUTRIN SR?
Seizures: There is a chance of having a seizure (convulsion, fit) with
WELLBUTRIN SR, especially in people:
with certain medical problems.
who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN SR.
For more information, see the sections “Who should not take WELLBUTRIN SR?”
32
Reference ID: 3594816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
and “What should I tell my healthcare provider before taking WELLBUTRIN SR?”
Tell your healthcare provider about all of your medical conditions and all the
medicines you take. Do not take any other medicines while you are taking
WELLBUTRIN SR unless your healthcare provider has said it is okay to
take them.
If you have a seizure while taking WELLBUTRIN SR, stop taking the
tablets and call your healthcare provider right away. Do not take
WELLBUTRIN SR again if you have a seizure.
High blood pressure (hypertension). Some people get high blood
pressure, that can be severe, while taking WELLBUTRIN SR. The chance
of high blood pressure may be higher if you also use nicotine replacement
therapy (such as a nicotine patch) to help you stop smoking.
Manic episodes. Some people may have periods of mania while taking
WELLBUTRIN SR, including:
Greatly increased energy
Severe trouble sleeping
Racing thoughts
Reckless behavior
Unusually grand ideas
Excessive happiness or irritability
Talking more or faster than usual
If you have any of the above symptoms of mania, call your healthcare provider.
Unusual thoughts or behaviors. Some patients have unusual thoughts or
behaviors while taking WELLBUTRIN, including delusions (believe you are
someone else), hallucinations (seeing or hearing things that are not there),
paranoia (feeling that people are against you), or feeling confused. If this
happens to you, call your healthcare provider.
Visual problems.
eye pain
changes in vision
swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an
eye examination to see if you are at risk and receive preventative treatment if
you are.
Severe allergic reactions. Some people can have severe allergic
reactions to WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your
healthcare provider right away if you get a rash, itching, hives, fever,
swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
33
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the lips or tongue, chest pain, or have trouble breathing. These could be signs of
a serious allergic reaction.
What is WELLBUTRIN SR?
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type
of depression called major depressive disorder.
Who should not take WELLBUTRIN SR?
Do not take WELLBUTRIN SR if you
have or had a seizure disorder or epilepsy.
have or had an eating disorder such as anorexia nervosa or bulimia.
are taking any other medicines that contain bupropion, ZYBAN (used to
help people stop smoking) APLENZIN®, FORFIVO XL™, WELLBUTRIN®, or
WELLBUTRIN XL® . Bupropion is the same active ingredient that is in
WELLBUTRIN SR.
drink a lot of alcohol and abruptly stop drinking, or use medicines called
sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines,
and you stop using them all of a sudden.
take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
do not take an MAOI within 2 weeks of stopping WELLBUTRIN SR unless
directed to do so by your healthcare provider.
do not start WELLBUTRIN SR if you stopped taking an MAOI in the last 2
weeks unless directed to do so by your healthcare provider.
are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of
the inactive ingredients. See the end of this Medication Guide for a complete list
of ingredients in WELLBUTRIN SR.
What should I tell my healthcare provider before taking WELLBUTRIN SR?
Tell your healthcare provider if you have ever had depression, suicidal thoughts or
actions, or other mental health problems. See “Antidepressant Medicines,
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”
Tell your healthcare provider about your other medical conditions including
if you:
have liver problems, especially cirrhosis of the liver.
have kidney problems.
have, or have had, an eating disorder, such as anorexia nervosa or bulimia.
have had a head injury.
34
Reference ID: 3594816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
have had a seizure (convulsion, fit).
have a tumor in your nervous system (brain or spine).
have had a heart attack, heart problems, or high blood pressure.
are a diabetic taking insulin or other medicines to control your blood sugar.
drink alcohol.
abuse prescription medicines or street drugs.
are pregnant or plan to become pregnant.
are breastfeeding. WELLBUTRIN passes into your milk in small amounts.
Tell your healthcare provider about all the medicines you take, including
prescription, over-the-counter medicines, vitamins, and herbal supplements.
Many medicines increase your chances of having seizures or other serious side
effects if you take them while you are taking WELLBUTRIN SR.
How should I take WELLBUTRIN SR?
Take WELLBUTRIN SR exactly as prescribed by your healthcare provider.
Swallow WELLBUTRIN SR Tablets whole. Do not chew, cut, or crush
WELLBUTRIN SR Tablets. If you do, the medicine will be released into your
body too quickly. If this happens you may be more likely to get side effects
including seizures. Tell your healthcare provider if you cannot swallow
tablets.
Take WELLBUTRIN SR at the same time each day.
Take your doses of WELLBUTRIN SR at least 8 hours apart.
You may take WELLBUTRIN SR with or without food.
If you miss a dose, do not take an extra dose to make up for the dose you
missed. Wait and take your next dose at the regular time. This is very
important. Too much WELLBUTRIN SR can increase your chance of having a
seizure.
If you take too much WELLBUTRIN SR, or overdose, call your local emergency
room or poison control center right away.
Do not take any other medicines while taking WELLBUTRIN SR unless
your healthcare provider has told you it is okay.
If you are taking WELLBUTRIN SR for the treatment of major depressive
disorder, it may take several weeks for you to feel that WELLBUTRIN SR is
working. Once you feel better, it is important to keep taking WELLBUTRIN SR
exactly as directed by your healthcare provider. Call your healthcare provider if
you do not feel WELLBUTRIN SR is working for you.
Do not change your dose or stop taking WELLBUTRIN SR without talking with
your healthcare provider first.
35
Reference ID: 3594816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I avoid while taking WELLBUTRIN SR?
Limit or avoid using alcohol during treatment with WELLBUTRIN SR. If you
usually drink a lot of alcohol, talk with your healthcare provider before suddenly
stopping. If you suddenly stop drinking alcohol, you may increase your chance
of having seizures.
Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR
affects you. WELLBUTRIN SR can affect your ability to do these things safely.
What are possible side effects of WELLBUTRIN SR?
See “What Other Important Information Should I Know About
WELLBUTRIN SR?”
WELLBUTRIN SR can cause serious side effects.
The most common side effects of WELLBUTRIN SR include:
Headache
Dry mouth
Nausea
Trouble sleeping
Dizziness
Sore throat
Constipation
If you have nausea, take your medicine with food. If you have trouble sleeping, do
not take your medicine too close to bedtime.
Tell your healthcare provider right away about any side effects that bother you.
These are not all the possible side effects of WELLBUTRIN SR. 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.
You may also report side effects to GlaxoSmithKline at 1-888-825-5249.
How should I store WELLBUTRIN SR?
Store WELLBUTRIN SR at room temperature between 59°F and 86°F (15°C to
30°C).
Keep WELLBUTRIN SR dry and out of the light.
WELLBUTRIN SR Tablets may have an odor.
36
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Keep WELLBUTRIN SR and all medicines out of the reach of children.
General Information about WELLBUTRIN SR.
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use WELLBUTRIN SR for a condition for which it was not
prescribed. Do not give WELLBUTRIN SR to other people, even if they have the
same symptoms you have. It may harm them.
If you take a urine drug screening test, WELLBUTRIN SR may make the test result
positive for amphetamines. If you tell the person giving you the drug screening test
that you are taking WELLBUTRIN SR, they can do a more specific drug screening
test that should not have this problem.
This Medication Guide summarizes important information about WELLBUTRIN SR. If
you would like more information, talk with your healthcare provider. You can ask
your healthcare provider or pharmacist for information about WELLBUTRIN SR that
is written for healthcare professionals.
For more information about WELLBUTRIN SR, go to www.wellbutrin.com or call 1
888-825-5249.
What are the ingredients in WELLBUTRIN SR?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80,
and titanium dioxide. In addition, the 100-mg tablet contains FD&C Blue No. 1
Lake, the 150-mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake,
and the 200-mg tablet contains FD&C Red No. 40 Lake. The tablets are printed with
edible black ink.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of the GSK group of companies. The other brands listed are
trademarks of their respective owners and are not trademarks of the GSK group of
companies. The makers of these brands are not affiliated with and do not endorse
the GSK group of companies or its products.
37
Reference ID: 3594816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
Research Triangle Park, NC 27709
©2014, the GSK group of companies. All rights reserved.
Month 2014
WLS:XXMG
38
Reference ID: 3594816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:31.725592
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020358s056lbl.pdf', 'application_number': 20358, 'submission_type': 'SUPPL ', 'submission_number': 56}
|
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|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
FAMVIR® safely and effectively. See full prescribing information for
FAMVIR.
FAMVIR(famciclovir) tablets
Initial U.S. Approval: 1994
--------------INDICATIONS AND USAGE---------------------
FAMVIR, a prodrug of penciclovir, is a nucleoside analogue DNA
polymerase inhibitor indicated for:
Immunocompetent Adult Patients (1.1)
• Herpes labialis (cold sores)
• Genital herpes
o Treatment of recurrent episodes
o Suppressive therapy of recurrent episodes
• Herpes zoster (shingles)
HIV-Infected Adult Patients (1.2)
• Treatment of recurrent episodes of orolabial or genital herpes
Limitation of Use (1.3)
The efficacy and safety of FAMVIR have not been established for:
• Patients <18 years of age
• Immunocompromised patients other than for the treatment of recurrent
episodes of orolabial or genital herpes in HIV-infected patients
------------DOSAGE AND ADMINISTRATION-------------
Immunocompetent Adult Patients (2.1)
Herpes labialis (cold sores)
1500 mg as a single dose
Genital herpes
Treatment of recurrent episodes
Suppressive therapy
1000 mg twice daily for 1 day
250 mg twice daily
Herpes zoster (shingles)
500 mg every 8 hours for 7 days
HIV-Infected Adult Patients (2.2)
Recurrent episodes of orolabial or genital
herpes
500 mg twice daily for 7 days
Patients with renal impairment: Adjust dose based on creatinine clearance (2.3)
-----------DOSAGE FORMS AND STRENGTHS------------
Tablets: 125 mg, 250 mg, 500 mg (3)
---------------------CONTRAINDICATIONS-------------------
Known hypersensitivity to the product, its components, or Denavir
(penciclovir cream) (4)
---------------WARNINGS AND PRECAUTIONS-----------
Acute renal failure: May occur in patients with underlying renal disease who
receive higher than recommended doses of FAMVIR for their level of renal
function. Reduce dosage in patients with renal impairment (2.3, 8.6)
-------------------ADVERSE REACTIONS----------------------
The most common adverse events reported in at least one indication by >10%
of adult patients are headache and nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA
1088 or www.fda.gov/medwatch.
-------------------DRUG INTERACTIONS----------------------
Probenecid: May increase penciclovir levels. Monitor for evidence of
penciclovir toxicity (7.2)
-------------------USE IN SPECIFIC POPULATIONS----------------------
Nursing mothers: Caution should be exercised when administered to a nursing
woman (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 12/2009
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Immunocompetent Adult Patients
1.2 HIV-Infected Adult Patients
1.3 Limitation of Use
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Recommendation in Immunocompetent Adult Patients
2.2 Dosing Recommendation in HIV-Infected Adult Patients
2.3 Dosing Recommendation in Patients with Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience in Adult Patients
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Patients with Renal Impairment
8.7 Patients with Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Virology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal toxicology
14 CLINICAL STUDIES
14.1 Herpes Labialis (Cold Sores)
14.2 Genital Herpes
14.3 Recurre t Orolabial or Genital Herpes in HIV-Infected
n
Patients
14.4 Herpes Zoster (Shingles)
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Herpes Labialis (Cold Sores)
17.2 Genital Herpes
17.3 Herpes Zoster (Shingles)
* Sections or subsections omitted from the full prescribing
information are not listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Immunocompetent Adult Patients
Herpes labialis (cold sores): FAMVIR is indicated for the treatment of recurrent herpes labialis.
Genital herpes:
Recurrent episodes: FAMVIR is indicated for the treatment of recurrent episodes of genital herpes. The efficacy
of FAMVIR when initiated more than 6 hours after onset of symptoms or lesions has not been established.
Suppressive therapy: FAMVIR is indicated for chronic suppressive therapy of recurrent episodes of genital
herpes. The efficacy and safety of FAMVIR for the suppression of recurrent genital herpes beyond 1 year have not been
established.
Herpes zoster (shingles): FAMVIR is indicated for the treatment of herpes zoster. The efficacy of FAMVIR when
initiated more than 72 hours after onset of rash has not been established.
1.2 HIV-Infected Adult Patients
Recurrent orolabial or genital herpes: FAMVIR is indicated for the treatment of recurrent episodes of orolabial or
genital herpes in HIV-infected adults. The efficacy of FAMVIR when initiated more than 48 hours after onset of
symptoms or lesions has not been established.
1.3 Limitation of Use
The efficacy and safety of FAMVIR have not been established for:
• Patients <18 years of age
• Patients with first episode of genital herpes
• Patients with ophthalmic zoster
• Immunocompromised patients other than for the treatment of recurrent orolabial or genital herpes in HIV-
infected patients
2 DOSAGE AND ADMINISTRATION
FAMVIR may be taken with or without food.
2.1 Dosing Recommendation in Immunocompetent Adult Patients
Herpes labialis (cold sores): The recommended dosage of FAMVIR for the treatment of recurrent herpes labialis
is 1500 mg as a single dose. Therapy should be initiated at the first sign or symptom of herpes labialis (e.g., tingling,
itching, burning, pain, or lesion).
Genital herpes:
Recurrent episodes: The recommended dosage of FAMVIR for the treatment of recurrent episodes of genital
herpes is 1000 mg twice daily for 1 day. Therapy should be initiated at the first sign or symptom of a recurrent episode
(e.g., tingling, itching, burning, pain, or lesion).
Suppressive therapy: The recommended dosage of FAMVIR for chronic suppressive therapy of recurrent
episodes of genital herpes is 250 mg twice daily.
Herpes zoster (shingles): The recommended dosage of FAMVIR for the treatment of herpes zoster is 500 mg
every 8 hours for 7 days. Therapy should be initiated as soon as herpes zoster is diagnosed.
2.2 Dosing Recommendation in HIV-Infected Adult Patients
Recurrent orolabial or genital herpes: The recommended dosage of FAMVIR for the treatment of recurrent
orolabial or genital herpes in HIV-infected patients is 500 mg twice daily for 7 days. Therapy should be initiated at the
first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).
2.3 Dosing Recommendation in Patients with Renal Impairment
Dosage recommendations for adult patients with renal impairment are provided in Table 1 [see Use in Specific
Populations (8.6), Clinical Pharmacology (12.3)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Dosage Recommendations for Adult Patients with Renal Impairment
Indication and Normal Dosage
Creatinine Clearance
Adjusted Dosage
Regimen
(mL/min.)
Regimen Dose (mg)
Dosing Interval
Single-Day Dosing Regimens
Recurrent Genital Herpes
1000 mg every 12 hours for 1 day
≥60
1000
every 12 hours for 1 day
40-59
500
every 12 hours for 1 day
20-39
500
single dose
<20
250
single dose
HD*
250
single dose following
dialysis
Recurrent Herpes Labialis
1500 mg single dose
≥60
1500
single dose
40-59
750
single dose
20-39
500
single dose
<20
250
single dose
HD*
250
single dose following
dialysis
Multiple-Day Dosing Regimens
Herpes Zoster
500 mg every 8 hours
≥60
500
every 8 hours
40-59
500
every 12 hours
20-39
500
every 24 hours
<20
250
every 24 hours
HD*
250
following each dialysis
Suppression of Recurrent
Genital Herpes
250 mg every 12 hours
≥40
250
every 12 hours
20-39
125
every 12 hours
<20
125
every 24 hours
HD*
125
following each dialysis
Recurrent Orolabial
or Genital Herpes
in HIV-Infected Patients
500 mg every 12 hours
≥40
500
every 12 hours
20-39
500
every 24 hours
<20
250
every 24 hours
HD*
250
following each dialysis
*Hemodialysis
3 DOSAGE FORMS AND STRENGTHS
FAMVIR tablets are available in three strengths:
• 125 mg : White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and
“125” on the other side
• 250 mg: White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and
“250” on the other side
• 500 mg: White, oval film-coated, biconvex, debossed with “FAMVIR” on one side and “500” on the other
side
4 CONTRAINDICATIONS
FAMVIR is contraindicated in patients with known hypersensitivity to the product, its components, or Denavir®
(penciclovir cream).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
Acute renal failure: Cases of acute renal failure have been reported in patients with underlying renal disease who
have received inappropriately high doses of FAMVIR for their level of renal function. Dosage reduction is recommended
when administering FAMVIR to patients with renal impairment [see Dosage and Administration (2.3), Use in Specific
Populations (8.6)].
6 ADVERSE REACTIONS
Acute renal failure is discussed in greater detail in other sections of the label [see Warnings and Precautions (5)].
The most common adverse events reported in at least 1 indication by >10% of adult patients treated with
FAMVIR are headache and nausea.
6.1 Clinical Trials Experience in Adult Patients
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the
rates observed in practice.
Immunocompetent patients: The safety of FAMVIR has been evaluated in active- and placebo-controlled clinical
studies involving 816 FAMVIR-treated patients with herpes zoster (FAMVIR, 250 mg three times daily to 750 mg three
times daily); 163 FAMVIR-treated patients with recurrent genital herpes (FAMVIR, 1000 mg twice daily); 1,197 patients
with recurrent genital herpes treated with FAMVIR as suppressive therapy (125 mg once daily to 250 mg three times
daily) of which 570 patients received FAMVIR (open-labeled and/or double-blind) for at least 10 months; and 447
FAMVIR-treated patients with herpes labialis (FAMVIR, 1500 mg once or 750 mg twice daily). Table 2 lists selected
adverse events.
Table 2
Selected Adverse Events (all grades and without regard to causality) Reported by ≥ 2% of Patients
in Placebo-Controlled Famvir Trials*
Incidence
Events
Herpes Zoster†
Recurrent
Genital Herpes‡
Genital Herpes-
Suppression§
Herpes Labialis‡
Famvir
(n=273)
%
Placebo
(n=146)
%
Famvir
(n=163)
%
Placebo
(n=166)
%
Famvir
(n=458)
%
Placebo
(n=63)
%
Famvir
(n=447)
%
Placebo
(n=254)
%
Nervous System
Headache
22.7
17.8
13.5
5.4
39.3
42.9
8.5
6.7
Paresthesia
2.6
0.0
0.0
0.0
0.9
0.0
0.0
0.0
Migraine
0.7
0.7
0.6
0.6
3.1
0.0
0.2
0.0
Gastrointestinal
Nausea
12.5
11.6
2.5
3.6
7.2
9.5
2.2
3.9
Diarrhea
7.7
4.8
4.9
1.2
9.0
9.5
1.6
0.8
Vomiting
4.8
3.4
1.2
0.6
3.1
1.6
0.7
0.0
Flatulence
1.5
0.7
0.6
0.0
4.8
1.6
0.2
0.0
Abdominal Pain
1.1
3.4
0.0
1.2
7.9
7.9
0.2
0.4
Body as a Whole
Fatigue
4.4
3.4
0.6
0.0
4.8
3.2
1.6
Skin and Appendages
Pruritus
3.7
2.7
0.0
0.6
2.2
0.0
0.0
0.0
Rash
0.4
0.7
0.0
0.0
3.3
1.6
0.0
0.0
Reproductive (Female)
Dysmenorrhea
0.0
0.7
1.8
0.6
7.6
6.3
0.4
*Patients may have entered into more than one clinical trial.
†7 days of treatment
‡1 day of treatment
§daily treatment
0.4
0.0
This label may not be the latest approved by FDA.
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Table 3 lists selected laboratory abnormalities in genital herpes suppression trials.
Table 3
Selected Laboratory Abnormalities in Genital Herpes Suppression Studies*
Parameter
Famvir
Placebo
(n = 660)
†
(n = 210)
†
%
%
Anemia (<0.8 x NRL)
0.1
0.0
Leukopenia (<0.75 x NRL)
1.3
0.9
Neutropenia (<0.8 x NRL)
3.2
1.5
AST (SGOT) (>2 x NRH)
2.3
1.2
ALT (SGPT) (>2 x NRH)
3.2
1.5
Total Bilirubin (>1.5 x NRH)
1.9
1.2
Serum Creatinine (>1.5 x NRH)
0.2
0.3
Amylase (>1.5 x NRH)
1.5
1.9
Lipase (>1.5 x NRH)
4.9
4.7
*Percentage of patients with laboratory abnormalities that were increased or decreased from baseline and were outside of specified ranges.
†n values represent the minimum number of patients assessed for each laboratory parameter.
NRH = Normal Range High.
NRL = Normal Range Low.
HIV-infected patients: In HIV-infected patients, the most frequently reported adverse events for FAMVIR (500
mg twice daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (17% vs. 15%), nausea (11%
vs. 13%), diarrhea (7% vs. 11%), vomiting (5% vs. 4%), fatigue (4% vs. 2%), and abdominal pain (3% vs. 6%).
6.2 Postmarketing Experience
The adverse events listed below have been reported during post-approval use of FAMVIR. Because these 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:
Blood and lymphatic system disorders: Thrombocytopenia
Hepatobiliary disorders: Abnormal liver function tests, cholestatic jaundice
Nervous system disorders: Dizziness, somnolence
Psychiatric disorders: Confusion (including delirium, disorientation, and confusional state occurring
predominantly in the elderly), hallucinations
Skin and subcutaneous tissue disorders: Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic
epidermal necrolysis
7 DRUG INTERACTIONS
7.1 Potential for FAMVIR to Affect Other Drugs
The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of
famciclovir (500 mg three times daily). No clinically significant effect on the pharmacokinetics of zidovudine, its
metabolite zidovudine glucuronide, or emtricitabine was observed following a single oral dose of 500 mg famciclovir co
administered with zidovudine or emtricitabine.
An in vitro study using human liver microsomes suggests that famciclovir is not an inhibitor of CYP3A4
enzymes.
7.2 Potential for Other Drugs to Affect Penciclovir
No clinically significant alterations in penciclovir pharmacokinetics were observed following single-dose
administration of 500 mg famciclovir after pre-treatment with multiple doses of allopurinol, cimetidine, theophylline,
zidovudine, promethazine, when given shortly after an antacid (magnesium and aluminum hydroxide), or concomitantly
with emtricitabine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose
(three times daily) administration of famciclovir (500 mg) with multiple doses of digoxin.
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Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may
result in increased plasma concentrations of penciclovir.
The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other
drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of
famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the
formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of
penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between
penciclovir and raloxifene has not been conducted.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy category B: After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug).
There are no adequate and well-controlled studies of famciclovir or penciclovir use in pregnant women. No adverse
effects on embryofetal development were observed in animal reproduction studies using famciclovir and penciclovir at
doses higher than the maximum recommended human dose (MRHD) and human exposure. Because animal reproduction
studies are not always predictive of human response, famciclovir should be used during pregnancy only if needed.
In animal reproduction studies, pregnant rats and rabbits received oral famciclovir at doses (up to 1000
mg/kg/day) that provided 2.7 to 10.8 times (rats) and 1.4 to 5.4 times (rabbits) the human systemic exposure based on
AUC. No adverse effects were observed on embryo-fetal development. In other studies, pregnant rats and rabbits received
intravenous famciclovir at doses (360 mg/kg/day) 1.5 to 6 times (rats) and (120 mg/kg/day) 1.1 to 4.5 times (rabbits) or
penciclovir at doses (80/mg/kg/day) 0.3 to 1.3 times (rats) and (60 mg/kg/day) 0.5 to 2.1 times (rabbits) the MRHD based
on body surface area comparisons. No adverse effects were observed on embryo-fetal development.
Pregnancy exposure reporting: To monitor maternal-fetal outcomes of pregnant women exposed to FAMVIR,
Novartis Pharmaceuticals Corporation maintains a FAMVIR Pregnancy Reporting system. Physicians are encouraged to
report their patients by calling 1-888-NOW-NOVA (669-6682).
8.3 Nursing Mothers
It is not known whether famciclovir (prodrug) or penciclovir (active drug) are excreted in human milk. Following
oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than
those seen in the plasma. There are no data on the safety of FAMVIR in infants. FAMVIR should not be used in nursing
mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.
8.4 Pediatric Use
The efficacy and safety of FAMVIR tablets have not been established in pediatric patients. The pharmacokinetic
profile and safety of famciclovir experimental granules mixed with OraSweet® were studied in two open-label studies.
Study 1 was a single-dose pharmacokinetic and safety study in infants 1 month to <1 year of age who had an
active herpes simplex virus (HSV) infection or who were at risk for HSV infection. Eighteen subjects were enrolled and
received a single dose of famciclovir experimental granules mixed with OraSweet® based on the patient’s body weight
(doses ranged from 25 mg to 175 mg). These doses were selected to provide penciclovir systemic exposures similar to the
penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. The efficacy and safety of
famciclovir have not been established as suppressive therapy in infants following neonatal HSV infections. In addition,
the efficacy cannot be extrapolated from adults to infants because there is no similar disease in adults. Therefore,
famciclovir is not recommended in infants.
Study 2 was an open-label, single-dose pharmacokinetic, multiple-dose safety study of famciclovir experimental
granules mixed with OraSweet® in children 1 to <12 years of age with clinically suspected HSV or varicella zoster virus
(VZV) infection. Fifty-one subjects were enrolled in the pharmacokinetic part of the study and received a single body
weight adjusted dose of famciclovir (doses ranged from 125 mg to 500 mg). These doses were selected to provide
penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of
500 mg famciclovir. Based on the pharmacokinetic data observed with these doses in children, a new weight-based dosing
algorithm was designed and used in the multiple-dose safety part of the study. Pharmacokinetic data were not obtained
with the revised weight-based dosing algorithm.
A total of 100 patients were enrolled in the multiple-dose safety part of the study; 47 subjects with active or latent
HSV infection and 53 subjects with chickenpox. Patients with active or latent HSV infection received famciclovir twice a
day for seven days. The daily dose of famciclovir ranged from 150 mg to 500 mg twice daily depending on the patient’s
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body weight. Patients with chickenpox received famciclovir three times daily for seven days. The daily dose of
famciclovir ranged from 150 mg to 500 mg three times daily depending on the patient’s body weight. The clinical adverse
events and laboratory test abnormalities observed in this study were similar to these seen in adults. The available data are
insufficient to support the use of famciclovir for the treatment of children with chickenpox or infections due to HSV for
the following reasons:
Chickenpox: The efficacy of famciclovir for the treatment of chickenpox has not been established in either
pediatric or adult patients. Famciclovir is approved for the treatment of herpes zoster in adult patients. However,
extrapolation of efficacy data from adults with herpes zoster to children with chickenpox would not be
appropriate. Although chickenpox and herpes zoster are caused by the same virus, the diseases are different.
Genital herpes: Clinical information on genital herpes in children is limited. Therefore, efficacy data from adults
cannot be extrapolated to this population. Further, famciclovir has not been studied in children 1 to <12 years of
age with recurrent genital herpes. None of the children in Study 2 had genital herpes.
Herpes labialis: There are no pharmacokinetic and safety data in children to support a famciclovir dose that
provides penciclovir systemic exposures comparable to the penciclovir systemic exposures in adults after a single
dose administration of 1500 mg.
8.5 Geriatric Use
Of 816 patients with herpes zoster in clinical studies who were treated with FAMVIR, 248 (30.4%) were ≥65
years of age and 103 (13%) were ≥75 years of age. No overall differences were observed in the incidence or types of
adverse events between younger and older patients. Of 610 patients with recurrent herpes simplex (type 1 or type 2) in
clinical studies who were treated with FAMVIR, 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age.
Clinical studies of FAMVIR in patients with recurrent genital herpes did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects.
No famciclovir dosage adjustment based on age is recommended unless renal function is impaired [see Dosage
and Administration (2.3), Clinical Pharmacology (12.3)]. In general, appropriate caution should be exercised in the
administration and monitoring of FAMVIR in elderly patients reflecting the greater frequency of decreased renal function
and concomitant use of other drugs.
8.6 Patients with Renal Impairment
Apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased
linearly with reductions in renal function. After the administration of a single 500-mg famciclovir oral dose (n=27) to
healthy volunteers and to volunteers with varying degrees of renal impairment (CLCR ranged from 6.4 to 138.8 mL/min),
the following results were obtained (Table 4):
Table 4
Pharmacokinetic Parameters of Penciclovir in Subjects with Different Degrees of Renal
Impairment
Parameter
(mean ± S.D.)
CLCR
† ≥60
(mL/min)
(n=15)
CLCR 40-59
(mL/min)
(n=5)
CLCR 20-39
(mL/min)
(n=4)
CLCR <20
(mL/min)
(n=3)
CLCR (mL/min)
88.1 ± 20.6
49.3 ± 5.9
26.5 ± 5.3
12.7 ± 5.9
CLR (L/hr)
30.1 ± 10.6
13.0 ± 1.3‡
4.2 ± 0.9
1.6 ± 1.0
CL/F§ (L/hr)
66.9 ± 27.5
27.3 ± 2.8
12.8 ± 1.3
5.8 ± 2.8
Half-life (hr)
2.3 ± 0.5
3.4 ± 0.7
6.2 ± 1.6
13.4 ± 10.2
† CLCR is measured creatinine clearance.
‡ n=4.
§ CL/F consists of bioavailability factor and famciclovir to penciclovir conversion factor.
In a multiple-dose study of famciclovir conducted in subjects with varying degrees of renal impairment (n=18),
the pharmacokinetics of penciclovir were comparable to those after single doses.
A dosage adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].
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8.7 Patients with Hepatic Impairment
Well-compensated chronic liver disease (chronic hepatitis [n=6], chronic ethanol abuse [n=8], or primary biliary
cirrhosis [n=1]) had no effect on the extent of availability (AUC) of penciclovir following a single dose of 500-mg
famciclovir. However, there was a 44% decrease in penciclovir mean maximum plasma concentration (Cmax) and the time
to maximum plasma concentration (tmax) was increased by 0.75 hours in patients with hepatic impairment compared to
normal volunteers. No dosage adjustment is recommended for patients with well compensated hepatic impairment. The
pharmacokinetics of penciclovir have not been evaluated in patients with severe uncompensated hepatic impairment.
10 OVERDOSAGE
Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis.
11 DESCRIPTION
The active ingredient in FAMVIR tablets is famciclovir, an orally administered prodrug of the antiviral agent
penciclovir. Chemically, famciclovir is known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. Its
molecular formula is C14H19N5O4; its molecular weight is 321.3. It is a synthetic acyclic guanine derivative and has the
following structure Structural Formula
Famciclovir is a white to pale yellow solid. It is freely soluble in acetone and methanol, and sparingly soluble in
ethanol and isopropanol. At 25°C famciclovir is freely soluble (>25% w/v) in water initially, but rapidly precipitates as
the sparingly soluble (2%-3% w/v) monohydrate. Famciclovir is not hygroscopic below 85% relative humidity. Partition
coefficients are: octanol/water (pH 4.8) P=1.09 and octanol/phosphate buffer (pH 7.4) P=2.08.
FAMVIR tablets contain 125 mg, 250 mg or 500 mg of famciclovir, together with the following inactive
ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycols,
sodium starch glycolate and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Famciclovir is an orally administered prodrug of the antiviral agent penciclovir [see Clinical Pharmacology
(12.4)].
12.3 Pharmacokinetics
Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral
administration famciclovir undergoes rapid and extensive metabolism to penciclovir and little or no famciclovir is
detected in plasma or urine. Penciclovir is predominantly eliminated unchanged by the kidney. Therefore, the dose of
FAMVIR needs to be adjusted in patients with different degrees of renal impairment [see Dosage and Administration
(2.3)].
Pharmacokinetics in adults:
Absorption and Bioavailability: The absolute bioavailability of penciclovir is 77 ± 8% as determined following
the administration of a 500 mg famciclovir oral dose and a 400 mg penciclovir intravenous dose to 12 healthy male
subjects.
Penciclovir concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 1000 mg
administered as a single dose. Table 5 shows the mean pharmacokinetic parameters of penciclovir after single
administration of FAMVIR to healthy male volunteers.
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Table 5
Mean Pharmacokinetic Parameters of Penciclovir in Healthy Adult Subjects*
Dose
AUC (0-inf)† (mcg hr/mL)
Cmax
‡ (mcg/mL)
Tmax
§ (h)
125 mg
2.24
0.8
0.9
250 mg
4.48
1.6
0.9
500 mg
8.95
3.3
0.9
1000 mg
17.9
6.6
0.9
* Based on pharmacokinetic data from 17 studies
† AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity.
‡ Cmax (mcg/mL)=maximum observed plasma concentration.
§ Tmax (h)= time to Cmax.
Following oral single-dose administration of 500-mg famciclovir to seven patients with herpes zoster, the AUC
(mean ± SD), Cmax, and Tmax were 12.1±1.7 mcg hr/mL, 4.0±0.7 mcg/mL, and 0.7±0.2 hours, respectively. The AUC of
penciclovir was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this
difference may be due to differences in renal function between the two groups.
There is no accumulation of penciclovir after the administration of 500-mg famciclovir three times daily for 7
days.
Penciclovir Cmax decreased approximately 50% and Tmax was delayed by 1.5 hours when a capsule formulation of
famciclovir was administered with food (nutritional content was approximately 910 Kcal and 26% fat). There was no
effect on the extent of availability (AUC) of penciclovir. There was an 18% decrease in Cmax and a delay in Tmax of about
1 hour when famciclovir was given 2 hours after a meal as compared to its administration 2 hours before a meal. Because
there was no effect on the extent of systemic availability of penciclovir, FAMVIR can be taken without regard to meals.
Distribution: The volume of distribution (Vdβ) was 1.08±0.17 L/kg in 12 healthy male subjects following a single
intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion. Penciclovir is <20% bound to
plasma proteins over the concentration range of 0.1 to 20 mcg/mL. The blood/plasma ratio of penciclovir is approximately
1.
Metabolism: Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir.
Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated
penciclovir (5%, <0.5% and <0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or
urine. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important
role in famciclovir metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase.
Cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of
penciclovir in vivo [see Drug Interactions (7.2)].
Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the
dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to
three healthy male volunteers. Penciclovir accounted for 91% of the radioactivity excreted in the urine.
Following the oral administration of a single 500 mg dose of radiolabeled famciclovir to three healthy male
volunteers, 73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively.
Penciclovir accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine.
Approximately 60% of the administered radiolabeled dose was collected in urine in the first 6 hours.
After intravenous administration of penciclovir in 48 healthy male volunteers, mean ± S.D. total plasma clearance
of penciclovir was 36.6±6.3 L/hr (0.48±0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5±8.8% of total
plasma clearance.
Renal clearance of penciclovir following the oral administration of a single 500 mg dose of famciclovir to 109
healthy male volunteers was 27.7±7.6 L/hr. Active tubular secretion contributes to the renal elimination of penciclovir.
The plasma elimination half-life of penciclovir was 2.0±0.3 hours after intravenous administration of penciclovir
to 48 healthy male volunteers and 2.3±0.4 hours after oral administration of 500-mg famciclovir to 124 healthy male
volunteers. The half-life in 17 patients with herpes zoster was 2.8±1.0 hours and 2.7±1.0 hours after single and repeated
doses, respectively.
Special populations:
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Geriatric patients: Based on cross study comparison, penciclovir AUC was 40% higher and penciclovir renal
clearance was 22% lower in elderly subjects (n=18, age 65-79 years) as compared with younger subjects Some of this
difference may be due to differences in renal function between the two groups. No famciclovir dosage adjustment based
on age is recommended unless renal function is impaired [see Dosage and Administration (2.3), Use in Specific
Populations (8.5)].
Patients with renal impairment: In subjects with varying degrees of renal impairment, apparent plasma clearance,
renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal
function, both after single and repeated dosing [see Use Specific Populations (8.6)]. A dosage adjustment is recommended
for patients with renal impairment [see Dosage and Administration (2.3)].
Patients with hepatic impairment: Well-compensated chronic liver disease had no effect on the extent of
availability (AUC) of penciclovir [see Use in Specific Populations (8.7)]. No dosage adjustment is recommended for
patients with well-compensated hepatic impairment.
HIV-infected patients: Following oral administration of a single dose of 500-mg famciclovir to HIV-positive
patients, the pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.
Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18 healthy female volunteers
after single-dose oral administration of 500-mg famciclovir. AUC of penciclovir was 9.3±1.9 mcg hr/mL and 11.1±2.1
mcg hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5±8.9 L/hr and 21.8±4.3 L/hr,
respectively. These differences were attributed to differences in renal function between the two groups. No famciclovir
dosage adjustment based on gender is recommended.
Race: The effect of race on the pharmacokinetics of penciclovir after oral administration of FAMVIR has not
been evaluated.
12.4 Virology
Mechanism of action: Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against
herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1,
HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted
by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir
triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes
viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-
life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture; however, the clinical
significance is unknown.
Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2
and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed
with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for
VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2
µM (range 1.2 to 2.4 µM, n = 7), 2.6 µM (range 1.6 to 11 µM, n = 6), and 34 µM (range 6.7 to 71 µM, n = 6),
respectively.
Resistance: Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thymidine
kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of TK activity (TK
negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug
without an equivalent loss in the ability to phosphorylate thymidine (TK altered). The most commonly encountered
acyclovir resistant mutants that are TK negative are also resistant to penciclovir. The median EC50 values observed in a
plaque reduction assay with penciclovir resistant HSV-1, HSV-2, and VZV were 69 µM (range 14 to 115 µM, n = 6), 46
µM (range 4 to >395 µM, n = 9), and 92 µM (range 51 to 148 µM, n = 4), respectively. The possibility of viral resistance
to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An
increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats
receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral
dose ranging between 2000 mg and 500 mg, based on area under the plasma concentration curve comparisons [24 hr
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AUC] for penciclovir). No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day
(0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).
Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic
potential in a battery of in vitro and in vivo assays. Famciclovir and penciclovir were negative in in vitro tests for gene
mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses
up to 10,000 and 5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse lymphoma assay
(5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg).
Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200
mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations,
with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir caused chromosomal
aberrations in the absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of
micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500
mg/kg), but not when administered orally.
Impairment of fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration
of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count,
and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity to male
reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of
dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect level for sperm and testicular toxicity in
rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6x the human systemic exposure based on
AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26
weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC),
respectively.
Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000
mg/kg/day (2.7 to 10.8x the human AUC).
Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8
week baseline period and recurrent genital herpes receiving oral FAMVIR (250 mg twice daily) (n=66) or placebo (n=64)
therapy for 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment
or during an 8-week follow-up.
13.2 Animal toxicology
Juvenile toxicity study in rats: In juvenile rats, famciclovir was administered daily at doses of 0, 40, 125, or 400
mg/kg/day for 10 weeks beginning on post-partum Day 4. There were no treatment related deaths or clinical observations.
The toxicity of famciclovir was not enhanced in juvenile rats compared to that in the adult animals.
14 CLINICAL STUDIES
14.1 Herpes Labialis (Cold Sores)
A randomized, double-blind, placebo-controlled trial was conducted in 701 immunocompetent adults with
recurrent herpes labialis. Patients self-initiated therapy within 1 hour of first onset of signs or symptoms of a recurrent
herpes labialis episode with FAMVIR1500 mg as a single dose (n=227), FAMVIR 750 mg twice daily (n=220) or placebo
(n=254) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule
stage) was 4.4 days in the FAMVIR 1500 mg single-dose group (n=152) as compared to 6.2 days in the placebo group
(n=168). The median difference in time to healing between the placebo and FAMVIR 1500 mg treated groups was 1.3
days (95% CI: 0.6 – 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule
stage) were observed between patients receiving FAMVIR or placebo: 33% for FAMVIR 1500 mg single dose and 34%
for placebo. The median time to loss of pain and tenderness was 1.7 days in FAMVIR 1500 mg single dose-treated
patients versus 2.9 days in placebo-treated patients.
14.2 Genital Herpes
Recurrent episodes: A randomized, double-blind, placebo-controlled trial was conducted in 329
immunocompetent adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or
symptom of a recurrent genital herpes episode with either FAMVIR 1000 mg twice daily (n=163) or placebo (n=166) for
1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.3
days in FAMVIR-treated patients (n=125) as compared to 6.1 days in placebo-treated patients (n=145). The median
difference in time to healing between the placebo and FAMVIR-treated groups was 1.2 days (95% CI: 0.5 – 2.0). Twenty-
three percent of FAMVIR-treated patients had aborted lesions (no lesion development beyond erythema) versus 13% in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
placebo-treated patients. The median time to loss of all symptoms (e.g., tingling, itching, burning, pain, or tenderness) was
3.3 days in FAMVIR-treated patients vs. 5.4 days in placebo-treated patients.
Suppressive therapy: Two randomized, double-blind, placebo-controlled, 12-month trials were conducted in 934
immunocompetent adults with a history of 6 or more recurrences of genital herpes episodes per year. Comparisons
included FAMVIR 125 mg three times daily, 250 mg twice daily, 250 mg three times daily, and placebo. At 12 months,
60% to 65% of patients were still receiving FAMVIR and 25% were receiving placebo treatment. Recurrence rates at 6
and 12 months in patients treated with the 250 mg twice daily dose are shown in Table 6.
Table 6
Recurrence Rates at 6 and 12 Months in Adults with Recurrent Genital Herpes on Suppressive
Therapy
Recurrence Rates
Recurrence Rates
at 6 Months
at 12 Months
Famvir
Placebo
Famvir
Placebo
250 mg twice daily
250 mg twice daily
(n=236)
(n=233)
(n=236)
(n=233)
Recurrence-free
39%
10%
29%
6%
Recurrences†
47%
74%
53%
78%
Lost to follow-up‡
14%
16%
17%
16%
†Based on patient reported data; not necessarily confirmed by a physician.
‡Patients recurrence-free at time of last contact prior to withdrawal.
FAMVIR-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-
treated patients. Higher doses of FAMVIR were not associated with an increase in efficacy.
14.3 Recurrent Orolabial or Genital Herpes in HIV-Infected Patients
A randomized, double-blind trial compared famciclovir 500 mg twice daily for 7 days (n=150) with oral acyclovir
400 mg 5 times daily for 7 days (n=143) in HIV-infected patients with recurrent orolabial or genital herpes treated within
48 hours of lesion onset. Approximately 40% of patients had a CD4
+ count below 200 cells/mm3, 54% of patients had
anogenital lesions and 35% had orolabial lesions. Famciclovir therapy was comparable to oral acyclovir in reducing new
lesion formation and in time to complete healing.
14.4 Herpes Zoster (Shingles)
Two randomized, double-blind trials, 1 placebo-controlled and 1 active-controlled, were conducted in 964
immunocompetent adults with uncomplicated herpes zoster. Treatment was initiated within 72 hours of first lesion
appearance and was continued for 7 days.
In the placebo-controlled trial, 419 patients were treated with either FAMVIR 500 mg three times daily (n=138),
FAMVIR 750 mg three times daily (n=135) or placebo (n=146). The median time to full crusting was 5 days among
FAMVIR 500 mg-treated patients as compared to 7 days in placebo-treated patients. The times to full crusting, loss of
vesicles, loss of ulcers, and loss of crusts were shorter for FAMVIR 500 mg-treated patients than for placebo-treated
patients in the overall study population. The effects of FAMVIR were greater when therapy was initiated within 48 hours
of rash onset; it was also more profound in patients 50 years of age or older. Among the 65.2% of patients with at least 1
positive viral culture, FAMVIR treated patients had a shorter median duration of viral shedding than placebo-treated
patients (1 day and 2 days, respectively).
There were no overall differences in the duration of pain before rash healing between FAMVIR- and placebo-
treated groups. In addition, there was no difference in the incidence of pain after rash healing (postherpetic neuralgia)
between the treatment groups. In the 186 patients (44.4% of total study population) who developed postherpetic neuralgia,
the median duration of postherpetic neuralgia was shorter in patients treated with FAMVIR 500 mg than in those treated
with placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher dose of
FAMVIR.
In the active-controlled trial, 545 patients were treated with one of three doses of FAMVIR three times daily or
with acyclovir 800 mg five times daily. Times to full lesion crusting and times to loss of acute pain were comparable for
all groups and there were no statistically significant differences in the time to loss of postherpetic neuralgia between
FAMVIR and acyclovir-treated groups.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
__________________________________________________________________________________________
17
16 HOW SUPPLIED/STORAGE AND HANDLING
FAMVIR tablets are supplied as film-coated tablets as follows: 125 mg in bottles of 30; 250 mg in bottles of 30;
500 mg in bottles of 30 and Single Unit Packages of 50 (intended for institutional use only).
• FAMVIR 125 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “125” on the other.
125 mg 30’s………………………………………………………………………………………… NDC 0078-0366-15
• FAMVIR 250 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “250” on the other.
250 mg 30’s………………………………………………………………………………………… NDC 0078-0367-15
• FAMVIR 500 mg tablet:
White, oval film-coated, biconvex, debossed with “FAMVIR” on one side and “500” on the other.
500 mg 30’s………………………………………………………………………………………… NDC 0078-0368-15
500 mg SUP 50’s……………………………………………………………………………...…… NDC 0078-0368-64
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling
There is no evidence that FAMVIR will affect the ability of a patient to drive or to use machines. However,
patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking
FAMVIR should refrain from driving or operating machinery.
Because FAMVIR contains lactose (FAMVIR 125 mg, 250 mg and 500 mg tablets contain lactose 26.9 mg, 53.7
mg and 107.4 mg, respectively), patients with rare hereditary problems of galactose intolerance, a severe lactase
deficiency or glucose-galactose malabsorption should be advised to discuss with their healthcare provider before taking
FAMVIR.
17.1 Herpes Labialis (Cold Sores)
Patients should be advised to initiate treatment at the earliest sign or symptom of a recurrence of cold sores (e.g.,
tingling, itching, burning, pain, or lesion). Patients should be instructed that treatment for cold sores should not exceed 1
dose. Patients should be informed that FAMVIR is not a cure for cold sores.
17.2 Genital Herpes
Patients should be informed that FAMVIR is not a cure for genital herpes. There are no data evaluating whether
FAMVIR will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease,
patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting
partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding.
Therefore, patients should be counseled to use safer sex practices.
If episodic therapy for recurrent genital herpes is indicated, patients should be advised to initiate therapy at the
first sign or symptom of an episode.
There are no data on safety or effectiveness of chronic suppressive therapy of longer than one year duration.
17.3 Herpes Zoster (Shingles)
There are no data on treatment initiated more than 72 hours after onset of zoster rash. Patients should be advised
to initiate treatment as soon as possible after a diagnosis of herpes zoster.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
FAMVIR® (Fam’-veer)
(famciclovir)
Tablets
Read this Patient Information before you start taking FAMVIR and each time you get a refill. There may be new
information. This information does not take the place of talking with your healthcare provider about your medical
condition or treatment.
What is FAMVIR?
Famvir is a prescription antiviral medicine used to:
• treat outbreaks of cold sores (fever blisters) in healthy adults
• treat outbreaks of genital herpes in healthy adults
• decrease the number of outbreaks of genital herpes in healthy adults
• treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV
• treat shingles (herpes zoster) in adults with normal immune system
It is not known if FAMVIR is safe and effective in children younger than 18 years of age.
FAMVIR is not a cure for herpes. It is not known if FAMVIR can stop the spread of herpes to others. If you are sexually
active, you can pass herpes to your partner even if you are taking FAMVIR. Herpes can be transmitted even if you do not
have active symptoms. You should continue to practice safer sex to lower the chances of spreading genital herpes to
others. Do not have sexual contact with your partner during an outbreak of genital herpes or if you have any symptoms of
genital herpes. Use a condom made of latex or polyurethane when you have a sexual contact. Ask your healthcare
provider for more information about safer sex practices.
Who should not take FAMVIR®?
Do not take FAMVIR if you are allergic to any of its ingredients. See the end of this Patient Information leaflet for a
complete list of ingredients in FAMVIR.
What should I tell my healthcare provider before taking FAMVIR?
Before you start taking FAMVIR, tell your healthcare provider if you:
• have kidney or liver problems
• have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-
galactose (malabsorption)
• are pregnant or planning to become pregnant. It is not known if FAMVIR will harm your unborn baby
• Pregnancy Exposure Reporting: Novartis Pharmaceuticals Corporation collects pregnancy reports which are reported
on a voluntary basis. In case of pregnancy, talk to your healthcare provider about reporting your pregnancy.
• are breast-feeding or plan to breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Especially tell your healthcare provider if you take:
• any other medicines and products you use to treat herpes outbreaks
• probenecid (Probalan)
Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist every
time you get a new medicine.
How should I take FAMVIR?
• Take FAMVIR exactly as prescribed
• Your healthcare provider will tell you how many FAMVIR to take and when to take them. Your dose of FAMVIR
and how often you take it may be different depending on your condition
• FAMVIR can be taken with or without food
• It is important for you to finish all of the medicine as prescribed, even if you begin to feel better
• Your symptoms may continue even after you finish all of your FAMVIR. This does not mean that you need more
medicine, since you have already finished a full course of FAMVIR and it will continue to work in your body. Talk to
your healthcare provider if you have any questions about your condition and your treatment
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of FAMVIR?
The most common side effects of FAMVIR include:
•
headache
•
nausea
•
diarrhea
•
vomiting
•
stomach-area (abdominal) pain
•
tiredness
Talk to 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 FAMVIR. Ask your healthcare provider or pharmacist for more information.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
How should I store FAMVIR?
•
Store FAMVIR at room temperature between 59° and 86°F (15° to 30°C).
Keep FAMVIR and all medicines out of reach from children.
General information about FAMVIR
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use
FAMVIR for a condition for which it was not prescribed. Do not give FAMVIR to other people, even if they have the
same symptoms you have. It may harm them.
This leaflet summarizes the most important information about FAMVIR. If you would like more information, talk with
your healthcare provider. Your healthcare provider or pharmacist can give you information about FAMVIR that is written
for health professionals. For more information, go to www.FAMVIR.com or call 1-888-669-6682.
What are the ingredients in FAMVIR?
Active ingredient: famciclovir
Inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,
polyethylene glycols, sodium starch glycolate, and titanium dioxide
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Revised: 12/2009
©Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:47:31.861675
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020363s036lbl.pdf', 'application_number': 20363, 'submission_type': 'SUPPL ', 'submission_number': 36}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
FAMVIR® safely and effectively. See full prescribing information for
FAMVIR.
FAMVIR (famciclovir) tablets
Initial U.S. Approval: 1994
--------------RECENT MAJOR CHANGES---------------------
Indications and Usage (1.3)
01/2011
--------------INDICATIONS AND USAGE---------------------
FAMVIR, a prodrug of penciclovir, is a nucleoside analog DNA polymerase
inhibitor indicated for:
Immunocompetent Adult Patients (1.1)
• Herpes labialis (cold sores)
o Treatment of recurrent episodes
• Genital herpes
o Treatment of recurrent episodes
o Suppressive therapy of recurrent episodes
• Herpes zoster (shingles)
HIV-Infected Adult Patients (1.2)
• Treatment of recurrent episodes of orolabial or genital herpes
Limitation of Use (1.3)
The efficacy and safety of FAMVIR have not been established for:
• Patients <18 years of age
• Immunocompromised patients other than for the treatment of recurrent
episodes of orolabial or genital herpes in HIV-infected patients
• Black and African American patients with recurrent genital herpes
------------DOSAGE AND ADMINISTRATION-------------
Immunocompetent Adult Patients (2.1)
Herpes labialis (cold sores)
1500 mg as a single dose
Genital herpes
Treatment of recurrent episodes
Suppressive therapy
1000 mg twice daily for 1 day
250 mg twice daily
Herpes zoster (shingles)
500 mg every 8 hours for 7 days
Patients with renal impairment: Adjust dose based on creatinine clearance. (2.3)
HIV-Infected Adult Patients (2.2)
Recurrent episodes of orolabial or genital
herpes
500 mg twice daily for 7 days
-----------DOSAGE FORMS AND STRENGTHS------------
Tablets: 125 mg, 250 mg, 500 mg (3)
---------------------CONTRAINDICATIONS-------------------
Known hypersensitivity to the product, its components, or Denavir®
(penciclovir cream). (4)
---------------WARNINGS AND PRECAUTIONS-----------
Acute renal failure: May occur in patients with underlying renal disease who
receive higher than recommended doses of FAMVIR for their level of renal
function. Reduce dosage in patients with renal impairment. (2.3, 8.6)
-------------------ADVERSE REACTIONS----------------------
The most common adverse events reported in at least one indication by >10%
of adult patients are headache and nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA
1088 or www.fda.gov/medwatch.
-------------------DRUG INTERACTIONS----------------------
Probenecid: May increase penciclovir levels. Monitor for evidence of
penciclovir toxicity. (7.2)
-------------------USE IN SPECIFIC POPULATIONS----------------------
Nursing mothers: FAMVIR should not be used in nursing mothers unless the
potential benefits outweigh the potential risks associated with treatment. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 01/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Immunocompetent Adult Patients
1.2 HIV-Infected Adult Patients
1.3 Limitation of Use
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Recommendation in Immunocompetent Adult Patients
2.2 Dosing Recommendation in HIV-Infected Adult Patients
2.3 Dosing Recommendation in Patients with Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience in Adult Patients
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Potential for FAMVIR to Affect Other Drugs
7.2 Potential for Other Drugs to Affect Penciclovir
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Patients with Renal Impairment
8.7 Patients with Hepatic Impairment
8.8 Black and African American Patients
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Virology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal toxicology
14 CLINICAL STUDIES
14.1 Herpes Labialis (Cold Sores)
14.2 Genital Herpes
14.3 Recurrent Orolabial or Genital Herpes in HIV-Infected Patients
14.4 Herpes Zoster (Shingles)
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Herpes Labialis (Cold Sores)
17.2 Genital Herpes
17.3 Herpes Zoster (Shingles)
* Sections or subsections omitted from the full prescribing
information are not listed
Reference ID: 2898708
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 Immunocompetent Adult Patients
Herpes labialis (cold sores): FAMVIR is indicated for the treatment of recurrent herpes labialis.
Genital herpes:
Recurrent episodes: FAMVIR is indicated for the treatment of recurrent episodes of genital herpes. The efficacy of
FAMVIR when initiated more than 6 hours after onset of symptoms or lesions has not been established.
Suppressive therapy: FAMVIR is indicated for chronic suppressive therapy of recurrent episodes of genital herpes. The
efficacy and safety of FAMVIR for the suppression of recurrent genital herpes beyond 1 year have not been established.
Herpes zoster (shingles): FAMVIR is indicated for the treatment of herpes zoster. The efficacy of FAMVIR when
initiated more than 72 hours after onset of rash has not been established.
1.2 HIV-Infected Adult Patients
Recurrent orolabial or genital herpes: FAMVIR is indicated for the treatment of recurrent episodes of orolabial or genital
herpes in HIV-infected adults. The efficacy of FAMVIR when initiated more than 48 hours after onset of symptoms or
lesions has not been established.
1.3 Limitation of Use
The efficacy and safety of FAMVIR have not been established for:
• Patients <18 years of age
• Patients with first episode of genital herpes
• Patients with ophthalmic zoster
• Immunocompromised patients other than for the treatment of recurrent orolabial or genital herpes in HIV-infected
patients
• Black and African American patients with recurrent genital herpes
2 DOSAGE AND ADMINISTRATION
FAMVIR may be taken with or without food.
2.1 Dosing Recommendation in Immunocompetent Adult Patients
Herpes labialis (cold sores): The recommended dosage of FAMVIR for the treatment of recurrent herpes labialis is 1500
mg as a single dose. Therapy should be initiated at the first sign or symptom of herpes labialis (e.g., tingling, itching,
burning, pain, or lesion).
Genital herpes:
Recurrent episodes: The recommended dosage of FAMVIR for the treatment of recurrent episodes of genital herpes is
1000 mg twice daily for 1 day. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g.,
tingling, itching, burning, pain, or lesion).
Suppressive therapy: The recommended dosage of FAMVIR for chronic suppressive therapy of recurrent episodes of
genital herpes is 250 mg twice daily.
Herpes zoster (shingles): The recommended dosage of FAMVIR for the treatment of herpes zoster is 500 mg every 8
hours for 7 days. Therapy should be initiated as soon as herpes zoster is diagnosed.
2.2 Dosing Recommendation in HIV-Infected Adult Patients
Recurrent orolabial or genital herpes: The recommended dosage of FAMVIR for the treatment of recurrent orolabial or
genital herpes in HIV-infected patients is 500 mg twice daily for 7 days. Therapy should be initiated at the first sign or
symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).
2.3 Dosing Recommendation in Patients with Renal Impairment
Dosage recommendations for adult patients with renal impairment are provided in Table 1 [see Use in Specific
Populations (8.6), Clinical Pharmacology (12.3)].
Reference ID: 2898708
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Dosage Recommendations for Adult Patients with Renal Impairment
Indication and Normal Dosage
Creatinine Clearance
Adjusted Dosage
Regimen
(mL/min)
Regimen Dose (mg)
Dosing Interval
Single-Day Dosing Regimens
Recurrent Genital Herpes
1000 mg every 12 hours for 1 day
≥60
1000
every 12 hours for 1 day
40-59
500
every 12 hours for 1 day
20-39
500
single dose
<20
250
single dose
HD*
250
single dose following
dialysis
Recurrent Herpes Labialis
1500 mg single dose
≥60
1500
single dose
40-59
750
single dose
20-39
500
single dose
<20
250
single dose
HD*
250
single dose following
dialysis
Multiple-Day Dosing Regimens
Herpes Zoster
500 mg every 8 hours
≥60
500
every 8 hours
40-59
500
every 12 hours
20-39
500
every 24 hours
<20
250
every 24 hours
HD*
250
following each dialysis
Suppression of Recurrent
Genital Herpes
250 mg every 12 hours
≥40
250
every 12 hours
20-39
125
every 12 hours
<20
125
every 24 hours
HD*
125
following each dialysis
Recurrent Orolabial
or Genital Herpes
in HIV-Infected Patients
500 mg every 12 hours
≥40
500
every 12 hours
20-39
500
every 24 hours
<20
250
every 24 hours
HD*
250
following each dialysis
*Hemodialysis
3 DOSAGE FORMS AND STRENGTHS
FAMVIR tablets are available in three strengths:
•
125 mg: White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “125” on
the other side
•
250 mg: White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “250” on
the other side
•
500 mg: White, oval film-coated, biconvex, debossed with “FAMVIR” on one side and “500” on the other side
4 CONTRAINDICATIONS
FAMVIR is contraindicated in patients with known hypersensitivity to the product, its components, or Denavir®
(penciclovir cream).
Reference ID: 2898708
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
Acute renal failure: Cases of acute renal failure have been reported in patients with underlying renal disease who have
received inappropriately high doses of FAMVIR for their level of renal function. Dosage reduction is recommended when
administering FAMVIR to patients with renal impairment [see Dosage and Administration (2.3), Use in Specific
Populations (8.6)].
6 ADVERSE REACTIONS
Acute renal failure is discussed in greater detail in other sections of the label [see Warnings and Precautions (5)].
The most common adverse events reported in at least 1 indication by >10% of adult patients treated with FAMVIR are
headache and nausea.
6.1 Clinical Trials Experience in Adult Patients
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Immunocompetent patients: The safety of FAMVIR has been evaluated in active- and placebo-controlled clinical studies
involving 816 FAMVIR-treated patients with herpes zoster (FAMVIR, 250 mg three times daily to 750 mg three times
daily); 163 FAMVIR-treated patients with recurrent genital herpes (FAMVIR, 1000 mg twice daily); 1,197 patients with
recurrent genital herpes treated with FAMVIR as suppressive therapy (125 mg once daily to 250 mg three times daily) of
which 570 patients received FAMVIR (open-labeled and/or double-blind) for at least 10 months; and 447 FAMVIR-
treated patients with herpes labialis (FAMVIR, 1500 mg once daily or 750 mg twice daily). Table 2 lists selected adverse
events.
Table 2
Selected Adverse Events (all grades and without regard to causality) Reported by ≥ 2% of Patients
in Placebo-Controlled Famvir Trials*
Incidence
Events
Herpes Zoster†
Recurrent
Genital Herpes‡
Genital Herpes-
Suppression§
Herpes Labialis‡
Famvir
(n=273)
%
Placebo
(n=146)
%
Famvir
(n=163)
%
Placebo
(n=166)
%
Famvir
(n=458)
%
Placebo
(n=63)
%
Famvir
(n=447)
%
Placebo
(n=254)
%
Nervous System
Headache
22.7
17.8
13.5
5.4
39.3
42.9
8.5
6.7
Paresthesia
2.6
0.0
0.0
0.0
0.9
0.0
0.0
0.0
Migraine
0.7
0.7
0.6
0.6
3.1
0.0
0.2
0.0
Gastrointestinal
Nausea
12.5
11.6
2.5
3.6
7.2
9.5
2.2
3.9
Diarrhea
7.7
4.8
4.9
1.2
9.0
9.5
1.6
0.8
Vomiting
4.8
3.4
1.2
0.6
3.1
1.6
0.7
0.0
Flatulence
1.5
0.7
0.6
0.0
4.8
1.6
0.2
0.0
Abdominal Pain
1.1
3.4
0.0
1.2
7.9
7.9
0.2
0.4
Body as a Whole
Fatigue
4.4
3.4
0.6
0.0
4.8
3.2
1.6
Skin and Appendages
Pruritus
3.7
2.7
0.0
0.6
2.2
0.0
0.0
0.0
Rash
0.4
0.7
0.0
0.0
3.3
1.6
0.0
0.0
Reproductive (Female)
Dysmenorrhea
0.0
0.7
1.8
0.6
7.6
6.3
0.4
*Patients may have entered into more than one clinical trial.
†7 days of treatment
‡1 day of treatment
§daily treatment
Reference ID: 2898708
0.4
0.0
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3 lists selected laboratory abnormalities in genital herpes suppression trials.
Table 3
Selected Laboratory Abnormalities in Genital Herpes Suppression Studies*
Parameter
Famvir
Placebo
(n = 660)
†
(n = 210)
†
%
%
Anemia (<0.8 x NRL)
0.1
0.0
Leukopenia (<0.75 x NRL)
1.3
0.9
Neutropenia (<0.8 x NRL)
3.2
1.5
AST (SGOT) (>2 x NRH)
2.3
1.2
ALT (SGPT) (>2 x NRH)
3.2
1.5
Total Bilirubin (>1.5 x NRH)
1.9
1.2
Serum Creatinine (>1.5 x NRH)
0.2
0.3
Amylase (>1.5 x NRH)
1.5
1.9
Lipase (>1.5 x NRH)
4.9
4.7
*Percentage of patients with laboratory abnormalities that were increased or decreased from baseline and were outside of specified ranges.
†n values represent the minimum number of patients assessed for each laboratory parameter.
NRH = Normal Range High.
NRL = Normal Range Low.
HIV-infected patients: In HIV-infected patients, the most frequently reported adverse events for FAMVIR (500 mg twice
daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (17% vs. 15%), nausea (11% vs. 13%),
diarrhea (7% vs. 11%), vomiting (5% vs. 4%), fatigue (4% vs. 2%), and abdominal pain (3% vs. 6%).
6.2 Postmarketing Experience
The adverse events listed below have been reported during post-approval use of FAMVIR. Because these 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:
Blood and lymphatic system disorders: Thrombocytopenia
Hepatobiliary disorders: Abnormal liver function tests, cholestatic jaundice
Nervous system disorders: Dizziness, somnolence
Psychiatric disorders: Confusion (including delirium, disorientation, and confusional state occurring predominantly in the
elderly), hallucinations
Skin and subcutaneous tissue disorders: Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal
necrolysis
7 DRUG INTERACTIONS
7.1 Potential for FAMVIR to Affect Other Drugs
The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of
famciclovir (500 mg three times daily). No clinically significant effect on the pharmacokinetics of zidovudine, its
metabolite zidovudine glucuronide, or emtricitabine was observed following a single oral dose of 500 mg famciclovir co
administered with zidovudine or emtricitabine.
An in vitro study using human liver microsomes suggests that famciclovir is not an inhibitor of CYP3A4 enzymes.
7.2 Potential for Other Drugs to Affect Penciclovir
No clinically significant alterations in penciclovir pharmacokinetics were observed following single-dose administration
of 500 mg famciclovir after pre-treatment with multiple doses of allopurinol, cimetidine, theophylline, zidovudine,
promethazine, when given shortly after an antacid (magnesium and aluminum hydroxide), or concomitantly with
emtricitabine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose
(three times daily) administration of famciclovir (500 mg) with multiple doses of digoxin.
Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in
increased plasma concentrations of penciclovir.
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The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs
metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of
famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the
formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of
penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between
penciclovir and raloxifene has not been conducted.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy category B. After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug). There
are no adequate and well-controlled studies of famciclovir or penciclovir use in pregnant women. No adverse effects on
embryofetal development were observed in animal reproduction studies using famciclovir and penciclovir at doses higher
than the maximum recommended human dose (MRHD) and human exposure. Because animal reproduction studies are
not always predictive of human response, famciclovir should be used during pregnancy only if needed.
In animal reproduction studies, pregnant rats and rabbits received oral famciclovir at doses (up to 1000 mg/kg/day) that
provided 2.7 to 10.8 times (rats) and 1.4 to 5.4 times (rabbits) the human systemic exposure based on AUC. No adverse
effects were observed on embryo-fetal development. In other studies, pregnant rats and rabbits received intravenous
famciclovir at doses (360 mg/kg/day) 1.5 to 6 times (rats) and (120 mg/kg/day) 1.1 to 4.5 times (rabbits) or penciclovir at
doses (80 mg/kg/day) 0.3 to 1.3 times (rats) and (60 mg/kg/day) 0.5 to 2.1 times (rabbits) the MRHD based on body
surface area comparisons. No adverse effects were observed on embryo-fetal development.
Pregnancy exposure reporting. To monitor maternal-fetal outcomes of pregnant women exposed to FAMVIR, Novartis
Pharmaceuticals Corporation maintains a FAMVIR Pregnancy Reporting system. Physicians are encouraged to report
their patients by calling 1-888-NOW-NOVA (669-6682).
8.3 Nursing Mothers
It is not known whether famciclovir (prodrug) or penciclovir (active drug) are excreted in human milk. Following oral
administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those
seen in the plasma. There are no data on the safety of FAMVIR in infants. FAMVIR should not be used in nursing
mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.
8.4 Pediatric Use
The efficacy and safety of FAMVIR tablets have not been established in pediatric patients. The pharmacokinetic profile
and safety of famciclovir experimental granules mixed with OraSweet® were studied in two open-label studies.
Study 1 was a single-dose pharmacokinetic and safety study in infants 1 month to <1 year of age who had an active herpes
simplex virus (HSV) infection or who were at risk for HSV infection. Eighteen subjects were enrolled and received a
single dose of famciclovir experimental granules mixed with OraSweet® based on the patient’s body weight (doses ranged
from 25 mg to 175 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir
systemic exposures observed in adults after administration of 500 mg famciclovir. The efficacy and safety of famciclovir
have not been established as suppressive therapy in infants following neonatal HSV infections. In addition, the efficacy
cannot be extrapolated from adults to infants because there is no similar disease in adults. Therefore, famciclovir is not
recommended in infants.
Study 2 was an open-label, single-dose pharmacokinetic, multiple-dose safety study of famciclovir experimental granules
mixed with OraSweet® in children 1 to <12 years of age with clinically suspected HSV or varicella zoster virus (VZV)
infection. Fifty-one subjects were enrolled in the pharmacokinetic part of the study and received a single body weight
adjusted dose of famciclovir (doses ranged from 125 mg to 500 mg). These doses were selected to provide penciclovir
systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg
famciclovir. Based on the pharmacokinetic data observed with these doses in children, a new weight-based dosing
algorithm was designed and used in the multiple-dose safety part of the study. Pharmacokinetic data were not obtained
with the revised weight-based dosing algorithm.
A total of 100 patients were enrolled in the multiple-dose safety part of the study; 47 subjects with active or latent HSV
infection and 53 subjects with chickenpox. Patients with active or latent HSV infection received famciclovir twice a day
for seven days. The daily dose of famciclovir ranged from 150 mg to 500 mg twice daily depending on the patient’s body
weight. Patients with chickenpox received famciclovir three times daily for seven days. The daily dose of famciclovir
ranged from 150 mg to 500 mg three times daily depending on the patient’s body weight. The clinical adverse events and
Reference ID: 2898708
laboratory test abnormalities observed in this study were similar to these seen in adults. The available data are insufficient
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to support the use of famciclovir for the treatment of children with chickenpox or infections due to HSV for the following
reasons:
Chickenpox: The efficacy of famciclovir for the treatment of chickenpox has not been established in either pediatric or
adult patients. Famciclovir is approved for the treatment of herpes zoster in adult patients. However, extrapolation of
efficacy data from adults with herpes zoster to children with chickenpox would not be appropriate. Although chickenpox
and herpes zoster are caused by the same virus, the diseases are different.
Genital herpes: Clinical information on genital herpes in children is limited. Therefore, efficacy data from adults cannot
be extrapolated to this population. Further, famciclovir has not been studied in children 1 to <12 years of age with
recurrent genital herpes. None of the children in Study 2 had genital herpes.
Herpes labialis: There are no pharmacokinetic and safety data in children to support a famciclovir dose that provides
penciclovir systemic exposures comparable to the penciclovir systemic exposures in adults after a single dose
administration of 1500 mg.
8.5 Geriatric Use
Of 816 patients with herpes zoster in clinical studies who were treated with FAMVIR, 248 (30.4%) were ≥65 years of age
and 103 (13%) were ≥75 years of age. No overall differences were observed in the incidence or types of adverse events
between younger and older patients. Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies
who were treated with FAMVIR, 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age. Clinical studies of
FAMVIR in patients with recurrent genital herpes did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently compared to younger subjects.
No famciclovir dosage adjustment based on age is recommended unless renal function is impaired [see Dosage and
Administration (2.3), Clinical Pharmacology (12.3)]. In general, appropriate caution should be exercised in the
administration and monitoring of FAMVIR in elderly patients reflecting the greater frequency of decreased renal function
and concomitant use of other drugs.
8.6 Patients with Renal Impairment
Apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly
with reductions in renal function. After the administration of a single 500 mg famciclovir oral dose (n=27) to healthy
volunteers and to volunteers with varying degrees of renal impairment (CLCR ranged from 6.4 to 138.8 mL/min), the
following results were obtained (Table 4):
Table 4
Pharmacokinetic Parameters of Penciclovir in Subjects with Different Degrees of Renal
Impairment
Parameter
(mean ± S.D.)
CLCR
† ≥60
(mL/min)
(n=15)
CLCR 40-59
(mL/min)
(n=5)
CLCR 20-39
(mL/min)
(n=4)
CLCR <20
(mL/min)
(n=3)
CLCR (mL/min)
88.1 ± 20.6
49.3 ± 5.9
26.5 ± 5.3
12.7 ± 5.9
CLR (L/hr)
30.1 ± 10.6
13.0 ± 1.3‡
4.2 ± 0.9
1.6 ± 1.0
CL/F§ (L/hr)
66.9 ± 27.5
27.3 ± 2.8
12.8 ± 1.3
5.8 ± 2.8
Half-life (hr)
2.3 ± 0.5
3.4 ± 0.7
6.2 ± 1.6
13.4 ± 10.2
† CLCR is measured creatinine clearance.
‡ n=4.
§ CL/F consists of bioavailability factor and famciclovir to penciclovir conversion factor.
In a multiple-dose study of famciclovir conducted in subjects with varying degrees of renal impairment (n=18), the
pharmacokinetics of penciclovir were comparable to those after single doses.
A dosage adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].
8.7 Patients with Hepatic Impairment
Well-compensated chronic liver disease (chronic hepatitis [n=6], chronic ethanol abuse [n=8], or primary biliary cirrhosis
[n=1]) had no effect on the extent of availability (AUC) of penciclovir following a single dose of 500 mg famciclovir.
However, there was a 44% decrease in penciclovir mean maximum plasma concentration (Cmax) and the time to maximum
plasma concentration (tmax) was increased by 0.75 hours in patients with hepatic impairment compared to normal
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volunteers. No dosage adjustment is recommended for patients with well compensated hepatic impairment. The
pharmacokinetics of penciclovir have not been evaluated in patients with severe uncompensated hepatic impairment.
8.8 Black and African American Patients
In a randomized, double-blind, placebo-controlled trial conducted in 304 immunocompetent Black and African American
adults with recurrent genital herpes there was no difference in median time to healing between patients receiving
FAMVIR or placebo. In general, the adverse reaction profile was similar to that observed in other FAMVIR clinical trials
for adult patients [see Adverse Reactions (6.1)]. The relevance of these study results to other indications in Black and
African American patients is unknown [see Clinical Studies (14.2)].
10 OVERDOSAGE
Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis.
11 DESCRIPTION
The active ingredient in FAMVIR tablets is famciclovir, an orally administered prodrug of the antiviral agent penciclovir.
Chemically, famciclovir is known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. Its molecular formula
is C14H19N5O4; its molecular weight is 321.3. It is a synthetic acyclic guanine derivative and has the following structure structure
Famciclovir is a white to pale yellow solid. It is freely soluble in acetone and methanol, and sparingly soluble in ethanol
and isopropanol. At 25°C famciclovir is freely soluble (>25% w/v) in water initially, but rapidly precipitates as the
sparingly soluble (2%-3% w/v) monohydrate. Famciclovir is not hygroscopic below 85% relative humidity. Partition
coefficients are: octanol/water (pH 4.8) P=1.09 and octanol/phosphate buffer (pH 7.4) P=2.08.
FAMVIR tablets contain 125 mg, 250 mg or 500 mg of famciclovir, together with the following inactive ingredients:
hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycols, sodium
starch glycolate and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Famciclovir is an orally administered prodrug of the antiviral agent penciclovir [see Clinical Pharmacology (12.4)].
12.3 Pharmacokinetics
Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration
famciclovir undergoes rapid and extensive metabolism to penciclovir and little or no famciclovir is detected in plasma or
urine. Penciclovir is predominantly eliminated unchanged by the kidney. Therefore, the dose of FAMVIR needs to be
adjusted in patients with different degrees of renal impairment [see [see Dosage and Administration (2.3)].
Pharmacokinetics in adults:
Absorption and Bioavailability: The absolute bioavailability of penciclovir is 77 ± 8% as determined following the
administration of a 500 mg famciclovir oral dose and a 400 mg penciclovir intravenous dose to 12 healthy male subjects.
Penciclovir concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 1000 mg
administered as a single dose. Table 5 shows the mean pharmacokinetic parameters of penciclovir after single
administration of FAMVIR to healthy male volunteers.
Table 5
Mean Pharmacokinetic Parameters of Penciclovir in Healthy Adult Subjects*
Dose
AUC (0-inf)† (mcg hr/mL)
Cmax
‡ (mcg/mL)
tmax
§ (h)
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125 mg
2.24
0.8
0.9
250 mg
4.48
1.6
0.9
500 mg
8.95
3.3
0.9
1000 mg
17.9
6.6
0.9
* Based on pharmacokinetic data from 17 studies
† AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity.
‡ Cmax (mcg/mL)=maximum observed plasma concentration.
§ tmax (h)= time to Cmax.
Following oral single-dose administration of 500 mg famciclovir to seven patients with herpes zoster, the AUC (mean ±
SD), Cmax, and tmax were 12.1±1.7 mcg hr/mL, 4.0±0.7 mcg/mL, and 0.7±0.2 hours, respectively. The AUC of penciclovir
was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this difference
may be due to differences in renal function between the two groups.
There is no accumulation of penciclovir after the administration of 500 mg famciclovir three times daily for 7 days.
Penciclovir Cmax decreased approximately 50% and tmax was delayed by 1.5 hours when a capsule formulation of
famciclovir was administered with food (nutritional content was approximately 910 Kcal and 26% fat). There was no
effect on the extent of availability (AUC) of penciclovir. There was an 18% decrease in Cmax and a delay in tmax of about 1
hour when famciclovir was given 2 hours after a meal as compared to its administration 2 hours before a meal. Because
there was no effect on the extent of systemic availability of penciclovir, FAMVIR can be taken without regard to meals.
Distribution: The volume of distribution (Vdβ) was 1.08±0.17 L/kg in 12 healthy male subjects following a single
intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion. Penciclovir is <20% bound to
plasma proteins over the concentration range of 0.1 to 20 mcg/mL. The blood/plasma ratio of penciclovir is approximately
1.
Metabolism: Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir. Metabolites that
are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%,
<0.5% and <0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or urine. An in vitro
study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir
metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Cimetidine and
promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir in vivo
[see Drug Interactions (7.2)].
Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose
was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to three
healthy male volunteers. Penciclovir accounted for 91% of the radioactivity excreted in the urine.
Following the oral administration of a single 500 mg dose of radiolabeled famciclovir to three healthy male volunteers,
73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively. Penciclovir
accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately
60% of the administered radiolabeled dose was collected in urine in the first 6 hours.
After intravenous administration of penciclovir in 48 healthy male volunteers, mean ± SD total plasma clearance of
penciclovir was 36.6±6.3 L/hr (0.48±0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5±8.8% of total plasma
clearance.
Renal clearance of penciclovir following the oral administration of a single 500 mg dose of famciclovir to 109 healthy
male volunteers was 27.7±7.6 L/hr. Active tubular secretion contributes to the renal elimination of penciclovir.
The plasma elimination half-life of penciclovir was 2.0±0.3 hours after intravenous administration of penciclovir to 48
healthy male volunteers and 2.3±0.4 hours after oral administration of 500 mg famciclovir to 124 healthy male volunteers.
The half-life in 17 patients with herpes zoster was 2.8±1.0 hours and 2.7±1.0 hours after single and repeated doses,
respectively.
Special populations:
Geriatric patients: Based on cross study comparison, penciclovir AUC was 40% higher and penciclovir renal clearance
was 22% lower in elderly subjects (n=18, age 65-79 years) as compared with younger subjects Some of this difference
may be due to differences in renal function between the two groups. No famciclovir dosage adjustment based on age is
recommended unless renal function is impaired [see Dosage and Administration (2.3), Use in Specific Populations (8.5).]
Reference ID: 2898708
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Patients with renal impairment: In subjects with varying degrees of renal impairment, apparent plasma clearance, renal
clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function,
after both single and repeated dosing [see Use in Specific Populations (8.6)]. A dosage adjustment is recommended for
patients with renal impairment [see Dosage and Administration (2.3)].
Patients with hepatic impairment: Well-compensated chronic liver disease had no effect on the extent of availability
(AUC) of penciclovir [see Use in Specific Populations (8.7)]. No dosage adjustment is recommended for patients with
well-compensated hepatic impairment.
HIV-infected patients: Following oral administration of a single dose of 500 mg famciclovir to HIV-positive patients, the
pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.
Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18 healthy female volunteers after
single-dose oral administration of 500 mg famciclovir. AUC of penciclovir was 9.3±1.9 mcg hr/mL and 11.1±2.1 mcg
hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5±8.9 L/hr and 21.8±4.3 L/hr, respectively.
These differences were attributed to differences in renal function between the two groups. No famciclovir dosage
adjustment based on gender is recommended.
Race: A retrospective evaluation was performed to compare the pharmacokinetic parameters obtained in Black and
Caucasian subjects after single and repeat once-daily, twice-daily, or three times-daily administration of famciclovir 500
mg. Data from a study in healthy volunteers (single dose), a study in subjects with varying degrees of renal impairment
(single and repeat dose) and a study in subjects with hepatic impairment (single dose) did not indicate any significant
differences in the pharmacokinetics of penciclovir between Black and Caucasian subjects.
12.4 Virology
Mechanism of action: Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes
simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or
VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by
cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate
inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA
synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10
hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. However, the clinical
significance of the intracellular half-life is unknown.
Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2 and
VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed
with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for
VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2
µM (range 1.2 to 2.4 µM, n = 7), 2.6 µM (range 1.6 to 11 µM, n = 6), and 34 µM (range 6.7 to 71 µM, n = 6),
respectively.
Resistance: Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thymidine kinase (TK)
and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative),
reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an
equivalent loss in the ability to phosphorylate thymidine (TK altered). The median EC50 values observed in a plaque
reduction assay with penciclovir resistant HSV-1, HSV-2, and VZV were 69 µM (range 14 to 115 µM, n = 6), 46 µM
(range 4 to >395 µM, n = 9), and 92 µM (range 51 to 148 µM, n = 4), respectively. The possibility of viral resistance to
penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.
Cross-resistance: Cross-resistance has been observed among HSV DNA polymerase inhibitors. The most commonly
encountered acyclovir resistant mutants that are TK negative are also resistant to penciclovir.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An increase
in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats
receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral
dose ranging between 500 mg and 2000 mg, based on area under the plasma concentration curve comparisons [24 hr
AUC] for penciclovir). No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day
(0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).
Reference ID: 2898708
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Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a
battery of in vitro and in vivo assays. Famciclovir and penciclovir were negative in in vitro tests for gene mutations in
bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses up to 10,000
and 5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse lymphoma assay (5000
mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg). Famciclovir
induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL).
Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and
without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir caused chromosomal aberrations in the
absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of micronuclei in mouse bone
marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when
administered orally.
Impairment of fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration of
famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count,
and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity to male
reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of
dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect level for sperm and testicular toxicity in
rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6x the human systemic exposure based on
AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26
weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC),
respectively.
Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day
(2.7 to 10.8x the human AUC).
Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8-week
baseline period and recurrent genital herpes receiving oral FAMVIR (250 mg twice daily) (n=66) or placebo (n=64)
therapy for 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment
or during an 8-week follow-up.
13.2 Animal Toxicology
Juvenile toxicity study in rats: In juvenile rats, famciclovir was administered daily at doses of 0, 40, 125, or 400
mg/kg/day for 10 weeks beginning on post-partum Day 4. There were no treatment related deaths or clinical observations.
The toxicity of famciclovir was not enhanced in juvenile rats compared to that in the adult animals.
14 CLINICAL STUDIES
14.1 Herpes Labialis (Cold Sores)
A randomized, double-blind, placebo-controlled trial was conducted in 701 immunocompetent adults with recurrent
herpes labialis. Patients self-initiated therapy within 1 hour of first onset of signs or symptoms of a recurrent herpes
labialis episode with FAMVIR 1500 mg as a single dose (n=227), FAMVIR 750 mg twice daily (n=220) or placebo
(n=254) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule
stage) was 4.4 days in the FAMVIR 1500 mg single-dose group (n=152) as compared to 6.2 days in the placebo group
(n=168). The median difference in time to healing between the placebo and FAMVIR 1500 mg treated groups was 1.3
days (95% CI: 0.6 – 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule
stage) were observed between patients receiving FAMVIR or placebo: 33% for FAMVIR 1500 mg single dose and 34%
for placebo. The median time to loss of pain and tenderness was 1.7 days in FAMVIR 1500 mg single dose-treated
patients versus 2.9 days in placebo-treated patients.
14.2 Genital Herpes
Recurrent episodes: A randomized, double-blind, placebo-controlled trial was conducted in 329 immunocompetent adults
with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent
genital herpes episode with either FAMVIR 1000 mg twice daily (n=163) or placebo (n=166) for 1 day. The median time
to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.3 days in FAMVIR-
treated patients (n=125) as compared to 6.1 days in placebo-treated patients (n=145). The median difference in time to
healing between the placebo and FAMVIR-treated groups was 1.2 days (95% CI: 0.5 to 2.0). Twenty-three percent of
FAMVIR-treated patients had aborted lesions (no lesion development beyond erythema) versus 13% in placebo-treated
patients. The median time to loss of all symptoms (e.g., tingling, itching, burning, pain, or tenderness) was 3.3 days in
FAMVIR-treated patients vs. 5.4 days in placebo-treated patients.
Reference ID: 2898708
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A randomized (2:1), double-blind, placebo-controlled trial was conducted in 304 immunocompetent Black and African
American adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of
a recurrent genital herpes episode with either FAMVIR 1000 mg twice daily (n=206) or placebo (n=98) for 1 day. The
median time to healing among patients with non-aborted lesions was 5.4 days in FAMVIR-treated patients (n=152) as
compared to 4.8 days in placebo-treated patients (n=78). The median difference in time to healing between the placebo
and FAMVIR-treated groups was -0.26 days (95% CI: -0.98 to 0.40).
Suppressive therapy: Two randomized, double-blind, placebo-controlled, 12-month trials were conducted in 934
immunocompetent adults with a history of 6 or more recurrences of genital herpes episodes per year. Comparisons
included FAMVIR 125 mg three times daily, 250 mg twice daily, 250 mg three times daily, and placebo. At 12 months,
60% to 65% of patients were still receiving FAMVIR and 25% were receiving placebo treatment. Recurrence rates at 6
and 12 months in patients treated with the 250 mg twice daily dose are shown in Table 6.
Table 6
Recurrence Rates at 6 and 12 Months in Adults with Recurrent Genital Herpes on Suppressive
Therapy
Recurrence Rates
Recurrence Rates
at 6 Months
at 12 Months
Famvir
Placebo
Famvir
Placebo
250 mg twice daily
250 mg twice daily
(n=236)
(n=233)
(n=236)
(n=233)
Recurrence-free
39%
10%
29%
6%
Recurrences†
47%
74%
53%
78%
Lost to follow-up‡
14%
16%
17%
16%
†Based on patient reported data; not necessarily confirmed by a physician.
‡Patients recurrence-free at time of last contact prior to withdrawal.
FAMVIR-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated
patients. Higher doses of FAMVIR were not associated with an increase in efficacy.
14.3 Recurrent Orolabial or Genital Herpes in HIV-Infected Patients
A randomized, double-blind trial compared famciclovir 500 mg twice daily for 7 days (n=150) with oral acyclovir 400 mg
5 times daily for 7 days (n=143) in HIV-infected patients with recurrent orolabial or genital herpes treated within 48 hours
of lesion onset. Approximately 40% of patients had a CD4
+ count below 200 cells/mm3, 54% of patients had anogenital
lesions and 35% had orolabial lesions. Famciclovir therapy was comparable to oral acyclovir in reducing new lesion
formation and in time to complete healing.
14.4 Herpes Zoster (Shingles)
Two randomized, double-blind trials, 1 placebo-controlled and 1 active-controlled, were conducted in 964
immunocompetent adults with uncomplicated herpes zoster. Treatment was initiated within 72 hours of first lesion
appearance and was continued for 7 days.
In the placebo-controlled trial, 419 patients were treated with either FAMVIR 500 mg three times daily (n=138),
FAMVIR 750 mg three times daily (n=135) or placebo (n=146). The median time to full crusting was 5 days among
FAMVIR 500 mg-treated patients as compared to 7 days in placebo-treated patients. The times to full crusting, loss of
vesicles, loss of ulcers, and loss of crusts were shorter for FAMVIR 500 mg-treated patients than for placebo-treated
patients in the overall study population. The effects of FAMVIR were greater when therapy was initiated within 48 hours
of rash onset; it was also more profound in patients 50 years of age or older. Among the 65.2% of patients with at least 1
positive viral culture, FAMVIR treated patients had a shorter median duration of viral shedding than placebo-treated
patients (1 day and 2 days, respectively).
There were no overall differences in the duration of pain before rash healing between FAMVIR- and placebo-treated
groups. In addition, there was no difference in the incidence of pain after rash healing (postherpetic neuralgia) between
the treatment groups. In the 186 patients (44.4% of total study population) who developed postherpetic neuralgia, the
median duration of postherpetic neuralgia was shorter in patients treated with FAMVIR 500 mg than in those treated with
placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher dose of FAMVIR.
In the active-controlled trial, 545 patients were treated with one of three doses of FAMVIR three times daily or with
acyclovir 800 mg five times daily. Times to full lesion crusting and times to loss of acute pain were comparable for all
groups and there were no statistically significant differences in the time to loss of postherpetic neuralgia between
Reference ID: 2898708
FAMVIR and acyclovir-treated groups.
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
FAMVIR tablets are supplied as film-coated tablets as follows: 125 mg in bottles of 30; 250 mg in bottles of 30; 500 mg
in bottles of 30 and Single Unit Packages of 50 (intended for institutional use only).
• FAMVIR 125 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “125” on the other.
125 mg 30’s………………………………………………………………………………………… NDC 0078-0366-15
• FAMVIR 250 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “250” on the other.
250 mg 30’s………………………………………………………………………………………… NDC 0078-0367-15
• FAMVIR 500 mg tablet:
White, oval film-coated, biconvex, debossed with “FAMVIR” on one side and “500” on the other.
500 mg 30’s………………………………………………………………………………………… NDC 0078-0368-15
500 mg SUP 50’s……………………………………………………………………………...…… NDC 0078-0368-64
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information)
There is no evidence that FAMVIR will affect the ability of a patient to drive or to use machines. However, patients who
experience dizziness, somnolence, confusion or other central nervous system disturbances while taking FAMVIR should
refrain from driving or operating machinery.
Because FAMVIR contains lactose (FAMVIR 125 mg, 250 mg and 500 mg tablets contain lactose 26.9 mg, 53.7 mg and
107.4 mg, respectively), patients with rare hereditary problems of galactose intolerance, a severe lactase deficiency or
glucose-galactose malabsorption should be advised to discuss with their healthcare provider before taking FAMVIR.
17.1 Herpes Labialis (Cold Sores)
Patients should be advised to initiate treatment at the earliest sign or symptom of a recurrence of cold sores (e.g., tingling,
itching, burning, pain, or lesion). Patients should be instructed that treatment for cold sores should not exceed 1 dose.
Patients should be informed that FAMVIR is not a cure for cold sores.
17.2 Genital Herpes
Patients should be informed that FAMVIR is not a cure for genital herpes. There are no data evaluating whether FAMVIR
will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should
avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital
herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients
should be counseled to use safer sex practices.
If episodic therapy for recurrent genital herpes is indicated, patients should be advised to initiate therapy at the first sign or
symptom of an episode.
There are no data on safety or effectiveness of chronic suppressive therapy of longer than one year duration.
17.3 Herpes Zoster (Shingles)
There are no data on treatment initiated more than 72 hours after onset of zoster rash. Patients should be advised to initiate
treatment as soon as possible after a diagnosis of herpes zoster.
Reference ID: 2898708
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
FAMVIR® (Fam’-veer)
(famciclovir)
Tablets
Read this Patient Information before you start taking FAMVIR and each time you get a refill. There may be new
information. This information does not take the place of talking with your healthcare provider about your medical
condition or treatment.
What is FAMVIR?
Famvir is a prescription antiviral medicine used to:
• treat outbreaks of cold sores (fever blisters) in healthy adults
• treat outbreaks of genital herpes in healthy adults
• decrease the number of outbreaks of genital herpes in healthy adults
• treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV
• treat shingles (herpes zoster) in adults with normal immune system
It is not known if FAMVIR is safe and effective in children younger than 18 years of age.
FAMVIR is not a cure for herpes. It is not known if FAMVIR can stop the spread of herpes to others. If you are sexually
active, you can pass herpes to your partner even if you are taking FAMVIR. Herpes can be transmitted even if you do not
have active symptoms. You should continue to practice safer sex to lower the chances of spreading genital herpes to
others. Do not have sexual contact with your partner during an outbreak of genital herpes or if you have any symptoms of
genital herpes. Use a condom made of latex or polyurethane when you have a sexual contact. Ask your healthcare
provider for more information about safer sex practices.
Who should not take FAMVIR?
Do not take FAMVIR if you are allergic to any of its ingredients or to Denavir® (penciclovir cream). See the end of this
Patient Information leaflet for a complete list of ingredients in FAMVIR.
What should I tell my healthcare provider before taking FAMVIR?
Before you start taking FAMVIR, tell your healthcare provider if you:
• have kidney or liver problems
• have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-
galactose (malabsorption)
• are pregnant or planning to become pregnant. It is not known if FAMVIR will harm your unborn baby
• Pregnancy Exposure Reporting: Novartis Pharmaceuticals Corporation collects pregnancy reports which are reported
on a voluntary basis. In case of pregnancy, talk to your healthcare provider about reporting your pregnancy.
• are breast-feeding or plan to breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Especially tell your healthcare provider if you take:
• any other medicines and products you use to treat herpes outbreaks
• probenecid (Probalan)
Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist every
time you get a new medicine.
How should I take FAMVIR?
• Take FAMVIR exactly as prescribed
• Your healthcare provider will tell you how many FAMVIR to take and when to take them. Your dose of FAMVIR
and how often you take it may be different depending on your condition
• FAMVIR can be taken with or without food
• It is important for you to finish all of the medicine as prescribed, even if you begin to feel better
Reference ID: 2898708
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Your symptoms may continue even after you finish all of your FAMVIR. This does not mean that you need more
medicine, since you have already finished a full course of FAMVIR and it will continue to work in your body. Talk to
your healthcare provider if you have any questions about your condition and your treatment
What are the possible side effects of FAMVIR?
The most common side effects of FAMVIR include:
• headache
•
nausea
Talk to 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 FAMVIR. Ask your healthcare provider or pharmacist for more information.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
How should I store FAMVIR?
• Store FAMVIR at room temperature between 59° and 86°F (15° to 30°C).
Keep FAMVIR and all medicines out of reach from children.
General information about FAMVIR
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use
FAMVIR for a condition for which it was not prescribed. Do not give FAMVIR to other people, even if they have the
same symptoms you have. It may harm them.
This leaflet summarizes the most important information about FAMVIR. If you would like more information, talk with
your healthcare provider. Your healthcare provider or pharmacist can give you information about FAMVIR that is written
for health professionals. For more information, go to www.FAMVIR.com or call 1-888-669-6682.
What are the ingredients in FAMVIR?
Active ingredient: famciclovir
Inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,
polyethylene glycols, sodium starch glycolate, and titanium dioxide
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Revised: January 2011
T2011-02
©Novartis
Reference ID: 2898708
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:47:31.965410
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020363s037lbl.pdf', 'application_number': 20363, 'submission_type': 'SUPPL ', 'submission_number': 37}
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